ABSTRACTIntroduction:Since the health information system (HIS) in public health care services in Serbia was introduced in 2009, it has gradually expanded. However, it is unclear how well the HIS components have developed and the whole system’s stage of maturity.Method:In June–September 2021, a maturity assessment of the Serbian HIS was conducted for the first time using the HIS Stages of Continuous Improvement (SOCI) toolkit. The toolkit measures HIS status across 5 HIS domains: leadership and governance, management and workforce, information and communication technology (ICT), standards and interoperability, and data quality and use. The domains were further divided into 13 components and 39 subcomponents whose maturity stage was assessed on a 5-point Likert scale, indicating the level of development: (1) emerging/ad hoc; (2) repeatable; (3) defined; (4) managed; and (5) optimized. The toolkit was applied in a working group of 32 professionals and experts who were engaged in developing the new national eHealth strategy and action plan.Results:The overall maturity score of the Serbian HIS was 1.6, which indicates a low level. The highest baseline score (2) was given to the standards and interoperability domain, and the lowest (1.1) was given to ICT infrastructure. The remaining 3 domains (leadership and governance, Management and Workforce, and Data Quality and Use) were similarly rated (1.7, 1.7, and 1.6, respectively).Conclusion:A baseline assessment of the maturity level of Serbian HIS indicates that the majority of components are between the emerging/ad hoc stage and repeatable, which represent isolated, ad hoc efforts, with some basic processes in place and existing and accessible policies. This exercise provided an opportunity to address identified weaknesses in the upcoming national eHealth strategy.

ABSTRACTIntroduction:Emergency contraceptive pills (ECPs) are effective and can be used safely at any age repeatedly within the same cycle. They are often favored by youth yet are underutilized. Private facilities can increase ECP access but present barriers including cost. Identifying effective public-sector ECP distribution models can help ensure equitable access. The Malawi Ministry of Health developed a strategy to improve ECP access in 2020. We documented ECP provision through select public, youth-serving channels recommended by the strategy: general and youth-specific outreach, paid and unpaid community health workers (CHWs), and youth clubs.Methods:We conducted this mixed methods study from November 2022–March 2023 in 2 rural districts (Mchinji and Phalombe) implementing the strategy. We conducted qualitative interviews with 10 national stakeholders, 46 providers, and 24 clients aged 15–24 years about ECP service delivery. Additionally, 25 providers collected quantitative tally data about clients seeking ECPs. We analyzed qualitative data using grounded theory and quantitative data descriptively.Results:Stakeholders and providers reported ECP uptake increased in geographies where the strategy was implemented, especially among youth. Providers documented 3,988 client visits for ECPs over 3 months. Of these visits, 26% were from male clients, 36% were from clients aged younger than 20 years, and 64% received ECPs for the first time. Across channels, youth club leaders and unpaid CHWs reported the most client visits per provider and served the youngest clients. However, no ECPs were dispensed during 29% of visits due to stock-outs. While many providers were supportive of youth accessing ECPs, most held unfavorable attitudes toward repeat use.Conclusion:ECP access should be expanded through provision in the studied channels, especially youth clubs and CHWs. However, to meet demand, the supply chain must be strengthened. We recommend addressing providers’ attitudes about repeat use to ensure informed method choice.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), 8-tetrahydrocannabinol (8-THC), and 9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose 8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose 8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential.

In nuclear medicine, estimating the number of radioactive decays that occur in a source organ per unit administered activity of a radiopharmaceutical (i.e., the time-integrated activity coefficient [TIAC]) is an essential task within the internal dosimetry workflow. TIAC estimation is commonly derived by least-squares fitting of various exponential models to organ time–activity data (radiopharmaceutical biodistribution). Rarely, however, are methods used to objectively determine the model that best characterizes the data. Additionally, the uncertainty associated with the resultant TIAC is generally not evaluated. As part of the MIRDsoft initiative, MIRDfit has been developed to offer a biodistribution fitting software solution that provides the following essential features and advantages for internal dose assessment: nuclear medicine–appropriate fit functions; objective metrics for guiding best-fit selection; TIAC uncertainty calculation; quality control and data archiving; integration with MIRDcalc software for dose calculation; and a user-friendly Excel-based interface. For demonstration and comparative validation of MIRDfit’s performance, TIACs were derived from serial imaging studies involving ¹⁸F-FDG and ¹⁷⁷Lu-DOTATATE using MIRDfit. These TIACs were then compared with TIAC estimates obtained using other software. In most cases, the TIACs agreed within approximately 10% between MIRDfit and the other software. MIRDfit has been endorsed by the MIRD Committee of the Society of Nuclear Medicine and Molecular Imaging and has been integrated into the MIRDsoft suite of free dosimetry software; it is available for download at no user cost (https://mirdsoft.org/).

²²⁶Ac (t_1/2 = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic -emissions and therapeutic α-emissions. ²²⁶Ac emits 158 and 230 keV -photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, ²²⁶Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical ²²⁶Ac-radiopharmaceutical for its theranostic efficacy and present the first ²²⁶Ac-targeted α-therapy study. Methods: ²²⁶Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [²²⁶Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [²²⁶Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [²²⁶Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of ²²⁶Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched ²²⁵Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of ²²⁶Ac-radiopharmaceuticals.

Neuroendocrine tumor (NET) metastases to the heart are found in 1%–4% of NET patients and have been reported primarily in the form of individual cases. We investigated the prevalence, clinical characteristics, imaging features, and outcomes of NET patients with cardiac metastases on ⁶⁸Ga-DOTATATE PET/CT. Methods: ⁶⁸Ga-DOTATATE PET/CT of 490 consecutive patients from a single institution were retrospectively reviewed for sites of metastases. The cumulative cardiovascular event rate and overall survival of patients with cardiac NET metastases (CNMs) were compared with those of a control group of metastatic NET patients without cardiac metastases. In patients with CNMs, the cardiac SUV_max with and without normalization to the myocardial background uptake was compared with a separate cohort of 11 patients with active cardiac sarcoidosis who underwent ⁶⁸Ga-DOTATATE PET/CT for research purposes. Results: In total, 270 patients with metastatic NETs were identified, 9 (3.3%) of whom had CNMs. All 9 patients had grade 1–2 gastroenteropancreatic NETs, most commonly from the small intestine (7 patients). The control group consisted of 140 patients with metastatic grade 1–2 gastroenteropancreatic NETs. On Kaplan–Meier analysis, there was no significant difference in the risk of cardiovascular adverse events (P = 0.91 on log-rank test) or mortality (P = 0.83) between the metastatic NET patients with and without cardiac metastases. The degree of cardiac DOTATATE uptake was significantly higher in CNMs than in patients with cardiac sarcoidosis without overlap, in terms of both cardiac SUV_max (P = 0.027) and SUV_max–to–myocardial background ratio (P = 0.021). Conclusion: Routine ⁶⁸Ga-DOTATATE PET/CT can be used to identify CNMs in 3% of patients with metastatic NETs. CNMs do not confer added cardiovascular or mortality risk. A distinguishing feature of CNMs is their high degree of DOTATATE uptake compared with focal myocardial inflammation.

