Title: Mental Health Issues Can Plague Families of Kids With Type 1 Diabetes
Category: Health News
Created: 8/5/2022 12:00:00 AM
Last Editorial Review: 8/5/2022 12:00:00 AM

Title: Certain Painkillers Raise Heart Failure Risk in People With Type 2 Diabetes
Category: Health News
Created: 8/24/2022 12:00:00 AM
Last Editorial Review: 8/24/2022 12:00:00 AM

Title: Rural Americans With Early Alzheimer's Find It Tough to See Specialists
Category: Health News
Created: 8/9/2022 12:00:00 AM
Last Editorial Review: 8/9/2022 12:00:00 AM

Title: AHA News: People With Dementia May Be Less Likely to Receive an Advanced Treatment For Stroke
Category: Health News
Created: 8/24/2022 12:00:00 AM
Last Editorial Review: 8/24/2022 12:00:00 AM

Title: Monkeypox Cases May Finally Be Ebbing, With Declines Seen in Europe, WHO Says
Category: Health News
Created: 8/25/2022 12:00:00 AM
Last Editorial Review: 8/25/2022 12:00:00 AM

Title: COVID Breakthrough Infections More Likely in People Living With HIV
Category: Health News
Created: 6/8/2022 12:00:00 AM
Last Editorial Review: 6/9/2022 12:00:00 AM

Title: New Approach Cuts Odds for Anal Cancer in People With HIV
Category: Health News
Created: 6/16/2022 12:00:00 AM
Last Editorial Review: 6/16/2022 12:00:00 AM

Title: Pets Have Helped People With HIV Through Two Pandemics
Category: Health News
Created: 6/23/2022 12:00:00 AM
Last Editorial Review: 6/23/2022 12:00:00 AM

Title: How Does a Man Deal With Menopause?
Category: Diseases and Conditions
Created: 4/27/2022 12:00:00 AM
Last Editorial Review: 4/27/2022 12:00:00 AM

Title: Menopause Linked With Higher Alzheimer's Risk
Category: Health News
Created: 6/30/2022 12:00:00 AM
Last Editorial Review: 6/30/2022 12:00:00 AM

Title: Health Conditions a Dentist Might Find That Have Nothing to Do With Your Teeth
Category: Health News
Created: 8/11/2022 12:00:00 AM
Last Editorial Review: 8/12/2022 12:00:00 AM

Title: 9 Vitamins That May Help With Vaginal Dryness
Category: Health and Living
Created: 8/3/2022 12:00:00 AM
Last Editorial Review: 8/3/2022 12:00:00 AM

Title: Kids With ADHD Have Differences in 'Neural Flexibility,' Brain Study Shows
Category: Health News
Created: 7/29/2022 12:00:00 AM
Last Editorial Review: 8/1/2022 12:00:00 AM

Title: witch hazel
Category: Medications
Created: 8/18/2022 12:00:00 AM
Last Editorial Review: 8/18/2022 12:00:00 AM

Pulmonary hypertension (PH) is highly prevalent in patients with interstitial lung disease (ILD) and is associated with increased morbidity and mortality. Widely available noninvasive screening tools are warranted to identify patients at risk for PH, especially severe PH, that could be managed at expert centres. This review summarises current evidence on noninvasive diagnostic modalities and prediction models for the timely detection of PH in patients with ILD. It critically evaluates these approaches and discusses future perspectives in the field. A comprehensive literature search was carried out in PubMed and Scopus, identifying 39 articles that fulfilled inclusion criteria. There is currently no single noninvasive test capable of accurately detecting and diagnosing PH in ILD patients. Estimated right ventricular pressure (RVSP) on Doppler echocardiography remains the single most predictive factor of PH, with other indirect echocardiographic markers increasing its diagnostic accuracy. However, RVSP can be difficult to estimate in patients due to suboptimal views from extensive lung disease. The majority of existing composite scores, including variables obtained from chest computed tomography, pulmonary function tests and cardiopulmonary exercise tests, were derived from retrospective studies, whilst lacking validation in external cohorts. Only two available scores, one based on a stepwise echocardiographic approach and the other on functional parameters, predicted the presence of PH with sufficient accuracy and used a validation cohort. Although several methodological limitations prohibit their generalisability, their use may help physicians to detect PH earlier. Further research on the potential of artificial intelligence may guide a more tailored approach, for timely PH diagnosis.

