Cobalt-Mediated Photochemical C-H Arylation of Pyrroles.

Precious metal complexes remain ubiquitous in photoredox catalysis (PRC) despite concerted efforts to find more earth-abundant catalysts and replacements based on 3d metals in particular. Most otherwise plausible 3d metal complexes are assumed to be unsuitable due to short-lived excited states, which has led researchers to prioritize the pursuit of longer excited-state lifetimes through careful molecular design. However, we report herein that the C-H arylation of pyrroles and related substrates (which are benchmark reactions for assessing the efficacy of photoredox catalysts) can be achieved using a simple and readily accessible octahedral bis(diiminopyridine) cobalt complex, [1­Co](PF6)2. Notably, [1­Co]2+ efficiently functionalizes both chloro- and bromoarene substrates despite the short excited-state lifetime of the key photoexcited intermediate *[1­Co]2+ (8 ps). We present herein the scope of this C-H arylation protocol and provide mechanistic insights derived from detailed spectroscopic and computational studies. These indicate that, despite its transient existence, reduction of *[1­Co]2+ is facilitated via pre-assembly with the NEt3 reductant, highlighting an alternative strategy for the future development of 3d metal-catalyzed PRC.

Variability in Surgical Case Volume Performed During ACGME-Accredited Orthopaedic Foot and Ankle Fellowship Training.

INTRODUCTION: Previous studies have demonstrated a positive correlation between case volume and outcomes in foot and ankle surgery. This study elucidates surgical case volume benchmarks for Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopaedic foot and ankle fellowship training in the United States. METHODS: The ACGME provided case logs for orthopaedic residents and foot and ankle fellows (2018-2021). Variabilities in reported fellowship case volumes were defined as the fold-difference between 90th and 10th percentiles. Reported case volumes were compared between training cohorts with parametric tests. RESULTS: Case logs from 65 orthopaedic foot and ankle fellows and 3146 orthopaedic residents were included. Fellows reported 1.3- to 1.5-fold more foot and ankle cases during fellowship training than during residency training (P < .001). On average, orthopaedic foot and ankle fellows reported 405.4 cases and most were arthrodesis (17%), forefoot reconstruction (17%), mid/hindfoot reconstruction (13%), tendon repair/transfer (12%), and trauma ankle hindfoot (11%). Case categories with the highest variabilities were amputation (14.8-fold difference), infection/tumor (11.6-fold difference), arthroscopy (9.2-fold difference), and calcaneus (8.7-fold difference). DISCUSSION: Case volume benchmarks can assist trainees and faculty during orthopaedic foot and ankle training. More research is needed to determine case minimum requirements needed for autonomous practice in foot and ankle surgery. LEVEL OF EVIDENCE: Level III.

The association of ASA score and outcomes following to.tal ankle arthroplasty.

BACKGROUND: This study seeks to evaluate the relationship between American Society of Anesthesiologist (ASA) score and postoperative outcomes following TAA. METHODS: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database was queried from 2007 to 2020 to identify 2210 TAA patients. Patients were stratified into low (n = 1328; healthy/mild systemic disease) or high (n = 881; severe/life-threatening systemic disease) ASA score cohorts. RESULTS: There was no statistically significant difference in complications, readmission, or reoperation rate based on ASA score. Increased ASA score was significantly associated with longer length of stay (low = 1.69 days, high = 1.98 days; p < .001) and higher rate of adverse discharge (low = 95.3 %, high = 87.4 %; p < .001). CONCLUSION: Higher ASA scores (3 and 4) were statically significantly associated with increased length of stay and non-home discharge disposition. These findings are valuable for physicians and patients to consider prior to TAA given the increased utilization of resources and cost associated with higher ASA scores. LEVEL OF EVIDENCE: Level III, Retrospective cohort study.

Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4.