The phase 3 VISION trial demonstrated that [¹⁷⁷Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]–positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor–signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [¹⁷⁷Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [¹⁷⁷Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.

[¹⁷⁷Lu]Lu-PSMA-617 was approved by the U.S. Food and Drug Administration for patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC). Since the time of regulatory approval, however, real-world data have been lacking. This study investigated the efficacy, safety, and outcome predictors of [¹⁷⁷Lu]Lu-PSMA-617 at a major U.S. academic center. Methods: Patients with mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 at the Johns Hopkins Hospital outside clinical trials were screened for inclusion. Patients who underwent [¹⁷⁷Lu]Lu-PSMA-617 and had available outcome data were included in this study. Outcome data included prostate-specific antigen (PSA) response (≥50% decline), PSA progression-free survival (PFS), and overall survival (OS). Toxicity data were evaluated according to the Common Terminology Criteria for Adverse Events version 5.03. The study tested the association of baseline circulating tumor DNA mutational status in homologous recombination repair, PI3K alteration pathway, and aggressive-variant prostate cancer–associated genes with treatment outcome. Baseline PSMA PET/CT images were analyzed using SelectPSMA, an artificial intelligence algorithm, to predict treatment outcome. Associations with the observed treatment outcome were evaluated. Results: All 76 patients with PSMA-positive mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 met the inclusion criteria. A PSA response was achieved in 30 of 74 (41%) patients. The median PSA PFS was 4.1 mo (95% CI, 2.0–6.2 mo), and the median OS was 13.7 mo (95% CI, 11.3–16.1 mo). Anemia of grade 3 or greater, thrombocytopenia, and neutropenia were observed in 9 (12%), 3 (4%), and 1 (1%), respectively, of 76 patients. Transient xerostomia was observed in 23 (28%) patients. The presence of aggressive-variant prostate cancer–associated genes was associated with a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P = 0.040). No other associations were observed between circulating tumor DNA mutational status and treatment outcomes. Eighteen of 71 (25%) patients classified by SelectPSMA as nonresponders had significantly lower rates of PSA response than patients classified as likely responders (6% vs. 51%; P < 0.001), a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P < 0.001), and a shorter OS (median, 6.3 vs. 14.5 mo; P = 0.046). Conclusion: [¹⁷⁷Lu]Lu-PSMA-617 offered in a real-world setting after regulatory approval in the United States demonstrated antitumor activity and a favorable toxicity profile. Artificial-intelligence–based analysis of baseline PSMA PET/CT images may improve patient selection. Validation of these findings on larger cohorts is warranted.

Intrapatient intermetastatic heterogeneity (IIH) has been demonstrated in metastatic castration-resistant prostate cancer (mCRPC) patients and is of the utmost importance for radiopharmaceutical therapy (RPT) eligibility. This study was designed to determine the prevalence of IIH and RPT eligibility in mCRPC patients through a triple-tracer PET imaging strategy. Methods: This was a multisite prospective observational study in which mCRPC patients underwent both ¹⁸F-FDG and ⁶⁸Ga-prostate-specific membrane antigen (PSMA)–617 PET/CT scans. A third scan with ⁶⁸Ga-DOTATATE, a potential biomarker of neuroendocrine differentiation, was performed if an ¹⁸F-FDG–positive/⁶⁸Ga-PSMA–negative lesion was found. Per-tracer lesion positivity was defined as having an uptake at least 50% above that of the liver. IIH prevalence was defined as the percentage of participants having at least 2 lesions with discordant features on multitracer PET. Results: IIH was observed in 81 patients (82.7%), and at least 1 ¹⁸F-FDG–positive/⁶⁸Ga-PSMA–negative lesion was found in 45 patients (45.9%). Of the 37 participants who also underwent ⁶⁸Ga-DOTATATE PET/CT, 6 (16.2%) had at least 1 ⁶⁸Ga-DOTATATE–positive lesion. In total, 12 different combinations of lesion imaging phenotypes were observed. On the basis of our prespecified criteria, 52 (53.1%) participants were determined to be eligible for PSMA RPT, but none for DOTATATE RPT. Patients with IIH had a significantly shorter median overall survival than patients without IIH (9.5 mo vs. not reached; log-rank P = 0.03; hazard ratio, 2.7; 95% CI, 1.1–6.8). Conclusion: Most mCRPC patients showed IIH, which was associated with shorter overall survival. On the basis of a triple-tracer PET approach, multiple phenotypic combinations were found. Correlation of these imaging phenotypes with genomics and treatment response will be relevant for precision medicine.

The clinical impact of 16α-¹⁸F-fluoro-17β-estradiol (¹⁸F-FES) PET/CT on patient management has not been well investigated. The aim of this study was to assess the clinical impact of ¹⁸F-FES PET/CT on the management of patients with recurrent or metastatic breast cancer. Methods: Study subjects were identified retrospectively from a database of a prospective trial for postmarketing surveillance of ¹⁸F-FES between 2021 and 2023. Patients who were suspected or known to have recurrent or metastatic estrogen receptor–positive breast cancer based on a routine standard workup were included. Planned management before and actual management after ¹⁸F-FES PET/CT were assessed by 2 experienced medical oncologists via medical chart review. A 5-point questionnaire was provided to evaluate the value of ¹⁸F-FES PET/CT for management planning. The rate of intention-to-treat and interdisciplinary changes, and the impact of ¹⁸F-FES PET/CT according to PET/CT result or clinical indication, were examined. Results: Of the 344 included patients, 120 (35%) experienced a change in management after ¹⁸F-FES PET/CT. In 139 (40%) patients,¹⁸F-FES PET/CT supported the existing management decision without a change in management. Intention-to-treat and interdisciplinary changes accounted for 64% (77/120) and 68% (82/120) of all changes, respectively. A higher rate of change was observed when lesions were ¹⁸F-FES–negative (44% [36/81]) than ¹⁸F-FES–positive (30% [51/172]) or mixed ¹⁸F-FES–positive/negative (36% [33/91]). Regarding clinical indications, the highest rate of change was shown when evaluating the origins of metastasis of double primary cancers (64% [9/14]). Conclusion: ¹⁸F-FES PET/CT modified the management of recurrent or metastatic breast cancer, serving as an impactful imaging modality in clinical practice.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

BACKGROUND AND PURPOSE:

Neuronal ceroid lipofuscinoses are a group of neurodegenerative disorders. Recently, enzyme replacement therapy (ERT) was approved for neuronal ceroid lipofuscinosis type 2 (CLN2), a subtype of neuronal ceroid lipofuscinoses. The aim of this study was to quantify brain volume loss in CLN2 disease in patients on ERT in comparison with a natural history cohort using MRI.

