Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow and decreasing glomerular filtration rate (GFR) and liver blood flow, thereby altering the absorption, distribution, metabolism, and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g., muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation P = a_iHRⁱ was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. The pharmacokinetics of midazolam, quinidine, digoxin, and lidocaine during exercise were predicted by a whole-body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within the 5^th–95^th percentiles of the simulations, and the estimated peak concentrations (C_max) and area under the curve (AUC) of drugs were also within 0.5–2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time, and alterations in physiological parameters significantly affected drug pharmacokinetics and the net effect depending on drug characteristics and exercise conditions. In conclusion, the pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small-molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99- to 1.31-fold from clinical trial results for inhibition with itraconazole, whereas exposure predictions for the induction with rifampicin were less accurate, with deviations of 0.22- to 0.48-fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method.

Over the past 20 years, quantitative proteomics has contributed a wealth of protein expression data, which are currently used for a variety of systems pharmacology applications, as a complement or a surrogate for activity of the corresponding proteins. A symposium at the 25th North American International Society for the Study of Xenobiotics meeting, in Boston, in September 2023, was held to explore current and emerging applications of quantitative proteomics in translational pharmacology and strategies for improved integration into model-informed drug development based on practical experience of each of the presenters. A summary of the talks and discussions is presented in this perspective alongside future outlook that was outlined for future meetings.

ABSTRACTIntroduction:Health risks associated with short interpregnancy intervals, coupled with women’s desires to avoid pregnancy following childbirth, underscore the need for effective postpartum family planning programs. The antenatal period provides an opportunity to intervene; however, evidence is limited on the effectiveness of interventions aimed at reaching women in the antenatal period to increase voluntary postpartum family planning in low- and middle-income countries (LMICs). This systematic review aimed to identify and describe interventions in LMICs that attempted to increase postpartum contraceptive use via contacts with pregnant women in the antenatal period.Methods:Studies published from January 2012 to July 2022 were considered if they were conducted in LMICs, evaluated an intervention delivered during the antenatal period, were designed to affect postpartum contraceptive use, were experimental or quasi-experimental, and were published in French or English. The main outcome of interest was postpartum contraceptive use within 1 year after birth, defined as the use of any method of contraception at the time of data collection. We searched EMBASE, Global Health, and Medline and manually searched the reference lists from studies included in the full-text screening.Results:We double-screened 771 records and included 34 reports on 31 unique interventions in the review. Twenty-three studies were published from 2018 on, with 21 studies conducted in sub-Saharan Africa. Approximately half of the study designs (n=16) were randomized controlled trials, and half (n=15) were quasi-experimental. Interventions were heterogeneous. Among the 24 studies that reported on the main outcome of interest, 18 reported a positive intervention effect, with intervention recipients having greater contraceptive use in the first year postpartum.Conclusion:While the studies in this systematic review were heterogeneous, the findings suggest that interventions that included a multifaceted package of initiatives appeared to be most likely to have a positive effect.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperidine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left, whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine and d-methamphetamine discrimination dose-effect functions to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures.

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration–approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032–1.0 mg/kg), nalbuphine (0.32–10 mg/kg), buprenorphine (0.0032–0.032 mg/kg), methadone (0.32–1.0 mg/kg), or flumazenil (1–3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse–related behaviors.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7–10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain.

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.