Bronchiectasis is a chronic lung condition which is characterised by recurrent chest infections, chronic sputum production and cough, and limited exercise tolerance. While bronchiectasis may be caused by various aetiologies, these features are shared by most patients with bronchiectasis regardless of the cause. This review consolidates the existing evidence on patient-managed interventions for adults with bronchiectasis, while also outlining areas for future research. Airway clearance techniques and hyperosmolar agents are key components of the bronchiectasis management and consistently recommended for clinical implementation. Questions around their prescription, such as optimal sequence of delivery, are still to be answered. Pulmonary rehabilitation and exercise are also recommended for patients with bronchiectasis. Relatively strong evidence underpins this recommendation during a clinically stable stage of the disease, although the role of pulmonary rehabilitation following an exacerbation is still unclear. Additionally, self-management programmes feature prominently in bronchiectasis treatment, yet the lack of consensus regarding their definition and outcomes presents hurdles to establishing a cohesive evidence base. Moreover, cough, a cardinal symptom of bronchiectasis, warrants closer examination. Although managing cough in bronchiectasis may initially appear risky, further research is necessary to ascertain whether strategies employed in other respiratory conditions can be safely and effectively adapted to bronchiectasis, particularly through identifying patient responder populations and criteria where cough may not enhance airway clearance efficacy and its control is needed. Overall, there is a growing recognition of the importance of patient-managed interventions in the bronchiectasis management. Efforts to improve research methodologies and increase research funding are needed to further advance our understanding of these interventions, and their role in optimising patient care and outcomes.

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

Background

In adults with serious respiratory illness, fatigue is prevalent and under-recognised, with few treatment options. The aim of this review was to assess the impact of graded exercise therapy (GET) on fatigue in adults with serious respiratory illness.

Background

In adults with serious respiratory illness, breathlessness is prevalent and associated with reduced health-related quality of life. The aim of this review was to assess the impact of breathing techniques on breathlessness in adults with serious respiratory illness.

Background

People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear.

Understanding the evolution of chromatin conformation among species is fundamental to elucidate the architecture and plasticity of genomes. Nonrandom interactions of linearly distant loci regulate gene function in species-specific patterns, affecting genome function, evolution, and, ultimately, speciation. Yet, data from nonmodel organisms are scarce. To capture the macroevolutionary diversity of vertebrate chromatin conformation, here we generate de novo genome assemblies for two cryptodiran (hidden-neck) turtles via Illumina sequencing, chromosome conformation capture, and RNA-seq: Apalone spinifera (ZZ/ZW, 2n = 66) and Staurotypus triporcatus (XX/XY, 2n = 54). We detected differences in the three-dimensional (3D) chromatin structure in turtles compared to other amniotes beyond the fusion/fission events detected in the linear genomes. Namely, whole-genome comparisons revealed distinct trends of chromosome rearrangements in turtles: (1) a low rate of genome reshuffling in Apalone (Trionychidae) whose karyotype is highly conserved when compared to chicken (likely ancestral for turtles), and (2) a moderate rate of fusions/fissions in Staurotypus (Kinosternidae) and Trachemys scripta (Emydidae). Furthermore, we identified a chromosome folding pattern that enables "centromere–telomere interactions" previously undetected in turtles. The combined turtle pattern of "centromere–telomere interactions" (discovered here) plus "centromere clustering" (previously reported in sauropsids) is novel for amniotes and it counters previous hypotheses about amniote 3D chromatin structure. We hypothesize that the divergent pattern found in turtles originated from an amniote ancestral state defined by a nuclear configuration with extensive associations among microchromosomes that were preserved upon the reshuffling of the linear genome.

Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is owing to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.