BACKGROUND AND PURPOSE:

Previous studies have reported metal accumulation and microstructure changes in deep gray nuclei (DGN) in Wilson disease (WD). However, there are limited studies that investigate whether there is metal accumulation and microstructure changes in DGN of patients with WD with normal-appearing routine MRI. This study aimed to evaluate multiparametric changes in DGN of WD and whether the findings correlate with clinical severity in patients with WD.

BACKGROUND AND PURPOSE:

Brain atrophy occurs in the late stage of dementia, yet structural MRI is widely used in the work-up. Atrophy patterns can suggest a diagnosis of Alzheimer disease (AD) or frontotemporal dementia (FTD) but are difficult to assess visually. We hypothesized that the availability of a quantitative volumetric brain MRI report would increase neuroradiologists’ accuracy in diagnosing AD, FTD, or healthy controls compared with visual assessment.

Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, APC, ARID1A, CTNNB1, CDKN2A, KRAS, PTEN, and TP53, were identified. A PTEN nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this PTEN mutation, the only other recurrent mutation was KRAS G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The PTEN p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single PTEN mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease PTEN mutant allele fractions to precancerous levels.

Metastatic porocarcinomas (PCs) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PCs. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations. However, ex vivo drug testing predicted pazopanib efficacy, and indeed, administration of pazopanib elicited remarkable clinicoradiological response. Pazopanib and its class of drugs should be evaluated for efficacy in other cases of PC, and the rationale for efficacy should be determined when PC tumor models become available. A functional precision medicine approach could be useful to derive effective treatment options for rare cancers.

Affibody molecules are small (6-kDa) affinity proteins folded in a three-helical bundle and generated by directed evolution for specific binding to various target molecules. The most advanced affibody molecules are currently tested in the clinic, and data from more than 300 subjects show excellent activity and safety profiles. The generation of affibody molecules against a particular target starts with the generation of an affibody library, which can then be used for panning using multiple methods and selection systems. This protocol describes the molecular cloning of DNA-encoded affibody libraries to a display vector of choice, for either phage, Escherichia coli, or Staphylococcus carnosus display. The DNA library can come from different sources, such as error-prone polymerase chain reaction (PCR), molecular shuffling of mutations from previous selections, or, more commonly, from DNA synthesis using various methods. Restriction enzyme-based subcloning is the most common strategy for affibody libraries of higher diversity (e.g., >10⁷ variants) and is described here.

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 (NXNL1) gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The NXNL1 gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.

Imaging methods are fundamental tools to detect and diagnose lung diseases, monitor their treatment and detect possible complications. Each modality, starting from classical chest radiographs and computed tomography, as well as the ever more popular and easily available thoracic ultrasound, magnetic resonance imaging and nuclear medicine methods, and new techniques such as photon counting computed tomography, radiomics and application of artificial intelligence, has its strong and weak points, which we should be familiar with to properly choose between the methods and interpret their results. In this review, we present the indications, strengths and main limitations of methods for chest imaging.

Josh explains that all Genesis music is bad. Robert only has sub-standards for video games. Chris arm-chair quarterbacks the Persona 3 remake. Not the ramp!

The post RPG Cast – Episode 696: “Have You Met Video Game Fans?” appeared first on RPGamer.

Chris force feeds people desserts to make people like each other. Ryan likes bad games, just like Chris. Kelley has a penchant for losing pendants. Matt throws some garbage in the pot and suddenly it's pizza. Now let's grow old and lose stats together.

The post RPG Cast – Episode 721: “Skyrim Helmet Sleep Mask” appeared first on RPGamer.

When I was reviewing Final Fantasy VII Rebirth a few months ago, it looked set to be my Game of the Year. Metaphor: ReFantazio was still a distant concept and, I thought, communication of that concept was anything great. It turns out that I was really underestimating Atlus at the time. It's been eight years since Persona 5, and maybe I had begun to forget its magic, because as a JRPG from the creators of Persona 5, the magic is undoubtedly there in Metaphor: ReFantazio.

When I was younger, I used to watch the Columbo series, where you know the culprit's identity right away at the start. Metaphor: ReFantazio is a bit like that, because the introduction shows the King of Euchronia (Metaphor's fantasy world) being murdered in his sleep by an ambitious aristocrat named Louis, which throws the whole country into turmoil. From there, the protagonist and the comrades he meets all have different reasons for sharing the same goal: to prevent the wicked Louis from seizing the throne.

As simple as it seems, the narrative has its fair share of surprises. This has to do with the tremendous wealth of characters in the game. Due to a certain magic, the race for the throne is turned into an election, in which the protagonists gets to runs. Adding to the eight playable characters, you meet several competitors and followers who back you. All of them have personal stories and strange personalities that make Metaphor's adventure strikingly vivid.

The sub-stories are quite interesting for most part, for they convey a range of different emotions: sometime are heart-breaking, sometime heart-warming or just purely fun, and they'll keep you engaged for hours. They often leave you in suspense, since the structure of the game has you experiencing them little by little. And, just like in Persona, you can spend extensive time with your allies in a whole lot of mini sequences that play a great part in making the cast truly unforgettable.

But that doesn't mean you'll forget about the main story. Metaphor: ReFantazio offers some fascinating chapters. Take for instance the Opera house one, it's a breathtaking chapter very reminiscent of the great Final Fantasy VI, absolutely loaded with memorable sequences, grandiose fights, and striking reveals. And in the end, the whole game is like that. The thirst for more is real, as Atlus always drops a little something to make you eager to progress and feel engaged - a new character, intense combat, a shocking truth, stunning landscapes, etc. Even the most common NPCs sometimes tell a tale that blows your mind. Metaphor: ReFantazio has so much to offer in terms of characters, creativity, and storytelling that I couldn't help feeling overwhelmed at times.

