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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.

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]

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.

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]

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 FROM AUTHOR]

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.

Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by the mindset that higher dose provides higher efficacy. Examples of dose finding implemented by biopharmaceutical firms can change this mindset. The purpose of this article is to outline a pragmatic dose selection strategy for immuno‐oncology (IO) and other targeted monoclonal antibodies (mAbs). The approach was implemented for pembrolizumab. Selecting a recommended phase II dose (RP2D) with a novel mechanism of action is often challenging due to uncertain relationships between pharmacodynamics measurements and clinical end points. Additionally, phase I efficacy and safety data are generally inadequate for RP2D selection for IO mAbs. Here, the RP2D was estimated based on phase I (clinical study KN001 A and A2) pharmacokinetics data as the dose required for target saturation, which represents a surrogate for maximal pharmacological effect for antagonist mAbs. Due to limitations associated with collecting and analyzing tumor biopsies, characterizing intratumoral target engagement (TE) is challenging. To overcome this gap, a physiologically‐based pharmacokinetic model was implemented to predict intratumoral TE. As tumors are spatially heterogeneous, TE was predicted in well‐vascularized and poorly vascularized tumor regions. Additionally, impact of differences in target expression, for example, due to interindividual variability and cancer type, was simulated. Simulations showed that 200 mg every 3 weeks can achieve ≥ 90% TE in clinically relevant scenarios, resulting in the recommendation of 200 mg every 3 weeks as the RP2D. Randomized dose comparison studies (KN001 B2 and D) showing similar efficacy over a fivefold dose/exposure range confirmed the RP2D as the pivotal dose. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Co3C magnetic nanoparticles have been synthesized using supercritical conditions of ethanol. The phase structure of the samples has shown two phases of orthorhombic Co3C and Co structures. The morphology of the prepared nanoparticles reveals a spherical-like shape. Tailoring the synthesis parameters has led to controlling the magnetic properties depending on the ratio of Co3C:Co in the samples. The magnetic properties of the samples have been measured, revealing ferromagnetic behavior. The data yield coercivity (HC) was of 600–950 Oe and saturation magnetization (MS) of 20–38 emu/g. The results present alternative approach to nucleate Co3C magnetic nanoparticles. The synthesis method will be optimized in the future to produce a pure Co3C phase structure. [ABSTRACT FROM AUTHOR]

There is an increase in interest in the relationships between loneliness and psychosis. The notion of psychosis continuum implies that psychotic experiences extend from clinical populations with psychotic disorders to non-clinical populations. This meta-analytic review aimed to examine the respective associations of loneliness with positive and negative psychotic experiences along the psychosis continuum. A systematic database search was conducted and a total of 30 studies were included in the first meta-analysis and 15 studies were included in the second meta-analysis. There was a medium association between loneliness and positive psychotic experiences (r = 0.302, p < 0.001). In particular, the association between loneliness and paranoia was robust (r = 0.448, p < 0.001). The second meta-analysis revealed a medium association between loneliness and negative psychotic experiences (r = 0.347, p < 0.001). The associations between loneliness and both positive and negative psychotic experiences were found to be smaller among clinical than non-clinical samples. The above findings provided evidence for the associations between loneliness and the two core dimensions of psychotic experiences along the phenomenological continuum. Future research should examine the dynamics of these relationships in both clinical and non-clinical samples, preferably using a single-symptom approach. [ABSTRACT FROM AUTHOR]