The 10q11.22 chromosomal region is a duplication-rich interval of the human genome and one of the last to be fully assembled. It carries copy number–variable genes associated with intellectual disability, bipolar disorder, and obesity. In this study, we characterized the structural diversity at this locus by analyzing 64 haploid assemblies produced by the Human Pangenome Reference Consortium. We identified 11 alternative haplotypes that differ in the copy number and/or orientation of large genomic segments, ranging from hundreds of kilobase pairs (kbp) to over one megabase pair (Mbp). We uncovered a 2.4 Mbp size difference between the shortest and longest haplotypes. Breakpoint analysis revealed that genomic instability results from nonallelic homologous recombination between segmental duplication (SD) pairs with varying similarity (94.4%–99.6%). Nonetheless, these pairs generally recombine at positions where their identity is higher (>99.6%). Recurrent inversions occur with different breakpoints within the same inverted SD pair. Inversion polymorphisms shuffle the entire SD arrangement, creating new predispositions to copy-number variations. The SD architecture is associated with a catarrhine-specific subgroup of the AGAP gene family, which likely triggered the accumulation of SDs at this locus over the past 25 million years of human evolution. Our results reveal extensive structural diversity and genomic instability at the 10q11.22 locus, and expand the general understanding of the mutational mechanisms behind SD-mediated rearrangements.

Two decades into the era of Electronic Health Records (EHRs), the promise of streamlining clinical care, reducing burden, and improving patient outcomes has yet to be realized. A cross-sectional family physician census conducted by the American Board of Family Medicine in 2022 and 2023 included self-reported physician EHR satisfaction. Of the nearly 10,000 responding family physicians, only one-in-four (26.2%) report being very satisfied and one-in-three (33.8%) were not satisfied. These low levels of satisfaction point to the need for greater transparency in the marketplace and pressure to increase user-centric EHR design.

BACKGROUND:Home noninvasive ventilation (NIV) may improve chronic hypercarbia in COPD and patient-important outcomes. The efficacy of home high-flow nasal cannula (HFNC) as an alternative is unclear.METHODS:We searched MEDLINE, Embase, Cochrane CENTRAL, Scopus, and ClinicalTrials.gov for randomized trials of subjects from inception to March 31, 2023, and updated the search on July 14, 2023. We performed a frequentist network meta-analysis and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We analyzed randomized controlled trials (RCTs) comparing NIV, HFNC, or standard care in adult subjects with COPD with chronic hypercapnic respiratory failure. Outcomes included mortality, COPD exacerbations, hospitalizations, and quality of life (St George Respiratory Questionnaire [SGRQ]).RESULTS:We analyzed 24 RCTs (1,850 subjects). We found that NIV may reduce the risk of death compared to standard care (relative risk 0.82 [95% CI 0.66–1.00]) and probably reduces exacerbations (relative risk 0.71 [95% CI 0.58–0.87]). HFNC probably reduces exacerbations compared to standard care (relative risk 0.77 [0.68–0.88]), but its effect on mortality is uncertain (relative risk 1.20 [95% CI 0.63–2.28]). HFNC probably improves SGRQ scores (mean difference −7.01 [95% CI −12.27 to −1.77]) and may reduce hospitalizations (relative risk 0.87 [0.69–1.09]) compared to standard care. No significant difference was observed between HFNC and NIV in reducing exacerbations.CONCLUSIONS:Both NIV and HFNC reduce exacerbation risks in subjects with COPD compared to standard care. HFNC may offer advantages in improving quality of life.