Recent studies have demonstrated promising results of fibroblast activation protein (FAP) inhibitor (FAPI) PET in prognosticating and monitoring interstitial lung diseases (ILDs). As a first step toward successful translation, our primary aim was to validate the FAPI PET uptake through immunohistochemistry in patients with advanced ILD who underwent lung transplantation after a FAPI PET scan. Methods: This is a preliminary analysis of a single-center, open-label, single-arm, prospective exploratory biodistribution study of ⁶⁸Ga-FAPI-46 PET imaging in patients with ILD (NCT05365802). Patients with ILD confirmed by high-resolution CT and scheduled for lung transplant were included. Tissue samples of explanted lungs were obtained from both the central and peripheral lung parenchyma of each lobe. Additional samples were obtained from areas of the lung corresponding to regions of FAPI PET activity. Immunohistochemical staining was performed with an anti-FAP antibody. Percentages of FAP immunohistochemistry-positive area were measured semiautomatically using QuPath software. SUVs in the areas of pathologic samples were measured on FAPI PET/CT by referencing the gross photomap of the explanted lung. A Spearman correlation coefficient test was used to assess the relationship between FAPI PET uptake and FAP immunohistochemical expression in each specimen. Results: Four patients with advanced ILD who underwent FAPI PET/CT before lung transplantation were included. The types of ILD were idiopathic pulmonary fibrosis (n = 2), rheumatoid arthritis–associated ILD (n = 1), and nonspecific interstitial pneumonia (n = 1). FAPI uptake was visualized mainly in the fibrotic area on CT. Twenty-nine surgical pathology samples from 3 patients were analyzed. FAP staining was predominantly positive in fibroblastic foci. FAPI PET SUV_max and SUV_mean showed a positive correlation with the immunohistochemical FAP expression score (SUV_max: r = 0.57, P = 0.001; SUV_mean: r = 0.54, P = 0.002). Conclusion: In this analysis conducted in patients who underwent lung transplantation after a FAPI PET scan, FAPI PET uptake was positively correlated with FAP immunohistochemistry. These findings provide a rationale for further investigation of FAPI PET as a potential imaging biomarker for ILD.

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.

In Canada and across the globe, access to PSMA PET/CT is limited and expensive. For patients with biochemical recurrence (BCR) after treatment for prostate cancer, novel strategies are needed to better stratify patients who may or may not benefit from a PSMA PET scan. The role of the free-to-total prostate-specific antigen (PSA) ratio (FPSAR) in posttreatment prostate cancer, specifically in the PSMA PET/CT era, remains unknown. Our aim in this study was to determine the association of FPSAR in patients referred for ¹⁸F-DCFPyL PSMA PET/CT in the BCR setting and assess the correlation between FPSAR and ¹⁸F-DCFPyL PSMA PET/CT positivity (local recurrence or distant metastases). Methods: This prospective study included 137 patients who were referred for ¹⁸F-DCFPyL PSMA PET/CT and had BCR with a total PSA of less than 1 ng/mL after radical prostatectomy (RP) (including adjuvant or salvage radiotherapy). Blood samples were collected on the day of ¹⁸F-DCFPyL PSMA PET/CT. FPSAR was categorized as less than 0.10 or as 0.10 or more. A positive ¹⁸F-DCFPyL PSMA PET/CT scan was defined by a PROMISE classification lesion score of 2 or 3, irrespective of the site of increased tracer uptake (e.g., prostate, pelvic nodes, bone, or viscera). Results: Overall, 137 blood samples of patients with BCR after RP were analyzed to calculate FPSAR. The median age at ¹⁸F-DCFPyL PSMA PET/CT was 68.6 y (interquartile range, 63.0–72.4 y), and the median PSA at ¹⁸F-DCFPyL PSMA PET/CT was 0.3 ng/mL (interquartile range, 0.3–0.6 ng/mL). Eighty-six patients (62.8%) had an FPSAR of less than 0.10, whereas 51 patients (37.2%) had an FPSAR of 0.10 or more. An FPSAR of 0.10 or more was identified as an independent predictor of a positive ¹⁸F-DCFPyL PSMA PET/CT scan, with an odds ratio of 6.99 (95% CI, 2.96–16.51; P < 0.001). Conclusion: An FPSAR of 0.10 or more after RP independently correlated with increased odds of a positive ¹⁸F-DCFPyL PSMA PET/CT scan among BCR post-RP patients. These findings may offer an inexpensive method by which to triage access to ¹⁸F-DCFPyL PSMA PET/CT in jurisdictions where availability is not replete.