The incongruity of an election in a kingdom ruled by Royals for ages is in reality an occasion for the story to develop elaborate thoughts about democracy and society. The protagonist always carries with him a strange book about an ideal world, where people have equal chances, decide their own fates, and live in harmony. It's a dream-like realm wholly different from Euchronia, which is a medieval regime plagued by injustice, greed, and poverty.

But there are whispers of a past, of a very advanced civilisation that ultimately failed, creating a scenario that raises the question of the relationship between democracy and freedom. There are also different tribes in the game, and it's worth noticing that the protagonist's party has one representative of each tribe, like a call for tolerance in a kingdom known for its inequality. The narrative therefore has powerful philosophic elements - something that only the greatest works in JRPG history possess.

Metaphor: ReFantazio boasts world design like you seldom see, starting with the giant flying rock that has symbolized it since reveal. Here again Atlus' creativity is absolutely inspired. The designers left their comfort zone and came up with an innovative take on characters, meaning that they ditched the classical human hero or heroine. You befriend an elf-like girl, a bat-like character or a maiden with a third eye, but no real typical human. The result is a party that literally breathes fantasy, a bit like Final Fantasy Tactics Advance did in its time. Humans exist, though, but on the opposite side of the divide.

These so-called Humans are twisted and awfully misshapen creatures roaming Euchronia as dangerous enemies. Atlus went beyond the boundaries of the bizarre with these designs and the result is amazing. I could also mention the funny Runner, a land vessel with legs that the party owns. Just travelling with it feels incredible. There are numerous examples like this, but in short the world is packed with wonders that I've never seen in a game before.

As for combat, Metaphor: ReFantazio is a good old turn-based JRPG, where strategy and careful planning matter. Characters wield the power of Archetypes, abstract figures that party members turn into when attacking. Archetypes are essentially jobs, hence my mention of Final Fantasy Tactics above. You can equip a character with an archetype, and they then acquire attack and passive skills specific to that archetype. For example, the Gunner can deal what is called "pierce" damage from behind, the Warrior heavy "slash" damage with its greatsword, and the Mage masters the natural elements.

There are also very complex Archetypes like the Masked Dancer, which can wear different masks to mimic other Archetypes, or the all-powerful Summoner, who masters absolutely ever type of damage once you acquire the corresponding stones (needless to say, these are incredibly difficult to come by). Unlike Persona 5, every character can equip any archetype, so you can choose the allies you like the most. Besides that, the currently-equipped Archetype can also inherit a couple of skills or spells from another, allowing for very elaborate lineups.

Combat isn't simplistic or easy; basic skills won't do much against bosses or even the relatively big enemies within dungeons. For these, the player must analyze how Archetypes can cooperate. Two Healers can, for example, cast a light spell on all opponents, while a single healer only targets one. Three magic-type archetypes lets the Mage unleash the mightiest fire spell available, which comes in handy at times. Such cooperation skills take more than one turn crystal (as turns are represented in game), but you can save turn crystals by exploiting the enemy's weakness, like you can in Shin Megami Tensei and its spin-offs.

The possibilities offered by Archetypes are fantastic and their complexity goes well beyond anything I've experienced from Atlus thus far. You have several types of Archetypes that work against a set weakness (three Archetype lineages have fire spells, for example). So you can choose the ones that fit your current goal or preferences. Boss fights are no joke and it's a renewed pleasure to overcome the various (tough) challenges after devising the right strategy. Metaphor: ReFantazio also lives up to Persona 5 in two particular aspects: main dungeons are never short of surprises, and the presentation of the battle menu is once again fantastic.

Like in Persona, Metaphor: ReFantazio is played in limited time. There's an in-game calendar with deadlines set to clear the main dungeons. So you can't have everyone master every archetype - you need to choose and use every day wisely. Unlike Persona 5, which gives you fixed Personas that you have to figure out how to use optimally, building characters and Archetypes in Metaphor: ReFantazio must be planned well ahead of time. This a fundamental difference between the two and the reason why this new IP elevates Atlus' core gameplay conceits, which were already very good. Exploration is important and quite entertaining too: you can tackle tricky secondary dungeons, discover special shops, or visit your followers. 

The latter provide perks, like increased slots for inherited skills, greater experience gain and, most importantly, the ability to unlock advanced Archetypes. The Healer can become the Cleric, for instance, with far superior healing capabilities, and you can become a General after being a Commander, gaining powerful ice skills in addition to the potent fire skills the latter had.

The whole game must be seen as a wide array of possibilities, with the player finding their own way to victory with their choices and favorite characters. As far as I'm concerned, this feels rewarding beyond anything I expected. Overflowing with content, the game is very long (around 70 hours), even with Atlus allowing you save time (any low-level enemy on the map can be beaten instantly without entering a turn-based battle, and you'll still gain experience and materials). 

The visuals are Metaphor's clear weakness. The game modeling isn't what you'd expect from a PS5 game in 2024, and I'd say it's fairly underwhelming for PS4 too. The backgrounds aren't very sharp and you see aliasing here and there. Secondary dungeons look very common; actually, they don't look like much of anything really. And there are several towers to explore across Euchronia, but the interior of each tower looks the exact same everytime. This kind of reuse of assets is fairly disappointing for a game of this magnitude. I shiver at the thought of what Metaphor: ReFantazio could have looked like with a Final Fantasy-sized budget. I expect it would have been my first perfect score, but it looks like I'll need to withhold that one once again.

One aspect that does score perfect marks is the original music score. Here again, I was pretty sure that Final Fantasy VII Rebirth would be my soundtrack of the year, but Metaphor's music blows it away completely. Atlus' sound team has crafted vibrant choruses befitting the heroic fantasy genre, but with such unorthodox compositions that it felt fresh to my ears. Other vocals and melodies are bewitching to the point they lift your spirit in battle or dungeons. And there's the strange theme of Virga island, with its weird vocals and hypnotic murmurs. It sounds like a tribal chant from afar, a bit like what Genshin Impact achieved with the Natlan soundtrack two months ago. The music is a splendid journey in itself.   

Metaphor: ReFantazio is the type of game you feel was made to achieve something greater than just sales. It's a completely new world, boasting an immense wealth of gameplay, characters, locations, and music, redefining heroic fantasy like no JRPG has done for decades. Atlus' latest title is also a fantastic challenge for turn-based combat and strategy lovers, with highly enjoyable and rewarding dungeons. Put another way, Metaphor: ReFantazio is the golden age of fantasy JRPGs, revived from the ashes in all its majesty, no less.