COPD and asthma are two of the most common chronic lung diseases, affecting over 545 million people globally and 34 million in the United States. Annual health care costs related to chronic lung disease are estimated at €380 billion in the European Union, and $24–$50 billion in the United States averaging to $4,000 in out-of-pocket costs per person in the U.S. A full-text literature search was conducted for English publications between January 1, 2005–March 18, 2024. It returned over 5,000 publications that were further narrowed using key search words, resulting in 172 peer-reviewed articles. Using their experience and subject expertise, the authors further narrowed the peer-reviewed articles to 55 that were in their opinion relevant. Also, 38 recently published industry reports and news articles specific to downstream effects of inhaler market changes and the future impact were included. The literature suggests that individuals with chronic lung disease face increased challenges with access to inhaled medication due to rising medication costs, discontinuation of branded medications, introduction of generic medications not covered by insurance, exclusionary preferred drug list tactics that force health care providers into non-medical switching of medication or devices, and ongoing medication shortages. Providers experience ongoing hurdles in prescribing appropriate inhaled medications for individuals with chronic lung disease, including increased time and costs spent on administrative tasks due to inhaler denials, a loss of patient trust, and limits on their ability to prescribe appropriate inhaled medication for individuals with chronic lung disease.

BACKGROUND:Post–COVID-19 syndrome has affected millions of people, with rehabilitation being at the center of non-pharmacologic care. However, numerous published studies show conflicting results due to, among other factors, considerable variation in subject characteristics. Currently, the effects of age, sex, time of implementation, and prior disease severity on the outcomes of a supervised rehabilitation program after COVID-19 remain unknown.METHODS:This was a non-randomized case-control study. Subjects with post–COVID-19 sequelae were enrolled. Among study participants, those who could attend an 8-week, supervised rehabilitation program composed the intervention group, whereas those who couldn’t the control group. Measurements were collected at baseline and 8 weeks thereafter.RESULTS:Study groups (N = 119) had similar baseline measurements. Participation in rehabilitation (n = 47) was associated with clinically important improvements in the 6-min walk test (6MWT) distance, adjusted (for potential confounders) odds ratio (AOR) 4.56 (95% CI 1.95–10.66); 1-min sit-to-stand test, AOR 4.64 (1.88-11.48); Short Physical Performance Battery, AOR 7.93 (2.82–22.26); health-related quality of life (HRQOL) 5-level EuroQol-5D (Visual Analog Scale), AOR 3.12 (1.37–7.08); Montreal Cognitive Assessment, AOR 6.25 (2.16–18.04); International Physical Activity Questionnaire, AOR 3.63 (1.53–8.59); Fatigue Severity Scale, AOR 4.07 (1.51–10.98); Chalder Fatigue Scale (bimodal score), AOR 3.33 (1.45–7.67); Modified Medical Research Council dyspnea scale (mMRC), AOR 4.43 (1.83–10.74); Post–COVID-19 Functional Scale (PCFS), AOR 3.46 (1.51–7.95); and COPD Assessment Test, AOR 7.40 (2.92–18.75). Time from disease onset was marginally associated only with 6MWT distance, AOR 0.99 (0.99–1.00). Prior hospitalization was associated with clinically important improvements in the mMRC dyspnea scale, AOR 3.50 (1.06–11.51); and PCFS, AOR 3.42 (1.16–10.06). Age, sex, and ICU admission were not associated with the results of any of the aforementioned tests/grading scales.CONCLUSIONS:In this non-randomized, case-control study, post–COVID-19 rehabilitation was associated with improvements in physical function, activity, HRQOL, respiratory symptoms, fatigue, and cognitive impairment. These associations were observed independently of timing of rehabilitation, age, sex, prior hospitalization, and ICU admission.

Purpose Health care professionals (HCPs) working collaboratively can improve patient outcomes and also increase their understanding of each other’s professional roles. This descriptive study aimed to explore dental hygienists’ perceptions of collaboration with dentists and intraprofessional educational (IntraPE) experiences.Methods A convenience sampling method was used to assess DHs perceptions of collaboration with dentists using the Interprofessional Collaboration Scale (ICS), a validated scale that measures perceptions of communication, accommodation, and isolation among HCPs. One open-ended question was added to explore IntraPE. Demographics, work characteristics and responses from the ICS were analyzed using frequency, mean, standard deviation, Pearson’s correlation, t-test, ANOVA, and multivariable regression. Responses from the open-ended question were transcribed, organized, and coded. Themes were identified using the Delve Qualitative Analysis Tool.Results Of the 264 participants, the average age was 38.9, and most identified as female (98.9%). Data analysis revealed that DHs had positive perceptions of collaboration with dentists. Significant relationships were found between ICS factor accommodation and the average number of patients treated per day (rs = −0.242, p<0.001), dentists’ age (rs = −.145, p<0.05). Isolation showed a significant negative correlation with the average number of patients treated per day (rs = −0.156, p<0.05). Most reported having no opportunities for IntraPE education experiences with dentists. Five categories of themes were identified from the open-ended question: shared academic setting, clinic dentist, externships, desire for more shared learning, and shared patient experiences.Conclusion Dental hygienists in this study had an overall more positive than negative perception of collaboration with dentists. Dental and dental hygiene programs should focus on intraprofessional education experiences to continue to enhance collaboration.