[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.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of ¹⁸F-labeled fibroblast activation protein inhibitor ([¹⁸F]AlF-NOTA-FAPI-04, denoted as ¹⁸F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent ¹⁸F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On ¹⁸F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUV_max (area under the curve [AUC], 0.87; P = 0.0026), SUV_peak (AUC, 0.89; P = 0.0017), SUV_mean (AUC, 0.88; P = 0.0021), TBR_max (AUC, 0.86; P = 0.0031), and TBR_mean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%–81.82% and specificities of 83.33%–100%. Changes in SUV_max (AUC, 0.81; P = 0.0116), SUV_peak (AUC, 0.82; P = 0.0097), SUV_mean (AUC, 0.81; P = 0.0116), and TBR_mean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: ¹⁸F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

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.

The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol–cytochrome c reductase, are particularly rare in humans. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Anorectal malformations (ARMs) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (syndromic ARM) or as a nonsyndromic entity (nonsyndromic ARM). Despite the well-recognized heritability of nonsyndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies. Genome sequencing identified a novel, paternally inherited heterozygous Caudal type Homeobox 2 (CDX2) variant (c.722A > G (p.Glu241Gly)), that was present in all three affected siblings. The variant identified in this family is absent from population databases and predicted to be damaging by most in silico pathogenicity tools. So far, only two other reports implicate variants in CDX2 with ARMs. Remarkably, the individuals described in these studies had similar clinical phenotypes and genetic alterations in CDX2. CDX2 encodes a transcription factor and is considered the master regulator of gastrointestinal development. This variant maps to the homeobox domain of the encoded protein, which is critical for interaction with DNA targets. Our finding provides a potential molecular diagnosis for this family's condition and supports the role of CDX2 in anorectal anomalies. It also highlights the clinical heterogeneity and variable penetrance of ARM predisposition variants, another well-documented phenomenon. Finally, it underscores the diagnostic utility of genomic profiling of ARMs to identify the genetic etiology of these defects.

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).

Here, we highlight the case of a 31-yr-old man who had clinical features of primary hypertrophic osteoarthropathy (PHOAR) and harbored a homozygous variant (c.38C > A, p.Ala13Glu) in the HPGD gene, as indicated by whole-exome sequencing (WES). This variant has been previously classified by our laboratory as a variant of uncertain significance (VUS). However, another patient with the same phenotype and the same homozygous variant in HPGD was subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands, and specificity of the phenotype for HPGD, all provide sufficient evidence to reclassify the HPGD c.38C > A, p.Ala13Glu variant as likely pathogenic.

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

T-lymphoblastic lymphoma (T-LLy) is the most common lymphoblastic lymphoma in children and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here, we discuss the case of a previously healthy 3-yr-old male who presented with mediastinal T-LLy with bilateral suprarenal masses. Following initial treatment, surgical biopsy of persisting adrenal masses revealed bilateral neuroblastoma (NBL). A clinical genetics panel for germline cancer predisposition did not identify any pathogenic variants. Combination large panel (864 genes) profiling analysis in the context of a precision oncology study revealed two novel likely pathogenic heterozygous variants: SMARCA4 c.1420-1G > T p.? and EZH2 c.1943G > C p.(Ile631Phefs*44). Somatic analysis revealed potential second hits/somatic variants in EZH2 (in the T-LLy) and a segmental loss in Chromosome 19p encompassing SMARCA4 (in the NBL). Synchronous cancers, especially at a young age, warrant genetic evaluation for cancer predisposition; enrollment in a precision oncology program assessing germline and tumor DNA can fulfill that purpose, particularly when standard first-line genetic testing is negative and in the setting of tumors that are not classic for common cancer predisposition syndromes.

Patient expectations of receiving antibiotics for common symptoms can trigger unnecessary use. We conducted a survey (n = 564) between January 2020 to June 2021 in public and private primary care clinics in Texas to study the prevalence and predictors of patients’ antibiotic expectations for common symptoms/illnesses. We surveyed Black patients (33%) and Hispanic/Latine patients (47%), and over 93% expected to receive an antibiotic for at least 1 of the 5 pre-defined symptoms/illnesses. Public clinic patients were nearly twice as likely to expect antibiotics for sore throat, diarrhea, and cold/flu than private clinic patients. Lack of knowledge of potential risks of antibiotic use was associated with increased antibiotic expectations for diarrhea (odds ratio [OR] = 1.6; 95% CI, 1.1-2.4) and cold/flu symptoms (OR = 2.9; 95% CI, 2.0-4.4). Lower education and inadequate health literacy were predictors of antibiotic expectations for diarrhea. Future antibiotic stewardship interventions should tailor patient education materials to include information on antibiotic risks and guidance on appropriate antibiotic indications.