During the day, Thomas is a normal account manager. But at night he becomes Ryuzaki57, an extreme otaku gamer hungry for Japanese games (preferably with pretty girls in the main role). He spends a lot of time on F2P RPGs, but never misses the lastest interesting releases. Feel free to contact on twitter at @Ryuz4ki57

Full Article - https://www.vgchartz.com/article/463032/metaphor-refantazio-ps5/

I would never have predicted there'd be an isometric tactics game based on run-and-gun series Metal Slug, yet here Metal Slug Tactics is, and I am here for it. We've been following its development for a while but it's out now on Steam, and seemingly as strong as its demo suggested.

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Putting aside my natural annoyance at Metal Gear Solid Delta: Snake Eater for almost beating out the Twarhammer series in the headline real estate wars, I am more than a little excited to play. Some days, you simply must feast on a tree frog, and while we still don’t have a solid release date, that day doesn’t feel too far away. Good news for stealth fans, and perhaps gooder news for a dozen strapline writers sweating profusely, soiling themselves in anticipation of using “kept you waiting, huh?”.

Until then, I at least have a steady drip feed of new information to keep me sated, the latest of which is the substantial hint that there'll be some new dialogue in the game, as per the video below. Alongside that, the previously pseudonymous Suzetta Miñet - who was credited with voicing EVA in MGS3 and Peace Walker - has revealed herself to be Jodi Benson, the voice of Ariel in Disney’s The Little Mermaid. Cheers for the spot, Automaton West.

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JUDY WOODRUFF: The hashtag #MeToo has millions of women sharing stories of abuse, shining a spotlight on a troubling reality in our society.

It was first used in 2007, but when actor Alyssa Milano tweeted it Sunday night to talk about sexual harassment and assault in the wake of the Harvey Weinstein story, it went viral. The hashtag was tweeted nearly a million times in just 48 hours. Facebook reported 45 percent of its users have friends who posted #MeToo, as women wrote about their experiences about the workplace and culture, and what should change.

We explore some of those issues with Fatima Goss Graves. She’s president of the National Women’s Law Center. Lisa Senecal wrote about her own experience for the online news site Daily Beast. She’s with the Vermont Commission on Women. And Melissa Silverstein is the founder of the blog and Web site Women and Hollywood.

Thank you all for joining us.

Lisa Senecal, I’m going to start with you.

You have had a personal experience with sexual harassment. That’s in part what has drawn you to this #MeToo campaign movement.

Just tell us briefly about what happened.

LISA SENECAL, Member, Vermont Commission on Women: Sure.

Like most women, I have had a number of experiences with sexual harassment, beginning with my first job, when I was 15 years old. And it’s really been a threat off and on throughout my entire professional career.

The most egregious offense was an actual assault that occurred with a male executive. Unfortunately, because of an NDA — and we can go into the evils of nondisclosures another time — but because of that, there isn’t a lot that I’m able to say about the specific event.

But the issue of sexual harassment and finally having this come to the fore, so many women are already familiar with it from being on the receiving end. And I think, especially with the #MeToo campaign, it’s been really wonderful and an eye-opening experience for men to realize just how pervasive an issue this is.

JUDY WOODRUFF: So, in your experience, it was a business setting.

Melissa Silverstein, you have been writing about women in Hollywood for 10 years. Of course, that’s where the Harvey Weinstein story came from.

If it’s been going on in Hollywood forever, why hasn’t it been talked about more before now?

MELISSA SILVERSTEIN, Founder, Women and Hollywood: Well, I think there was a culture of silence created around this man and also within this industry.

People were afraid. People are afraid for their jobs. It’s a very relational industry, where if someone is going to blacklist you, you are not going to get your next job.

So I think the way that a person was able to conduct himself for 30 years like this was to build a culture of fear, to make people sign nondisclosure agreements, and to get them to shut up.

JUDY WOODRUFF: Fatima Goss Graves, here with me in Washington with the National Women’s Law Center, we have been talking about Hollywood.

We have talking about the business workplace. Is there any field of work where this isn’t going on?

FATIMA GOSS GRAVES, President, National Women’s Law Center: Right.

The issue of harassment and assault, it’s a Hollywood problem, but really it’s an everywhere problem. It infects industries across the board, whether you’re high-wage jobs, low-wage jobs, male-dominated fields, but also female-dominated fields.

Restaurants are some of the areas where you have some of the highest rates of EEOC charges. And that’s not a male-dominated field.

JUDY WOODRUFF: EEOC, the Equal Employment Opportunity Commission.

Lisa Senecal, some people are saying that they’re uncomfortable with this #MeToo campaign movement because they’re saying, once again, women are being asked to go public with what happened to them, but there is no promise that there is going to be anything done about it. How do you see this?

LISA SENECAL: I don’t necessarily believe that women are being asked to come forward.

I think this is an opportunity to come forward, if that’s something that women want to do, but there’s no obligation to do it. And there’s been a lot of support for letting women know that if this isn’t something you’re comfortable with at this time, no one is obligated to tell their story, and no one is allowed to force you to tell your story before you’re ready.

But the stories are important. Without them, the degree to which this happens across all industries, across genders as well — we know that this happens to men. This happens to the transgender.

It’s not specific to women, although it affects us most frequently. Until we have a critical mass of women who are able to get the men in their lives, the men that they work with to understand how pervasive a problem it is, and then can get men to begin to act on this, because this isn’t a women’s issue.

This is a violence issue, and an issue of power and who has the power. So until the people who still primarily do hold the power, which is primarily men and primarily white men, until they’re going to begin to act, then the problems are going to persist.

JUDY WOODRUFF: Melissa Silverstein, how do you see that? What is it going to take for this to be a change?

MELISSA SILVERSTEIN: The fact that we’re having a global conversation about sexual harassment — I have been doing media for the last week all over the world.

People are really enthralled by this and want to see change. This is a global issue. And, also, Hollywood is a global industry. Seventy cents of every dollar of Hollywood studio movies are made outside the United States.

So what people are looking for is Hollywood to step up. And, today, we had a leader in Hollywood, Kathleen Kennedy, to say we need to have a commission, cross-industry commission, of people who are going to look into this and put a stop to it once and for all.

JUDY WOODRUFF: And pick up on that, Fatima Goss Graves. Just across the board, what is it going to take?

FATIMA GOSS GRAVES: Right.