Human insulin-like peptide 5 (INSL5) is a gut hormone produced by colonic L-cells, and its biological functions are mediated by Relaxin Family Peptide Receptor 4 (RXFP4). Our preliminary data indicated that RXFP4 agonists are potential drug leads for the treatment of constipation. More recently, we designed and developed a novel RXFP4 antagonist, A13-nR that was shown to block agonist-induced activity in cells and animal models. We showed that A13-nR was able to block agonist-induced increases in colon motility in mice of both genders that express the receptor, RXFP4. Our data also showed that colorectal propulsion induced by intracolonic administration of short-chain fatty acids was antagonized by A13-nR. Therefore, A13-nR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrhea. However, A13-nR acted as a partial agonist at high concentrations in vitro and demonstrated modest antagonist potency (∼35 nM). Consequently, the primary objective of this study is to pinpoint novel modifications to A13-nR that eliminate partial agonist effects while preserving or augmenting antagonist potency. In this work, we detail the creation of a series of A13-nR-modified analogues, among which analogues 3, 4, and 6 demonstrated significantly improved RXFP4 affinity (∼3 nM) with reduced partial agonist activity, enhanced antagonist potency (∼10 nM) and maximum agonist inhibition (∼80 %) when compared with A13-nR. These compounds have potential as candidates for further preclinical evaluations, marking a significant stride toward innovative therapeutics for colon motility disorders.

Phase 3 Safety and Immunogenicity Study of a Three-dose Series of Twenty-valent Pneumococcal Conjugate Vaccine in Healthy Infants and Toddlers.

BACKGROUND: Global pediatric immunization programs with pneumococcal conjugate vaccines (PCVs) have reduced vaccine-type pneumococcal disease, but a substantial disease burden of non-PCV serotypes remains. METHODS: This phase 3, randomized (1:1), double-blind study evaluated safety and immunogenicity of 20-valent PCV (PCV20) relative to 13-valent PCV (PCV13) in healthy infants. Participants received 2 infant doses and a toddler dose of PCV20 or PCV13, with diphtheria-tetanus-acellular pertussis combination vaccine at all doses and measles, mumps, rubella and varicella vaccines at the toddler dose. Primary pneumococcal immunogenicity objectives were to demonstrate noninferiority (NI) of PCV20 to PCV13 for immunoglobulin G geometric mean concentrations after infant and toddler doses and percentages of participants with predefined serotype-specific immunoglobulin G concentrations after infant doses. Safety endpoints included local reactions, systemic events and adverse events. RESULTS: Overall, 1204 participants were vaccinated (PCV20, n = 601; PCV13, n = 603). One month after the toddler dose, 19/20 serotypes met NI for immunoglobulin G geometric mean concentrations; serotype 6B narrowly missed NI [PCV20/PCV13 geometric mean ratio: 0.57 (2-sided 95% confidence interval: 0.48-0.67); NI criterion: lower 2-sided 95% confidence interval >0.5]. Sixteen/twenty serotypes met NI for ≥1 primary objective after 2 infant doses. PCV20 induced robust opsonophagocytic activity, and boosting responses were observed for all vaccine serotypes, including those missing statistical NI. The safety/tolerability profile of PCV20 was like that of PCV13. CONCLUSIONS: PCV20 3-dose series in infants was safe and elicited robust immune responses. Based on these results and PCV13 experience, PCV20 3-dose series is expected to be protective for all 20 vaccine serotypes. NCT04546425.

A Phase 3, Single-Arm Trial to Evaluate the Safety and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine in Healthy Children 15 Months Through <18 Years of Age.