The strength of reproductive isolation (RI) between two or more lineages during the process of speciation can vary by the ecological conditions. However, most speciation research has been limited to studying how ecologically dependent RI varies among a handful of broadly categorized environments. Very few studies consider the variability of RI and its effects on speciation at finer scales—that is, within each environment due to spatial or temporal environmental heterogeneity. Such variation in RI across time and/or space may inhibit speciation through leaky reproductive barriers or promote speciation by facilitating reinforcement. To investigate this overlooked aspect of speciation research, we conducted a literature review of existing studies of variation in RI in the field and then conducted individual-based simulations to examine how variation in hybrid fitness across time and space affects the degree of gene flow. Our simulations indicate that the presence of variation in hybrid fitness across space and time often leads to an increase in gene flow compared to scenarios where hybrid fitness remains static. This observation can be attributed to the convex relationship between the degree of gene flow and the strength of selection on hybrids. Our simulations also show that the effect of variation in RI on facilitating gene flow is most pronounced when RI, on average, is relatively low. This finding suggests that it could serve as an important mechanism to explain why the completion of speciation is often challenging. While direct empirical evidence documenting variation in extrinsic RI is limited, we contend that it is a prevalent yet underexplored phenomenon. We support this argument by proposing common scenarios in which RI is likely to exhibit variability and thus influence the process of speciation.

Redox reactions control fundamental biochemical processes, including energy production, metabolism, respiration, detoxification, and signal transduction. Cancer cells, due to their generally active metabolism for sustained proliferation, produce high levels of reactive oxygen species (ROS) compared to normal cells and are equipped with antioxidant defense systems to counteract the detrimental effects of ROS to maintain redox homeostasis. The KEAP1-NRF2 system plays a major role in sensing and regulating endogenous antioxidant defenses in both normal and cancer cells, creating a bivalent contribution of NRF2 to cancer prevention and therapy. Cancer cells hijack the NRF2-dependent antioxidant program and exploit a very unique metabolism as a trade-off for enhanced antioxidant capacity. This work provides an overview of redox metabolism in cancer cells, highlighting the role of the KEAP1-NRF2 system, selenoproteins, sulfur metabolism, heme/iron metabolism, and antioxidants. Finally, we describe therapeutic approaches that can be leveraged to target redox metabolism in cancer.

Advancements in immunotherapy in the perioperative setting have revolutionised the treatment of resectable nonsmall cell lung cancer (NSCLC). Here we present the methodology and results of the clinical trial CheckMate 816 demonstrating the benefit of neoadjuvant therapy with nivolumab plus chemotherapy compared with chemotherapy alone. Furthermore, this article discusses the implications for future practice in resectable NSCLC and the need for future research.

Bone marrow transplantation, now often known as haematopoietic stem cell transplantation (HSCT), is a complex choreographed procedure used to treat both acquired and inherited disorders of the bone marrow. It has proven invaluable as therapy for haematological and immunological disorders, and more recently in the treatment of metabolic and enzyme disorders. As the number of performed transplants grows annually, and with patients enjoying improved survival, a knowledge of both early and late complications of HSCT is essential for respiratory trainees and physicians in practice. This article highlights the spectrum of respiratory complications, both infectious and non-infectious, the timeline of their likely occurrence, and the approaches used for diagnosis and treatment, keeping in mind that more than one entity may occur simultaneously. As respiratory issues are often a leading cause of short- and long-term morbidity, consideration of a combined haematology/respiratory clinic may prove useful in this patient population.

The head of one of the world's largest oil companies has had it with government flip-flopping.

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JUDY WOODRUFF: But first: Sunday’s elections Austria were the latest ample of a shift to the right Europe’s politics, as 31-year-old Christian Kurz was elected chancellor on an anti-immigration platform.

He may now form a government with a far-right party founded in the 1950s by former Nazis.