Massively parallel reporter assays (MPRAs) are powerful tools for quantifying the impacts of sequence variation on gene expression. Reading out molecular phenotypes with sequencing enables interrogating the impact of sequence variation beyond genome scale. Machine learning models integrate and codify information learned from MPRAs and enable generalization by predicting sequences outside the training data set. Models can provide a quantitative understanding of cis-regulatory codes controlling gene expression, enable variant stratification, and guide the design of synthetic regulatory elements for applications from synthetic biology to mRNA and gene therapy. This review focuses on cis-regulatory MPRAs, particularly those that interrogate cotranscriptional and post-transcriptional processes: alternative splicing, cleavage and polyadenylation, translation, and mRNA decay.

End-to-end RNA-sequencing methods that capture 5'-sequence content without cumbersome library manipulations are of great interest, particularly for analysis of long RNAs. While template-switching methods have been developed for RNA sequencing by distributive short-read RTs, such as the MMLV RTs used in SMART-Seq methods, they have not been adapted to leverage the power of ultraprocessive RTs, such as those derived from group II introns. To facilitate this transition, we dissected the individual processes that guide the enzymatic specificity and efficiency of the multistep template-switching reaction carried out by RTs, in this case, by MarathonRT. Remarkably, this is the first study of its kind, for any RT. First, we characterized the nucleotide specificity of nontemplated addition (NTA) reaction that occurs when the RT extends past the RNA 5'-terminus. We then evaluated the binding specificity of specialized template-switching oligonucleotides, optimizing their sequences and chemical properties to guide efficient template-switching reaction. Having dissected and optimized these individual steps, we then unified them into a procedure for performing RNA sequencing with MarathonRT enzymes, using a well-characterized RNA reference set. The resulting reads span a six-log range in transcript concentration and accurately represent the input RNA identities in both length and composition. We also performed RNA-seq from total human RNA and poly(A)-enriched RNA, with short- and long-read sequencing demonstrating that MarathonRT enhances the discovery of unseen RNA molecules by conventional RT. Altogether, we have generated a new pipeline for rapid, accurate sequencing of complex RNA libraries containing mixtures of long RNA transcripts.

Introduction

Exacerbation of COPD complicated by respiratory acidaemia is the commonest indication for noninvasive ventilation (NIV). The NIV outcomes (NIVO) score offers the best estimate of survival for those ventilated. Unfortunately, two-thirds of cases of COPD are unrecognised, and patients may present without COPD having been confirmed by spirometry.

Background

Quality of life is impaired in patients with sarcoidosis. The King's Sarcoidosis Questionnaire (KSQ) is a brief questionnaire assessing health-related quality of life in patients with sarcoidosis, comprising subdomains of General Health Status (GHS), Lung, Medication, Skin and Eyes. The aim of this study was to enhance the validation of the KSQ, incorporating longitudinal validation and known-groups validity in a cohort with mild sarcoidosis.

The management of chylothorax remains challenging given the limited evidence and significant heterogeneity in practice. In addition, there are no practical guidelines on the optimal approach to manage this complex condition. We convened an international group of 27 experts from 20 institutions across five countries and four specialties (pulmonary, interventional radiology, thoracic surgery and nutrition) with experience and expertise in managing adult patients with chylothorax. We performed a literature and internet search for reports addressing seven clinically relevant PICO (Patient, Intervention, Comparison and Outcome) questions pertaining to the management of adult patients with chylothorax. This consensus statement, consisting of best practice statements based on expert consensus addressing these seven PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience. Panel members participated in the development of the final best practice statements using the modified Delphi technique. Our consensus statement aims to offer guidance in clinical decision making when managing patients with chylothorax while also identifying gaps in knowledge and informing future research.