We know that there are things that would make a difference here. If employers had processes that their employees actually use, you wouldn’t have harassment in the shadows. Right now, most people don’t report harassment to anyone. And it’s because they think their employers won’t do anything, or, worse, that they would experience retaliation.

JUDY WOODRUFF: And that’s — because that’s been what happened.

FATIMA GOSS GRAVES: And that is. They’re right to believe that they will experience retaliation, because they do. They’re shamed. They’re blamed.

But employees could make a difference. Right? They can be — take it seriously and communicate that to their workplace. They can also have the right policies that are in place. And, finally, they could, when someone comes forward, be really clear that they take it seriously and that they will not tolerate retaliation.

Those are things that aren’t happening among employers frequently enough.

JUDY WOODRUFF: Lisa Senecal, as somebody who had it happen to you in a business environment, what changes need to be made in the workplace? What has to happen?

LISA SENECAL: Well, I agree completely with what was just said.

Too often, the workplace education that goes on is incredibly insufficient. It’s more of companies wanting to be able to check the box and say that they did their sexual harassment training. And it isn’t truly something within the culture of companies that they believe that this is a problem and that it is a right of all people working at that company not to be harassed.

So, until it starts to be taken more seriously, and when a woman or anyone comes forward with an accusation, it does have to be taken so much more seriously. And the knee-jerk response, as was in my case, cannot be to shame the woman, can’t be to blame her for somehow bringing this on herself, and putting women back in a position of being victimized a second time because they’re not taken seriously when they come forward.

JUDY WOODRUFF: Melissa Silverstein, yes, go ahead.

MELISSA SILVERSTEIN: I just wanted to add, one of the things that’s so fundamental about this is how this — how it’s so normalized for all of us to go through this kind of harassment, especially in Hollywood, and how people kind of laugh off, oh, you know, that’s locker room talk, or, you know, this is the movie business, get used to it.

And what we need to do is really pierce that veil of the normalization of this kind of conduct, because it starts with, you know, the comments, and then it can escalate very quickly.

So we really need to just change people’s attitudes and get rid of the toxic masculinity. Hollywood has no much institutionalized sexism that sometimes I feel like we need to just start over, if possible.

JUDY WOODRUFF: Joining us also is Leigh Gilmore, a professor at Wellesley College who’s written a book about why — titled “Why We Doubt What Women Say About Their Lives.”

Leigh Gilmore, why don’t women — why haven’t women been believed and taken seriously on this, and could we now be at a moment when they are?

LEIGH GILMORE, Wellesley College: It’s good to be with you, Judy.

I think we have a persistent and a pervasive culture of doubting what women say, especially when they’re bringing forward accounts of harm into the public sphere. So we have these pre-made default cultural narratives of women’s unreliability. We have he said/she said, which is a false equivalence narrative.

We have that notion that nobody knows what really happened. We have that notion that you can’t really trust what women say. None of these are based in fact, but they are part of a kind of cloud that enables us to doubt any woman before she speaks up.

And it’s quite intimidating. And so, if we’re at a point of change, we really are at a moment where I think we have a new level of visibility, and we have the opportunity to amplify the voices of women who are speaking out.

So, insofar as we have that opportunity, there is a form of solidarity, and more women speaking can lead to change.

JUDY WOODRUFF: Fatima Goss Graves, as somebody who works on these issues from a legal standpoint, are we, could we be at a watershed point, or is it just a whole lot more complicated?

FATIMA GOSS GRAVES: Well, the culture change typically has to go together with both the enforcement of the laws and the policy change.

And so we’re at a tipping point, surely, on culture change. But I will tell you, you know, the National Women’s Law Center runs a hot line. And over the last two weeks, we have had double the intake on harassment.

And we have a new network called the Legal Network for Gender Equity, so we’re — attorneys are joining with us and will be ready to take these cases. But those people who are making these calls and contacting us, I think that that shows that you have people who are ready to come forward on social media, and there is power there, but it seems like there are people who are ready to come forward in other ways, too.

JUDY WOODRUFF: I want to quickly go around and ask each one of you about the role of men in all of this.

Lisa Senecal?

LISA SENECAL: Oh, I think it’s critical for men as allies to be coming forward and supporting women who do come forward.

Men also need to be willing to call out other men, whether that’s one-on-one, whether it’s in a group setting within a company, or socially. If a man hears, sees someone doing something inappropriate, they need to have the courage to stand up, even in front of other men, and say, it’s not OK, it’s inappropriate behavior, and it’s not going to be tolerated.

And until it’s also men joining in, women can’t do this by themselves. There is an organization, A Call to Men, that I’m a big fan of. And one of their mantras is, if women could have stopped abuse and assault, they would have done it already.

And that’s completely true. It’s not something that women are going to be able to do alone. It shouldn’t be looked at as only a women’s issue. And until people look at this on a larger scale and understand that this affects the bottom line of companies, it affects productivity, it affects, you know, absenteeism, just across the board, this is not a women’s issue.

It is a human issue.

JUDY WOODRUFF: Right.

Melissa Silverstein, what about that?

And we should point out that men are themselves the victims of sexual harassment and abuse at times.

MELISSA SILVERSTEIN: I feel that this is on men.

The men are most of the perpetrators. They’re also the collaborators. And, at The Weinstein Company, their board was all men, and they were all complicit in creating an environment that allowed this to thrive.

In Hollywood, there’s not a single woman, even the people at the tippy-top of the industry, who don’t report to men. This is also about getting more women into leadership positions and getting the men — and holding the men accountable.

The men in this industry need to step up. They need to say, we want to be — we want to create this industry in a way that women can thrive and don’t have to experience this anymore.

JUDY WOODRUFF: Leigh Gilmore?

LEIGH GILMORE: We’re talking about awareness and accountability.

So, as wonderful as it is to have increased visibility, and it enables us to connect the dots and to see the long histories of sexual abuse, harassment and discrimination, we need new levels of accountability.

I will echo the notion that Harvey Weinstein’s board certainly knew about these accusations. There’s a DA who failed to charge him. We have ample examples of failures.

And what we really need to do is to correct those. The role of men is certainly important here. Minimally, they can show up and be witnesses.

JUDY WOODRUFF: And, finally, Fatima Goss Graves, the role of men and how we prevent this.

FATIMA GOSS GRAVES: We have had a little bit of conversation about men as survivors, but the conversation we haven’t really had is about what happens when men are abusers or enablers or allow this to happen in the workplaces, in schools, or in women’s everyday lives?

And so now we have an opportunity culturally for that conversation. That culture is going to have to hit where policy-makers are. It’s going to have to hit where employers are in order to make a real difference.