That follows recent elections in Germany, where a far-right party roiled the race and dealt a blow to returning leader Angela Merkel.

In Sweden, too, there is a strong challenge from the right and a neo-Nazi group that looks stand in elections next year.

Special correspondent Malcolm Brabant ha been surveying the political landscape in Germany and Sweden, and he begins his report in Scandinavia.

MALCOLM BRABANT, Special Correspondent: In a Gothenburg parking lot, supporters of the Nordic Resistance Movement form up for what they hope will be their biggest-ever march, to propagate an ideology espoused by mother of eight Paulina Forslund.

PAULINA FORSLUND, Nordic Resistance Movement: When white becomes the minority, they will be destroyed. I want my children to have a secure future. I want them not only for them to have a secure Sweden. I want them to have a secure world. And I want other people to fight for the same thing.

MALCOLM BRABANT: When addressing her fellow neo-Nazis, Forslund’s rhetoric sharpens.

PAULINA FORSLUND (through interpreter): I’m the welder’s daughter, the forester’s grandchild. My line consists of hardworking men and women. It’s people like them we can thank for the welfare system that our lying politicians are now giving away to imported scum.

MALCOLM BRABANT: Clearly expecting trouble, the movement’s leaders have a muscular protection detail, marching past a silent protest. The sign reads “No Nazis on our streets.”

This protester would only give her name as Johanna.

JOHANNA, Anti-Nazi Protester: They are racist people. They are people who think that certain people are better than others, and I will not stand for that. It’s not something I think has a place in a modern society.

MALCOLM BRABANT: Experts say the resistance movement is recruiting aggressively, and believe this demonstration is emblematic of the rise of the far right.

It took place on Yom Kippur, the Jewish day of atonement.

Allan Stutzinky is leader of Gothenburg’s Jewish community.

ALLAN STUTZINKY, Jewish Community Leader (through interpreter): Nazism has returned. The descendants of the murderers are organizing the same marches today, waving the same flags, shouting the same slogans, and have the same racist agenda.

MALCOLM BRABANT: Anna Johansson is a member of the governing Social Democrat Party. It’s considering outlawing the Nordic Resistance Movement.

ANNA JOHANSSON, Swedish Social Democratic Party: In Sweden and in Denmark, and in other countries, extreme parties are growing, and the hatred is spreading around.

MALCOLM BRABANT: “Go home to mama,” he shouts. “Nazi pigs,” chant the anti- fascist protesters, as a bottle flies through the air.

DAMON, Nordic Resistance Movement: If someone calls themselves a Nazi, most of us would dissociate with that person. That’s nothing we stand for ourselves. I never call myself a Nazi. I’m a national socialist.

MALCOLM BRABANT: Hitler’s party was also called National Socialist, but Damon, a 40-year-old welder, insists he’s a nonviolent family man.

DAMON: The demographic landscape of our — of the whole of Europe is changing, so, basically, it’s a concern on preserving my heritage for my family and our kin.

MALCOLM BRABANT: This demonstration has been stopped short of its destination. The Nordic Resistance Movement is currently trapped between a line of police and anti-fascist protesters. And it looks as though this demonstration isn’t going any further.

Violence briefly erupts as the resistance movement tries to break through police lines, and several marchers are arrested.

PAULINA FORSLUND: We are not your enemy. We are the government’s enemy.

They say we live in a democracy, but we have never had an election about if we want to take all these people in.

MALCOLM BRABANT: When Europe’s refugee crisis began in 2015, Sweden copied Germany’s open-door policy, and 160,000 migrants entered the country. Two years on, Sweden has tighter borders and has begun deporting some of the newcomers.

The new atmosphere alarms Floid Gumbo, entertaining an anti-Nazi rally.

FLOID GUMBO, Singer Originally from Zimbabwe: I came to Sweden over 20 years ago. The climate in Sweden, the people were so friendly, and things were completely different, more welcoming. And I feel like things have sort of gradually changed.

I’m very concerned, because I have children, because I’m thinking what I experienced here is not the same kind of climate, atmosphere that they are going to experience here.

ANNA JOHANSSON: It’s not so long ago that the Nazis ruined Europe. And that makes me very worried. The German elections were terrifying, I think.