Hepatocyte nuclear factor 4 alpha antisense 1 (HNF4A-AS1) is a long noncoding RNA (lncRNA) gene physically located next to the transcription factor HNF4A gene in the human genome. Its transcription products have been reported to inhibit the progression of hepatocellular carcinoma (HCC) and negatively regulate the expression of cytochrome P450s (CYPs), including CYP1A2, 2B6, 2C9, 2C19, 2E1, and 3A4. By altering CYP expression, lncRNA HNF4A-AS1 also contributes to the susceptibility of drug-induced liver injury. Thus, HNF4A-AS1 lncRNA is a promising target for controlling HCC and modulating drug metabolism. However, HNF4A-AS1 has four annotated alternative transcripts in the human genome browsers, and it is unclear which transcripts the small interfering RNAs or small hairpin RNAs used in the previous studies are silenced and which transcripts should be used as the target. In this study, four annotated and two newly identified transcripts were confirmed. These six transcripts showed different expression levels in different liver disease conditions, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and obesity. The expression patterns of all HNF4A-AS1 transcripts were further investigated in liver cell growth from human embryonic stem cells to matured hepatocyte-like cells, HepaRG differentiation, and exposure to rifampicin treatment. Several HNF4A-AS1 transcripts highly displayed correlations with these situations. In addition, some of the HNF4A-AS1 transcripts also showed a strong correlation with CYP3A4 during HepaRG maturation and rifampicin exposure. Our findings provide valuable insights into the specific roles of HNF4A-AS1 transcripts, paving the way for more targeted therapeutic strategies for liver diseases and drug metabolism.

Drug–drug interaction (DDI) assessment of therapeutic peptides is an evolving area. The industry generally follows DDI guidelines for small molecules, but the translation of data generated with commonly used in vitro systems to in vivo is sparse. In the current study, we investigated the ability of advanced human hepatocyte in vitro systems, namely HepatoPac, spheroids, and Liver-on-a-chip, to assess potential changes in regulation of CYP1A2, CYP2B6, CYP3A4, SLCO1B1, and ABCC2 in the presence of selected therapeutic peptides, proteins, and small molecules. The peptide NN1177, a glucagon and GLP-1 receptor co-agonist, did not suppress mRNA expression or activity of CYP1A2, CYP2B6, and CYP3A4 in HepatoPac, spheroids, or Liver-on-a-chip; these findings were in contrast to the data obtained in sandwich cultured hepatocytes. No effect of NN1177 on SLCO1B1 and ABCC2 mRNA was observed in any of the complex systems. The induction magnitude differed across the systems (e.g., rifampicin induction of CYP3A4 mRNA ranged from 2.8-fold in spheroids to 81.2-fold in Liver-on-a-chip). Small molecules, obeticholic acid and abemaciclib, showed varying responses in HepatoPac, spheroids, and Liver-on-a-chip, indicating a need for EC₅₀ determinations to fully assess translatability data. HepatoPac, the most extensively investigated in this study (3 donors), showed high potential to investigate DDIs associated with CYP regulation by therapeutic peptides. Spheroids and Liver-on-a-chip were only assessed in one hepatocyte donor and further evaluations are required to confirm their potential. This study establishes an excellent foundation toward the establishment of more clinically-relevant in vitro tools for evaluation of potential DDIs with therapeutic peptides.

