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Abstract Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia‐inducible factor 2α, approved for the treatment of certain patients with von Hippel–Lindau (VHL) disease‐associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. It is primarily metabolized by the polymorphic uridine 5′‐diphospho‐glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM version 7.3, based on demographics/PK data from three clinical pharmacology (food effect, formulation bridging, and genotype/race effect) and two clinical studies (phase I dose escalation/expansion in patients with RCC and other solid tumors; phase II in patients with VHL). Median (range) age for the combined studies was 55 years (19–84) and body weight was 73.6 kg (42.1–165.8). Belzutifan plasma PK was well‐characterized by a linear two‐compartment model with first‐order absorption and elimination. For patients with VHL, the predicted geometric mean (% coefficient of variation) apparent clearance was 7.3 L/h (51%), apparent total volume of distribution was 130 L (35%), and half‐life was 12.39 h (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model, dual UGT2B17 and CYP2C19 poor metabolizers (PMs) were estimated to have a 3.2‐fold higher area under the plasma concentration‐time curve compared to UGT2B17 extensive metabolizer and CYP2C19 non‐PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in the overall population and subpopulations for belzutifan labeling.

ABSTRACT Brain infections are a major public health problem in India and other parts of the world, causing both mortality and lifelong disability. Even after a thorough investigation, many cases remain without an etiological diagnosis. Primate erythroparvovirus 1 (B19V) has been identified as a pathogen associated with undiagnosed meningoencephalitis in other settings, including the United Kingdom, France, and Latvia. Here, we reported 13/403 (3.2%) B19V PCR positive cases of meningoencephalitis in West Bengal, India. The positive samples were mostly from children (10/13, 76.92%) and presented as a spectrum consisting of acute encephalitis (7/13), acute meningoencephalitis (3/13), and meningitis (3/13). Of the 13 cases, 8/13 (61.5%) had no known etiology and 5/13 (38.5%) had a previous etiological diagnosis. The cases did not cluster in time or by location, suggesting sporadic occurrence rather than outbreaks. We were able to retrieve the complete B19V genomes from cerebrospinal fluid (CSF) in 12/13 cases. The sequences clustered into genotype 3b with complete genomes from Brazil, Ghana, and France, and partial genomes from India and Kyrgyzstan. This is the first report of B19V in cases of neurological infections from India. It highlights the need to evaluate the causal relationship between B19V with meningoencephalitis in the country. These were also the first complete genomes of genotype 3b from CSF and will be critical in the evaluation of the relationship between genotypes and disease. IMPORTANCE Cases of meningoencephalitis with no known etiology remain a major challenge to clinical management of brain infections across the world. In this study, we detected and characterized the whole-genome of primate erythroparvovirus 1 (B19V) in cases of meningoencephalitis in India. Our work highlighted the association between B19V and brain infections which has been reported in other countries. Our work also emphasized the need to examine the role of B19V in meningoencephalitis, specifically whether it caused or contributed to the disease together with other pathogens in India. Our study provided the first 12 genomes of B19V from cerebrospinal fluid. These genomes will contribute to an understanding of how the virus is changing across different locations and over time.

Background: As the coronavirus disease 2019 (COVID-19) pandemic continues, the selection of genomic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated with higher transmission, more severe disease, re-infection, and immune escape are a cause for concern. Such variants have been reported from the UK (B.1.1.7), South Africa (B.1.351) and, Brazil (P.1/B.1.1.28). We performed this study to track the importation, spread, and emergence of variants locally. Methods: We sequenced whole genomes of SARS-CoV-2 from international travellers (n=75) entering Karnataka, South India, between Dec 22, 2020 and Jan 31, 2021, and from positive cases in the city of Bengaluru (n=108), between Nov 22, 2020- Jan 22, 2021, as well as a local outbreak. We present the lineage distribution and analysis of these sequences. Results: Genomes from the study group into 34 lineages. Variant B.1.1.7 was introduced by international travel (24/73, 32.9%). Lineage B.1.36 and B.1 formed a major fraction of both imported (B.1.36: 20/73, 27.4%; B.1: 14/73, 19.2%), and circulating viruses (B.1.36: 45/103; 43.7%,. B.1: 26/103; 25.2%). The lineage B.1.36 was also associated with a local outbreak. We detected nine amino acid changes, previously associated with immune escape, spread across multiple lineages. The N440K change was detected in 45/162 (27.7%) of the sequences, 37 of these were in the B.1.36 lineage (37/65, 56.92%) Conclusions: Our data support the idea that variants of concern spread by travel. Viruses with amino acid replacements associated with immune escape are already circulating. It is critical to check transmission and monitor changes in SARS-CoV-2 locally.

Karnataka, a state in south India, reported its first case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on March 8, 2020, more than a month after the first case was reported in India. We used a combination of contact tracing and genomic epidemiology to trace the spread of SARS-CoV-2 in the state up until May 21, 2020 (1578 cases). We obtained 91 genomes of SARS-CoV-2 which clustered into seven lineages (Pangolin lineages-A, B, B.1, B.1.80, B.1.1, B.4, and B.6). The lineages in Karnataka were known to be circulating in China, Southeast Asia, Iran, Europe and other parts of India and are likely to have been imported into the state both by international and domestic travel. Our sequences grouped into 17 contact clusters and 24 cases with no known contacts. We found 14 of the 17 contact clusters had a single lineage of the virus, consistent with multiple introductions and most (12/17) were contained within a single district, reflecting local spread. In most of the 17 clusters, the index case (12/17) and spreaders (11/17) were symptomatic. Of the 91 sequences, 47 belonged to the B.6 lineage, including eleven of 24 cases with no known contact, indicating ongoing transmission of this lineage in the state. Genomic epidemiology of SARS-CoV-2 in Karnataka suggests multiple introductions of the virus followed by local transmission in parallel with ongoing viral evolution. This is the first study from India combining genomic data with epidemiological information emphasizing the need for an integrated approach to outbreak response.

Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT) in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina.A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina- targeted (embryonic day 12.5) deletion of VAChT (VAChTSix3-Cre-flox/flox) and littermate controls at 5 and 12 months of age. VAChTSix3-Cre-flox/flox mice did not show any gross changes in nuclear layer cellularity or synaptic layer thickness. However, VAChTSix3-Cre-flox/flox mice showed reduced electrophysiological response of the retina to light stimulus under scotopic conditions at 5 and 12 months of age, including reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes and decreased OP peak power and total energy. Reduced a-wave amplitude was proportional to the reduction in b-wave amplitude and not associated with altered a-wave 10%-90% rise time or inner and outer segment thicknesses.This study used a novel genetic model in the first examination of function and structure of the mature mouse retina with disruption of cholinergic signalling. Reduced amplitude across the electroretinogram wave form does not suggest dysfunction in specific retinal cell types and could reflect underlying changes in the retinal and/or extraretinal microenvironment. Our findings suggest that release of acetylcholine by VAChT is essential for the normal electrophysiological response of the mature mouse retina.

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia‐inducible factor‐2α inhibitor, recently approved in the United States for the treatment of von Hippel–Lindau (VHL) disease‐associated renal cell carcinoma (RCC) and other VHL disease‐associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL‐RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure–response (E‐R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression‐free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time‐to‐event analyses. Efficacy E‐R was generally flat with non‐significant positive trends with exposure. The safety E‐R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure‐dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit–risk assessment in VHL disease‐associated neoplasms using E‐R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit–risk profile of belzutifan 120 mg once daily dosing in patients with VHL‐RCC for labeling and the overall development program. [ABSTRACT FROM AUTHOR]

There is a lack of consensus in the literature regarding optimal treatment methods for Lisfranc injuries, and recent literature has emphasized the need to compare open reduction and internal fixation (ORIF) with primary arthrodesis (PA). The purpose of the current study is to compare reoperation and complication rates between ORIF and PA following Lisfranc injury in a private, outpatient, orthopaedic practice. A retrospective chart review was performed on patients undergoing operative intervention for Lisfranc injury between January 2009 and September 2015. A total of 196 patients met the inclusion criteria (130 ORIF, 66 PA), with a mean follow-up of 61.3 and 81.7 weeks, respectively. The ORIF group had a higher reoperation rate than the PA group, due to hardware removal. When hardware removals were excluded, the reoperation rate was similar. Postsurgical complications were compared between the 2 groups with no significant difference. In conclusion, ORIF and PA had similar complication rates. When hardware removals were excluded, the reoperation rates were similar, although hardware removals were more common in the ORIF group compared with the PA group. Levels of Evidence: Level III [ABSTRACT FROM AUTHOR]

Joint arthroplasty of the first metatarsophalangeal (MTP) joint is an accepted surgical option for patients with hallux rigidus. However, this procedure has been reported to have a high complication rate and unpredictable survivorship. Implant arthroplasty failure is a devastating complication that results in significant osseous defect with altered biomechanics of the foot. Commonly, salvage options are limited to arthrodesis with bone grafting. However, outcomes are rarely reported. The purpose of this study is to investigate the fusion rates of first metatarsophalangeal joint arthrodesis after conversion from failed implant arthroplasty. A systematic review of electronic databases to find reports of conversion arthrodesis after failed implant arthroplasty was performed. Six studies involving a total of 76 patients with a weighted mean age of 54.9 met the inclusion criteria. Out of the 6 included articles, the nonunion rate was 16.5% at a weighted mean follow-up of 48.1 months. The nonunion rate in the current report is higher than reported nonunion rates of primary arthrodesis. More prospective studies with consistent and standard outcome measures are needed to further determine the success rate of this salvage procedure. Levels of Evidence: 4, Systematic Review of Level 4 Studies [ABSTRACT FROM AUTHOR]

Introduction: The association between cognitive functioning and mental health symptoms across the lifespan remains poorly understood. Understanding the directionality of the association between mental health and cognition is important as most gold-standard psychological therapies, such as cognitive-behaviour therapy, are cognitively demanding. Here, we examined the directionality of the association between cognitive and affective control with symptoms of depression and anxiety across the lifespan. Methods: 1002 participants (87.2 % female, age range: 11–89 years) completed self-report measures of depressive and anxiety symptoms and an affective backward digit span task thrice at 3-month intervals. Cross-lagged panel models (CLPMs) were used to model the longitudinal relationships between affective and cognitive control with depressive and anxiety symptoms. Multiple-group CLPMs were applied to test the model invariance between adolescents and adults. Results: The results supported a unidirectional relationship, where symptoms of depression and anxiety predicted impaired affective control across time points, over and above cognitive control. There was no evidence for affective or cognitive control capacity predicting emotional disorder symptomatology. In addition, multiple-group analysis revealed that depressive symptoms also predicted impaired cognitive control among adolescents only. There were no age-related differences in the associations between cognitive and affective control with anxiety symptoms. Conclusions: Our findings support depression and anxiety as antecedents, but not consequences, of impaired affective control. This suggests that timely management of emotional disorders, in particular for adolescents, is essential to prevent deterioration in cognitive functioning. The results further signal that practitioners should consider impaired affective control capacity in therapeutic contexts.