MALCOLM BRABANT: Johansson is referring to last month’s success of the right-wing Alternative For Germany Party, or AFD, when it entered Parliament for the first time with 13 percent of the vote.

HUGH BRONSON, Alternative For Germany Party: The AFD only came into existence because Merkel deserted the traditional conservative Christian voters. They were looking for a home, and the AFD has offered them a safe place.

MALCOLM BRABANT: Hugh Bronson is deputy leader of the AFD in Berlin.

Now his party, the third largest in Parliament, is demanding that Angela Merkel imposes tougher immigration rules.

Your opponents claim that you are a party of hate. What’s your response to that?

HUGH BRONSON: We embrace foreigners who respect our laws, pay their taxes, send their children to school, and go about their normal life. The problem is with people who abuse the system to have a better life, or let others pay for their better lives, or who are criminals.

MALCOLM BRABANT: Outside the opera house in Dresden, former East Germany, singer Luca Bergelt is dismayed by the political landscape shifting to the right.

LUCA BERGELT, Singer: My fear is that they will tear Europe apart. They are going to raise up the walls again. They’re going to build new walls between the countries, and that Europe will get more close into itself.

MALCOLM BRABANT: Anti-immigrant sentiment is strong in Dresden. The city was the birthplace of a pan-European anti-Islamic movement, and it delivered the largest number of votes for the right-wing party.

On a holiday to celebrate German unification after the fall of communism, retired engineer Wilfried Schmidt explained why he sent a message to Angela Merkel.

WILFRIED SCHMIDT, Retired Engineer (through interpretor): Let’s put it this way. We all need to recognize that Germany is undergoing social changes that are becoming harder to control. For one, there is mass immigration from difficult regions that is increasingly uncontrollable, of people with entirely different concepts of life, from fundamental differently structured societies that are problematic.

MALCOLM BRABANT: About one million migrants poured into Germany in 2015. Chancellor Merkel consistently defended her pro-refugee policies, but now she has been punished by voters who believe she ignored their concerns.

Chancellor Merkel has promised to listen to the people who voted for the AFD, and she says she’s going to try to win them over with what she calls good politics. But she will not countenance having the party in her coalition.

But the chancellor needs to find new partners who are prepared to be tough on immigration.

As she tries to forge a coalition, the chancellor has agreed to put an annual cap of 200,000 on the number of immigrants, something she previously refused to do. But will it be enough to woo back people who deserted her at the election?

A question for Werner Patzelt, a political scientist at Dresden University.

WERNER PATZELT, Dresden University: Since Chancellor Merkel has made so many U-turns in German domestic politics, it wouldn’t be a surprise if she would try to do a U-turn, also winning back AFD voters.

But this is a really hard political task, because so many of them are so much disappointed by the Christian Democratic Union in general, and by Chancellor Merkel in particular, that they will do anything to avoid going back.

MALCOLM BRABANT: Back in Sweden, the governing party is horrified at the concept of conceding ground to right-wingers, and is trying to isolate them.

ANNA JOHANSSON: Experience shows that, when you adopt the ideas from these right-wing parties, they spread. These parties have their agenda implemented by other parties. And I wouldn’t want to see that happen in Sweden.

FLOID GUMBO: We’re all human beings. We share this world. We’re all here. There’s enough space for us all.

MALCOLM BRABANT: But that’s an appeal that an increasing number of Swedes are rejecting, as the country and much of Europe go through a crisis of identity.

For the PBS NewsHour, I’m Malcolm Brabant in Gothenburg.

The post Far-right groups gain ground in Sweden and Germany amid migrant influx appeared first on PBS NewsHour.

Two thirds of Celtic fans believe the club should have an independently elected Fan Advisory Board according to new research from the University of Glasgow.

Human rights campaigners are calling on SNP ministers to do all they can to “mitigate” Prevent, the UK Government's controversial anti-terror strategy.