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na⁺/K⁺-ATPase (IUBMB Enzyme Nomenclature). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (k_on), dissociation rate (k_off), and equilibrium (K_i) constants of CTS for the structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of K_i of the cardenolides digitoxigenin, essentially due to a reduction of k_on. In contrast, the K_i of the structurally related bufadienolide bufalin increased much less due to the reduction of its k_off partially compensating the decrease of its k_on. When evaluating the kinetics of 15 natural and semisynthetic CTS, we observed that both k_on and k_off correlated with K_i (Spearman test), suggesting that differences in potency depend on variations of both k_on and k_off. A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of k_off rather than an increase of k_on. Raising the temperature did not alter the k_off of digitoxin, generating a H (k_off) of –10.4 ± 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of k_on, k_off, and K_i of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds.

ABSTRACTThe private health care sector is an important source of service delivery in low- and middle-income countries (LMICs). Yet, the private sector remains fragmented, making it difficult for health system actors to support and ensure the availability of quality health care services. In global health programs, social franchising is one model used to engage and organize the private health care sector. Two social franchise networks, ProFam in West Africa and Tunza in East and Central Africa, provide health care through branded networks of facilities. However, these social franchise networks include a limited number of private health care facilities, and in fragile contexts, like Burundi and Mali, they have faced challenges in integrating with national health systems. The MOMENTUM Private Healthcare Delivery (MPHD) project in Burundi and Mali sought to expand the number of health facilities it engaged beyond the existing ProFam and Tunza networks. The expansion aimed to help improve service quality in more private facilities while advancing localization and reducing fragmentation for improved stewardship by health system actors. MPHD achieved this expansion by removing barriers for private health facilities to join inclusive, nonbranded networks and engaging local partners to build and maintain these networks. We share lessons learned regarding the growing role of local organizations as actors within mixed health systems and provide insights on strengthening stewardship of the increasingly heterogeneous private health care delivery sector in LMICs, particularly in fragile settings.

The Registry of Fast Myocardial Perfusion Imaging with Next-Generation SPECT (REFINE SPECT) has been expanded to include more patients and CT attenuation correction imaging. We present the design and initial results from the updated registry. Methods: The updated REFINE SPECT is a multicenter, international registry with clinical data and image files. SPECT images were processed by quantitative software and CT images by deep learning software detecting coronary artery calcium (CAC). Patients were followed for major adverse cardiovascular events (MACEs) (death, myocardial infarction, unstable angina, late revascularization). Results: The registry included scans from 45,252 patients from 13 centers (55.9% male, 64.7 ± 11.8 y). Correlating invasive coronary angiography was available for 3,786 (8.4%) patients. CT attenuation correction imaging was available for 13,405 patients. MACEs occurred in 6,514 (14.4%) patients during a median follow-up of 3.6 y (interquartile range, 2.5–4.8 y). Patients with a stress total perfusion deficit of 5% to less than 10% (unadjusted hazard ratio [HR], 2.42; 95% CI, 2.23–2.62) and a stress total perfusion deficit of at least 10% (unadjusted HR, 3.85; 95% CI, 3.56–4.16) were more likely to experience MACEs. Patients with a deep learning CAC score of 101–400 (unadjusted HR, 3.09; 95% CI, 2.57–3.72) and a CAC of more than 400 (unadjusted HR, 5.17; 95% CI, 4.41–6.05) were at increased risk of MACEs. Conclusion: The REFINE SPECT registry contains a comprehensive set of imaging and clinical variables. It will aid in understanding the value of SPECT myocardial perfusion imaging, leverage hybrid imaging, and facilitate validation of new artificial intelligence tools for improving prediction of adverse outcomes incorporating multimodality imaging.

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.

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [¹¹C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60–90 or 70–90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD.

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.

BACKGROUND AND PURPOSE:

Low-field 64 mT portable brain MRI has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of portable MRI (pMRI) in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI.

BACKGROUND AND PURPOSE:

Percutaneous cement augmentation has been reported as an effective salvage procedure for frail patients with spinal instrumentation failure, such as screw loosening, hardware breakage, cage subsidence, and fractures within or adjacent to stabilized segments. Favorable results were reported during a median follow-up period of 16 months in a retrospective analysis of 31 consecutive procedures performed in 29 patients. In the present study, the long-term effectiveness of this treatment in avoiding or postponing revision surgery is reported.