BACKGROUND: A 20-valent pneumococcal conjugate vaccine (PCV20), containing 13-valent PCV (PCV13) components and 7 additional polysaccharide conjugates, was developed to extend protection for pneumococcal disease. This phase 3 study assessed the safety and immunogenicity of PCV20 in children. METHODS: In this single-arm study, children (≥15 months-<18 years of age) received 1 dose of PCV20. Children <5 years of age had ≥3 prior doses of PCV13; children ≥5 years were recruited regardless of previous PCV receipt. Serotype-specific IgG concentrations and opsonophagocytic activity (OPA) titers were measured before and 1 month after PCV20. Local reactions and systemic events, adverse events (AEs), serious AEs, and newly diagnosed chronic medical conditions were collected. RESULTS: Of 839 enrolled participants, 831 (>99%) were vaccinated, and 819 (>97%) completed all study visits. Local reactions and systemic events were mostly mild to moderate in severity. No serious AEs were considered PCV20-related. IgG geometric mean fold rises (GMFRs) from before to 1 month after PCV20 ranged from 27.9-1847.7 (7 additional serotypes) and 2.9-44.9 (PCV13 serotypes) in children <5 years of age, and 10.5-187.7 (7 additional serotypes) and 4.3-127.9 (PCV13 serotypes) in children ≥5 years old. OPA GMFRs from before to 1 month after PCV20 ranged from 12.4-983.6 to 2.8-52.9 in children <5 years of age and from 11.5-499.0 to 5.3-147.9 in children ≥5 years of age. CONCLUSIONS: Among children ≥15 months through <18 years of age, PCV20 was well tolerated and induced robust responses to all 20 serotypes, supporting the use of PCV20 in children.

A Phase Three Study of the Safety and Immunogenicity of a Four-dose Series of 20-valent Pneumococcal Conjugate Vaccine in Healthy Infants.

BACKGROUND: The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend pneumococcal disease protection beyond 13-valent PCV (PCV13). METHODS: This phase 3, double-blind study conducted in the United States/Puerto Rico evaluated PCV20 safety and immunogenicity. Healthy infants were randomized to receive a 4-dose series of PCV20 or PCV13 at 2, 4, 6 and 12-15 months old. Objectives included demonstrating noninferiority (NI) of PCV20 to PCV13 immunoglobulin G (IgG) geometric mean concentrations after doses 3 and 4 and percentages of participants with predefined IgG concentrations after dose 3, with 7 additional PCV20 serotypes compared with the lowest result among vaccine serotypes in the PCV13 group. Safety assessments included local reactions, systemic events, adverse events, serious adverse events and newly diagnosed chronic medical conditions. RESULTS: Overall, 1991 participants were vaccinated (PCV20, n = 1001; PCV13, n = 990). For IgG geometric mean concentrations 1 month after both doses 3 and 4, all 20 serotypes met NI criteria (geometric mean ratio lower 2-sided 95% confidence interval > 0.5). For percentages of participants with predefined IgG concentrations after dose 3, NI (percentage differences lower 2-sided 95% confidence interval > -10%) was met for 8/13 matched serotypes and 6/7 additional serotypes; 4 serotypes missed the statistical NI criterion by small margins. PCV20 also elicited functional and boosting responses to all 20 serotypes. The safety profile of PCV20 was similar to PCV13. CONCLUSION: A 4-dose series of PVC20 was well tolerated and elicited robust serotype-specific immune responses expected to help protect infants and young children against pneumococcal disease due to the 20 vaccine serotypes. Clinical trial registration: NCT04382326.

A Detailed Analysis of Workplace Foot and Ankle Injuries.

INTRODUCTION: This study analyzes the incidence rate and median workdays missed due to foot and ankle injuries across age groups, sexes, and industries. METHODS: Workplace injury data from 2003 to 2019 were obtained using the Nonfatal Cases Involving Day Away from Work: Selected Characteristics database provided by the Bureau of Labor Statistics (BLS). The data were grouped by injury location (ie, foot, ankle), injury type (ie, fracture, sprain), and industry, and reported with injury incidence rates and median workdays missed. RESULTS: The incidence rate of foot and ankle injuries significantly decreased from 2003 to 2019 (P < .001). With increasing age, the incidence rate of foot and ankle injuries decreased (P < .001) and median workdays missed increased (P < .001). Men had significantly higher rates of foot and ankle injuries (P < .001). Agriculture, forestry, fishing, and hunting (foot=10.23%, ankle=10.41%); construction (foot=8.14%, ankle=8.68%); and transportation and warehousing (foot=11.06%, ankle=13.80%) industries had the highest injury incidence rates. Transportation and warehousing (foot=16.8 days, ankle=16.3 days), mining (foot=44.9 days, ankle=17.1 days), and utilities (foot=26.7 days, ankle=24.4 days) industries had the highest median workdays missed. CONCLUSION: Increased incidence and severity of workplace foot and ankle injuries are associated with male sex and heavy labor industries. Age was positively associated with severity and negatively associated with incidence of workplace ankle injuries. LEVELS OF EVIDENCE: Level III, Retrospective cohort study.