International numbers are on the up but not everything in tourism is rosy

The plane is hailed as 'one of the most advanced aircraft available on the market'

Join Anna Marie, Chris, Josh, and Kelley this week, as things get a little weirder than usual. A sticky soda fracas kicks off the show. Meanwhile, Kelley runs the news section for the first time, which is good since Chris stomps off after discovering this is definitely the worst timeline of them all. And don't forget, #JRPGJuly continues for one more week!

The post RPG Cast – Episode 551: “I Don’t Want the Moe Future” appeared first on RPGamer.

Anna Marie briefly stops by to tell us about what she's been playing while recovering. The Series X has a price now, will the PS5 get one this week? Also, PAX is happening!

The post RPG Cast – Episode 555: “Kelley Just Wants to Fight You” appeared first on RPGamer.

Pascal falls asleep while playing every game except one. Chris knows nothing about pretty much every game. Matt needs to put some clothes on. And Josh gets a salt lick. Man this chafing sucks.

The post RPG Cast – Episode 583: “Tight Pants” appeared first on RPGamer.

What's the podcast trio been up to this week? Chris is now a punchy demi-fiend, Kelley muses if Scamper is part plumber, and Anna Marie campaigns on Hades for everyone. Also, stoats continue to be extremely cute.

The post RPG Cast – Episode 598: “I Want an Ermine With Angry Eyebrows” appeared first on RPGamer.

Kelley "accidentally" barbecues her horse. Josh slaps "Trails" onto Horizon: Forbidden West to get Americans to play it. Jason has to go get a tako taco.

The post RPG Cast – Episode 677: “My Parents Thought Final Fantasy Tactics Was a Strategy Guide” appeared first on RPGamer.

Chris kink-shames Red XIII. Kelley violates the time space continuum with cat cafes. Josh is better at keeping things afloat than Embracer Group. Robert fails at being family friendly.

The post RPG Cast – Episode 711: “I’ve Always Wanted a Gaming Napkin” appeared first on RPGamer.

Kelley eats radioactive sushi. Chris tries to learn what a "zound" is. Josh goes to the Millennium tower one last time and rips off his shirt. Johnathan makes his bi-annual visit to Suiko-shame Chris.

The post RPG Cast – Episode 724: “Can I Sell You a Battle Pass Warranty?” appeared first on RPGamer.

Square Enix has revealed the lifetime sales for two of its biggest franchises Final Fantasy and Dragon Quest.

The Final Fantasy series has now sold over 195 million units worldwide and the Dragon Quest series has sold over 91 million units worldwide.

"The Square Enix Group also boasts a valuable portfolio of intellectual property including: Final Fantasy, which has sold over 195 million units worldwide; Dragon Quest, which has sold over 91 million units worldwide; and the legendary Space Invaders," said Square Enix.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463021/final-fantasy-series-sales-top-195m-dragon-quest-series-tops-91m/

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/

Republican vice presidential candidate JD Vance boldly said “no,” Donald Trump did not lose the 2020 election, when pressed on the issue at a campaign event Wednesday in Williamsport, Pennsylvania.

The Ohio senator has avoided directly denying the results over the past few weeks.

When quizzed by The New York Times about the results over the weekend, for example, he refused multiple times to answer the question, on one occasion claiming he was “focused on the future”—echoing an answer he gave to Democratic opponent Tim Walz at the vice presidential debate.

Read more at The Daily Beast.

The Steam Deck is something of a talisman for gaming on Linux, its popularity and penguin-powered SteamOS having almost singlehandedly dragged it past MacOS as the second-most-used operating system among Steam users. Sadly, this also means the Valve handheld is the primary casualty when developers decide to stop bothering with Linux support, as Respawn Entertainment have decided to do for Apex Legends.

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One of my lesser quality tests for an RPG is whether the shopkeepers complain at you for not buying anything. Grumpy shopkeepers, good RPG. This most specific of litmus tests has served me well, although I must admit that I’d happily upgrade it to ‘shopkeepers you can attack’, would that not disqualify 99% of games. But not turn based dungeon crawler Thysiastery, it turns out. This “dungeon crawler RPG featuring traditional roguelike and turn-based gameplay” apparently trusts you enough to let you recklessly batter its friendly wandering lizard merchants. You’d be a monster for it, of course, but it’s nice to have options.

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