JUDY WOODRUFF: Well, it’s clear that everyone is hoping this is a watershed moment, that things will change as a result of what’s happened here. But we will see.

And we appreciate all of you joining us in this conversation, Fatima Goss Graves here with me in Washington, Lisa Senecal, Melissa Silverstein, and Leigh Gilmore.

We thank you all.

FATIMA GOSS GRAVES: Thank you.

MELISSA SILVERSTEIN: Thank you.

The post As survivors say #MeToo, what will it take to stop widespread sexual harassment? appeared first on PBS NewsHour.

It is nearly time for one of astronomy's top annual sights – the Perseid meteor shower. This year is a bit special, says Abigail Beall

Mars rocks that were blasted off the surface of the Red Planet millions of years ago have been traced back to craters where they originated, which could transform our understanding of Mars’s volcanism and evolution

After a star explodes, the resulting supernova remnant collapses in on itself and could begin the cycle again, creating generations of stars enriched with heavy elements

Comet C/2023 A3, also known as Tsuchinshan–ATLAS, is expected to grace our skies from mid-October. Abigail Beall is hoping for a dazzling display

As the space industry evolves, we need a new set of international regulations to decide who is responsible for safety, the number of satellites in space, and more

The ion tail of C/2023 A3 (Tsuchinshan-ATLAS) could appear as a blue streak across the northern hemisphere sky during October, in a rare event thought to happen only every few decades

In order to figure out how something came from nothing, we first need to explore the different types of nothing

A type of mathematical problem that was previously impossible to solve can now be successfully analysed with artificial intelligence

In the 1960s and 1970s, NASA spent a lot of time thinking about whether toroidal (donut-shaped) fuel tanks were the way to go with its spacecraft. Toroidal tanks have a bunch of potential advantages over conventional spherical fuel tanks. For example, you can fit nearly 40% more volume within a toroidal tank than if you were using multiple spherical tanks within the same space. And perhaps most interestingly, you can shove stuff (like the back of an engine) through the middle of a toroidal tank, which could lead to some substantial efficiency gains if the tanks could also handle structural loads.

Because of their relatively complex shape, toroidal tanks are much more difficult to make than spherical tanks. Even though these tanks can perform better, NASA simply doesn’t have the expertise to manufacture them anymore, since each one has to be hand-built by highly skilled humans. But a company called Machina Labs thinks that they can do this with robots instead. And their vision is to completely change how we make things out of metal.

The fundamental problem that Machina Labs is trying to solve is that if you want to build parts out of metal efficiently at scale, it’s a slow process. Large metal parts need their own custom dies, which are very expensive one-offs that are about as inflexible as it’s possible to get, and then entire factories are built around these parts. It’s a huge investment, which means that it doesn’t matter if you find some new geometry or technique or material or market, because you have to justify that enormous up-front cost by making as much of the original thing as you possibly can, stifling the potential for rapid and flexible innovation.

On the other end of the spectrum you have the also very slow and expensive process of making metal parts one at a time by hand. A few hundred years ago, this was the only way of making metal parts: skilled metalworkers using hand tools for months to make things like armor and weapons. The nice thing about an expert metalworker is that they can use their skills and experience to make anything at all, which is where Machina Labs’ vision comes from, explains CEO Edward Mehr who co-founded Machina Labs after spending time at SpaceX followed by leading the 3D printing team at Relativity Space.

“Craftsmen can pick up different tools and apply them creatively to metal to do all kinds of different things. One day they can pick up a hammer and form a shield out of a sheet of metal,” says Mehr. “Next, they pick up the same hammer, and create a sword out of a metal rod. They’re very flexible.”

The technique that a human metalworker uses to shape metal is called forging, which preserves the grain flow of the metal as it’s worked. Casting, stamping, or milling metal (which are all ways of automating metal part production) are simply not as strong or as durable as parts that are forged, which can be an important differentiator for (say) things that have to go into space. But more on that in a bit.

The problem with human metalworkers is that the throughput is bad—humans are slow, and highly skilled humans in particular don’t scale well. For Mehr and Machina Labs, this is where the robots come in.

“We want to automate and scale using a platform called the ‘robotic craftsman.’ Our core enablers are robots that give us the kinematics of a human craftsman, and artificial intelligence that gives us control over the process,” Mehr says. “The concept is that we can do any process that a human craftsman can do, and actually some that humans can’t do because we can apply more force with better accuracy.”

This flexibility that robot metalworkers offer also enables the crafting of bespoke parts that would be impractical to make in any other way. These include toroidal (donut-shaped) fuel tanks that NASA has had its eye on for the last half century or so.

Machina Labs’ CEO Edward Mehr (on right) stands behind a 15 foot toroidal fuel tank.Machina Labs

“The main challenge of these tanks is that the geometry is complex,” Mehr says. “Sixty years ago, NASA was bump-forming them with very skilled craftspeople, but a lot of them aren’t around anymore.” Mehr explains that the only other way to get that geometry is with dies, but for NASA, getting a die made for a fuel tank that’s necessarily been customized for one single spacecraft would be pretty much impossible to justify. “So one of the main reasons we’re not using toroidal tanks is because it’s just hard to make them.”

Machina Labs is now making toroidal tanks for NASA. For the moment, the robots are just doing the shaping, which is the tough part. Humans then weld the pieces together. But there’s no reason why the robots couldn’t do the entire process end-to-end and even more efficiently. Currently, they’re doing it the “human” way based on existing plans from NASA. “In the future,” Mehr tells us, “we can actually form these tanks in one or two pieces. That’s the next area that we’re exploring with NASA—how can we do things differently now that we don’t need to design around human ergonomics?”

Machina Labs’ ‘robotic craftsmen’ work in pairs to shape sheet metal, with one robot on each side of the sheet. The robots align their tools slightly offset from each other with the metal between them such that as the robots move across the sheet, it bends between the tools. Machina Labs

The video above shows Machina’s robots working on a tank that’s 4.572 m (15 feet) in diameter, likely destined for the Moon. “The main application is for lunar landers,” says Mehr. “The toroidal tanks bring the center of gravity of the vehicle lower than what you would have with spherical or pill-shaped tanks.”

Training these robots to work metal like this is done primarily through physics-based simulations that Machina developed in house (existing software being too slow), followed by human-guided iterations based on the resulting real-world data. The way that metal moves under pressure can be simulated pretty well, and although there’s certainly still a sim-to-real gap (simulating how the robot’s tool adheres to the surface of the material is particularly tricky), the robots are collecting so much empirical data that Machina is making substantial progress towards full autonomy, and even finding ways to improve the process.