The development of hallux interphalangeal joint (IPJ) arthritis after an arthrodesis of the first metatarsophalangeal joint has been established in the literature. However, the significance has not been well reported. A retrospective, radiographic review of patients who had undergone a first metatarsophalangeal joint arthrodesis was performed. The Coughlin classification for degree of arthritic degeneration, hallux abductus angle, and hallux interphalangeus angle were measured in 107 radiographs of 103 patients preoperatively and postoperatively. Postoperative angles were measured immediately following surgery at approximately 6 weeks, 3 months, 6 months, 12 months, and 24 months. We found that the hallux abductus angle had decreased in the patients postoperatively; however, the hallux abductus interphalangeus angle increased on average after first metatarsophalangeal fusion. The majority of patients started with a Coughlin classification I of the hallux IPJ, which remained unchanged over the postoperative period, with no statistically significant difference in IPJ degeneration in the patients with or without fusion of the first metatarsophalangeal joint. In addition, no patients had a symptomatic hallux IPJ postoperatively within our limited study period. Further prospective studies would be beneficial with longer follow-up times to assess IPJ degeneration following first metatarsophalangeal joint fusions. Levels of Evidence: Level III: Retrospective, comparative study. [ABSTRACT FROM AUTHOR]

Background: Given findings that generally support the benefits of information and communication technology (ICT) for older adults' psychosocial adjustment, one might surmise that lonely older adults, who have a stronger need for psychological support, would reap more psychosocial benefits from ICT use. However, scant research has examined this view, much less the likelihood that ICT use might worsen the psychological well-being of lonely older adults, as has been shown to be the case in younger adults.Objective: To examine whether the association between ICT use and psychological adjustment (i.e., psychological distress and sense of community [SOC]) among older adults depends on their loneliness levels.Methods: A representative sample of 738 Hong Kong SAR Chinese older adults aged 60 years or older (56% female) was interviewed in 2017 on loneliness, frequency of ICT use (i.e., Internet and smart devices), psychological distress (6-item Kessler scale; K6), and SOC.Results: Regression analyses showed that loneliness significantly moderated the relationship between ICT use frequency and psychological adjustment (psychological distress and SOC); more frequent ICT use was associated with more psychological distress and less SOC, with higher levels of loneliness.Conclusion: These findings suggest that ICT use may be a mixed blessing for older adults, i.e., using more ICT might predict worse psychological adjustment among lonelier older adults. Efforts that promote ICT use among older adults should take their loneliness levels into account. [ABSTRACT FROM AUTHOR]

Objectives: Information and communicative technology (ICT) use is a potential vehicle for improving the psychological well-being (PWB) of older people. We examined the roles of age, frailty, and social connectedness in the relationship between ICT use and PWB. Method: Telephone interviews were conducted in mid-2016 with 1201 participants aged 50 and above (55.7% female) residing in Hong Kong, China. The participants reported PWB, ICT use (frequency of using the Internet and smart devices), frailty status, contact with family, friends, and neighbors, self-rated health, subjective financial sufficiency, education level, and employment status. Results: We found that the association between ICT and PWB was moderated by age: ICT was associated with PWB only among old-olds (75+), but not in other age groups. This moderation was mediated by contact with family, but not with friends or neighbors. The moderation was further qualified by frailty status: the ICT-by-age moderation was found only among frail, but not pre-frail or robust older adults. Conclusion: The findings suggest that ICT use can potentially enhance the PWB of older adults aged 75+ through facilitating their contact with family members. These benefits might be particularly salient for those who were frail. Improving ICT access and literacy among older adults may be promising. [ABSTRACT FROM AUTHOR]

Introduction: There is an ongoing debate about whether negative affect are consequences or triggers of paranoid thinking. It has also been suggested that aberrant salience is central to the development of delusions. This study modelled the moment-to-moment relationships between negative affect, aberrant salience, and paranoia in acute inpatients with psychosis. Methods: Participants with active paranoid delusions were assessed using clinical rating scales and experience sampling method (ESM) over 14 days. ESM data were analysed using time-lagged multilevel regression modelling. Results: Both negative affect and aberrant salience predicted an increase in paranoia at the next time point. Conversely, the level of paranoia did not predict subsequent changes in negative affect or aberrant salience. Negative affect predicted an increase in aberrant salience at the next time point, and vice versa. Conclusions: Negative affect and aberrant salience appear to drive and exacerbate paranoia, rather than being merely the sequelae of the symptom. Our results suggest both direct and indirect (via aberrant salience) pathways from negative affect to paranoia. [ABSTRACT FROM AUTHOR]