An example of the kind of complex metal parts that Machina’s robots are able to make.Machina Labs

Ultimately, Machina wants to use robots to produce all kinds of metal parts. On the commercial side, they’re exploring things like car body panels, offering the option to change how your car looks in geometry rather than just color. The requirement for a couple of beefy robots to make this work means that roboforming is unlikely to become as pervasive as 3D printing, but the broader concept is the same: making physical objects a software problem rather than a hardware problem to enable customization at scale.

The water column is hazy as an unusual remotely operated vehicle glides over the seafloor in search of a delicate tilt meter deployed three years ago off the west side of Vancouver Island. The sensor measures shaking and shifting in continental plates that will eventually unleash another of the region’s 9.0-scale earthquakes (the last was in 1700). Dwindling charge in the instruments’ loggers threatens the continuity of the data.

The 4-metric-ton, C$8-million (US $5.8-million) remotely operated vehicle (ROV) is 50 meters from its target when one of the seismic science platforms appears on its sonar imaging system, the platform’s hard edges crystallizing from the grainy background like a surgical implant jumping out of an ultrasound image. After easing the ROV to the platform, operators 2,575 meters up at the Pacific’s surface instruct its electromechanical arms and pincer hands to deftly unplug a data logger, then plug in a replacement with a fresh battery.

This mission, executed in early October, marked an exciting moment for Josh Tetarenko, director of ROV operations at North Vancouver-based Canpac Marine Services. Tetarenko is the lead designer behind the new science submersible and recently dubbed it Jenny in homage to Forrest Gump, because the fictional character named all of his boats Jenny. Swapping out the data loggers west of Vancouver Island’s Clayoquot Sound was part of a weeklong shakedown to test Jenny’s unique combination of dexterity, visualization chops, power, and pressure resistance.

Jenny is only the third science ROV designed for subsea work to a depth of 6,000 meters.

By all accounts Jenny sailed through. Tetarenko says the worst they saw was a leaky O-ring and the need to add some spring to a few bumpers. “Usually you see more things come up the first time you dive a vehicle to those depths,” says Tetarenko.

Jenny’s successful maiden cruise is just as important for Victoria, B.C.–based Ocean Networks Canada (ONC), which operates the NEPTUNE undersea observatory. The North-East Pacific Time-series Undersea Networked Experiments array boasts thousands of sensors and instruments, including deep-sea video cameras, seismometers, and robotic rovers sprawled across this corner of Pacific. Most of these are connected to shore via an 812-kilometer power and communications cable. Jenny was custom-designed to perform the annual maintenance and equipment swaps that have kept live data streaming from that cabled observatory nearly continuously for the past 15 years, despite trawler strikes, a fault on its backbone cable, and insults from corrosion, crushing pressures, and fouling.

NEPTUNE remains one of the world’s largest installations for oceanographic science despite a proliferation of such cabled observatories since it went live in 2009. ONC’s open data portal has over 37,000 registered users tapping over 1.5 petabytes of ocean data—information that’s growing in importance with the intensification of climate change and the collapse of marine ecosystems.

Over the course of Jenny’s maiden cruise, her operators swapped devices in and out at half a dozen ONC sites, including at several of NEPTUNE’s five nodes and at one of NEPTUNE’s smaller sister observatories closer to Vancouver.

Inside Jenny

ROV Jenny aboard the Valour, Canpac’s 50-meter offshore workhorse, ahead of October’s NEPTUNE observatory maintenance cruise.Ocean Networks Canada

What makes Jenny so special?

• Jenny is only the third science ROV designed for subsea work to a depth of 6,000 meters.
• Motion sensors actively adjust her 7,000-meter-long umbilical cable to counteract topside wave action that would otherwise yank the ROV around at depth and, in rough seas, could damage or snap the cable.
• Dual high-dexterity manipulator arms are controlled by topside operators via a pair of replica mini-manipulators that mirror the movements.
• Each arm is capable of picking up objects weighing about 275 kilograms, and the ROV itself can transport equipment weighing up to 3,000 kg.
• 11 high-resolution cameras deliver 4K video, supported by 300,000 lumens of lighting that can be tuned to deliver the soft red light needed to observe bioluminescence.
• Dual multibeam sonar systems maximize visibility in turbid water.

Meghan Paulson, ONC’s executive director for observatory operations, says the sonar imaging system will be particularly invaluable during dives to shallower sites where sediments stirred up by waves and weather can cut visibility from meters to centimeters. “It really reduces the risk of running into things accidentally,” says Paulson.

To experience the visibility conditions for yourself, check out recordings of the live video broadcast from the NEPTUNE maintenance cruise. Tetarenko says that next year they hope to broadcast not only the main camera feed but also one of the sonar images.

3D video could be next, according to Canpac ROV pilot and Jenny codesigner, James Barnett. He says they would need to boost the computing power installed topside, to process that “firehose of data,” but insists that real-time 3D is “definitely not impossible.” Tetarenko says the science ROV community is collaborating on software to help make that workable: “3D imagining is kind of the very latest thing that’s being tested on lots of ROV systems right now, but nobody’s really there yet.”

More Than Science

Expansion of the cabled observatory concept is the more certain technological legacy for ONC and NEPTUNE. In fact, the technology has evolved beyond just oceanography applications.

ONC tapped Alcatel Submarine Networks (ASN) to design and build the Neptune backbone and the French firm delivered a system that has reliably delivered multigigabit Ethernet plus 10 kilovolts of direct-current electricity to the deep sea. Today ASN deploys a second-generation subsea power and communications networking solution, developed with the Norwegian international energy company Equinor.

ASN’s “Direct Current/Fiber Optic” or DC/FO system provides the 100-km backbone for the ARCA subsea neutrino observatory near Sicily, in addition to providing control systems for a growing number of offshore oil and gas installations. The latter include projects led by Equinor and BP where DC/FO networks drive the subsea injection of captured carbon dioxide and monitor its storage below the seabed. Future oil and gas projects will increasingly rely on the cables’ power supply to replace the hydraulic lines that have traditionally been used to operate machinery on the seafloor, according to Ronan Michel, ASN’s product line manager for oil and gas solutions.

Michel says DC/FO incorporates important lessons learned from the Neptune installation. And the latter’s existence was a crucial prerequisite. “The DC/FO solution would probably not exist if Neptune Canada would not have been developed,” says Michel. “It probably gave confidence to Equinor that ASN was capable to develop subsea power and coms infrastructure.”

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