Validity and reliability evidence support task-specific metrics for laparoscopic fundoplication.

BACKGROUND: Laparoscopic hiatal hernia repair (LHHR) is a complex operation requiring advanced surgical training. Surgical simulation offers a potential solution for learning complex operations without the need for high surgical volume. Our goal is to develop a virtual reality (VR) simulator for LHHR; however, data supporting task-specific metrics for this procedure are lacking. The purpose of this study was to develop and assess validity and reliability evidence of task-specific metrics for the fundoplication phase of LHHR. METHODS: In phase I, structured interviews with expert foregut surgeons were conducted to develop task-specific metrics (TSM). In phase II, participants with varying levels of surgical expertise performed a laparoscopic Nissen fundoplication procedure on a porcine stomach explant. Video recordings were independently assessed by two blinded graders using global and TSM. An intraclass correlation coefficient (ICC) was used to assess interrater reliability (IRR). Performance scores were compared using a Kruskal-Wallis test. Spearman's rank correlation was used to evaluate the association between global and TSM. RESULTS: Phase I of the study consisted of 12 interviews with expert foregut surgeons. Phase II engaged 31 surgery residents, a fellow, and 6 attendings in the simulation. Phase II results showed high IRR for both global (ICC = 0.84, p < 0.001) and TSM (ICC = 0.75, p < 0.001). Significant between-group differences were detected for both global (χ2 = 24.01, p < 0.001) and TSM (χ2 = 18.4, p < 0.001). Post hoc analysis showed significant differences in performance between the three groups for both metrics (p < 0.05). There was a strong positive correlation between the global and TSM (rs = 0.86, p < 0.001). CONCLUSION: We developed task-specific metrics for LHHR and using a fundoplication model, we documented significant reliability and validity evidence. We anticipate that these LHHR task-specific metrics will be useful in our planned VR simulator.

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist.

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.

Proficiency Levels and Validity Evidence for Scoring Metrics for a Virtual Reality and Inanimate Robotic Surgery Simulation Curriculum.

OBJECTIVE: Our institution recently implemented a virtual reality (VR) skills curriculum for general surgery residents using the SimNow simulator. Based on a content alignment study, we revised the curriculum to include only 20 of 33 VR tasks and we added 3 previously validated inanimate tasks. The purpose of this study was to establish expert-derived proficiency levels for all tasks and to evaluate the validity of the scoring for the VR tasks. DESIGN: Two expert robotic surgeons performed 5 repetitions of each VR and inanimate task. The trimmed mean (lowest scoring attempt and outliers [>2 standard deviations] were eliminated) was defined as the expert level for each task. For the VR tasks, expert levels were compared to resident performance to evaluate validity. SETTING: This study was conducted at the University of Texas Southwestern Medical Center (Dallas, TX), a tertiary care academic teaching hospital. PARTICIPANTS: Two expert robotic surgeons participated in this study. The data from 42 residents (PGY2-4) who completed the original curriculum was used to represent novice performance. RESULTS: Comparison of expert levels and resident performance was statistically significant for 15 VR tasks (supporting validity) and approached significance (p = 0.06, 0.09) for 2 VR tasks; expert levels were designated as proficiency levels for these 17 tasks. Group comparisons were clearly not significant (p = 0.2-0.8) for 3 VR tasks; 2 of these 3 tasks were retained as introductory exercises (with 3 repetitions required) and 1 was excluded. For the 3 inanimate tasks, expert levels minus 2 standard deviations were designated as proficiency levels. CONCLUSIONS: This analysis generated validity evidence for 15 VR tasks and established expert-derived proficiency levels for 17 VR tasks and 3 inanimate tasks. Our proposed curriculum now consists of 19 VR and 3 inanimate tasks using the selected proficiency levels. We anticipate that this design will maximize curriculum efficiency and effectiveness.

Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting.

Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. Substrates are recognized by substrate receptors, such as Fbox or BCbox proteins. Meanwhile, CRLs employ assorted ubiquitin-carrying enzymes (UCEs, which are a collection of E2 and ARIH-family E3s) specialized for either initial substrate ubiquitylation (priming) or forging poly-ubiquitin chains. We discovered specific human CRL-UCE pairings governing substrate priming. The results reveal pairing of CUL2-based CRLs and UBE2R-family UCEs in cells, essential for efficient PROTAC-induced neo-substrate degradation. Despite UBE2R2's intrinsic programming to catalyze poly-ubiquitylation, CUL2 employs this UCE for geometrically precise PROTAC-dependent ubiquitylation of a neo-substrate and for rapid priming of substrates recruited to diverse receptors. Cryo-EM structures illuminate how CUL2-based CRLs engage UBE2R2 to activate substrate ubiquitylation. Thus, pairing with a specific UCE overcomes E2 catalytic limitations to drive substrate ubiquitylation and targeted protein degradation.

Mechanism of millisecond Lys48-linked poly-ubiquitin chain formation by cullin-RING ligases.

E3 ubiquitin ligases, in collaboration with E2 ubiquitin-conjugating enzymes, modify proteins with poly-ubiquitin chains. Cullin-RING ligase (CRL) E3s use Cdc34/UBE2R-family E2s to build Lys48-linked poly-ubiquitin chains to control an enormous swath of eukaryotic biology. Yet the molecular mechanisms underlying this exceptional linkage specificity and millisecond kinetics of poly-ubiquitylation remain unclear. Here we obtain cryogenic-electron microscopy (cryo-EM) structures that provide pertinent insight into how such poly-ubiquitin chains are forged. The CRL RING domain not only activates the E2-bound ubiquitin but also shapes the conformation of a distinctive UBE2R2 loop, positioning both the ubiquitin to be transferred and the substrate-linked acceptor ubiquitin within the active site. The structures also reveal how the ubiquitin-like protein NEDD8 uniquely activates CRLs during chain formation. NEDD8 releases the RING domain from the CRL, but unlike previous CRL-E2 structures, does not contact UBE2R2. These findings suggest how poly-ubiquitylation may be accomplished by many E2s and E3s.

Identification of a Novel Subtype-Selective α1B-Adrenoceptor Antagonist.

α1A-, α1B-, and α1D-adrenoceptors (α1-ARs) are members of the adrenoceptor G protein-coupled receptor family that are activated by adrenaline (epinephrine) and noradrenaline. α1-ARs are clinically targeted using antagonists that have minimal subtype selectivity, such as prazosin and tamsulosin, to treat hypertension and benign prostatic hyperplasia, respectively. Abundant expression of α1-ARs in the heart and central nervous system (CNS) makes these receptors potential targets for the treatment of cardiovascular and CNS disorders, such as heart failure, epilepsy, and Alzheimer's disease. Our understanding of the precise physiological roles of α1-ARs, however, and their involvement in disease has been hindered by the lack of sufficiently subtype-selective tool compounds, especially for α1B-AR. Here, we report the discovery of 4-[(2-hydroxyethyl)amino]-6-methyl-2H-chromen-2-one (Cpd1), as an α1B-AR antagonist that has 10-15-fold selectivity over α1A-AR and α1D-AR. Through computational and site-directed mutagenesis studies, we have identified the binding site of Cpd1 in α1B-AR and propose the molecular basis of α1B-AR selectivity, where the nonconserved V19745.52 residue plays a major role, with contributions from L3146.55 within the α1B-AR pocket. By exploring the structure-activity relationships of Cpd1 at α1B-AR, we have also identified 3-[(cyclohexylamino)methyl]-6-methylquinolin-2(1H)-one (Cpd24), which has a stronger binding affinity than Cpd1, albeit with reduced selectivity for α1B-AR. Cpd1 and Cpd24 represent potential leads for α1B-AR-selective drug discovery and novel tool molecules to further study the physiology of α1-ARs.

Quantitative mechanical stimulation of GPR68 using a novel 96 well flow plugin.

Mechanosensitive proteins play a crucial role in a range of physiological processes, including hearing, tactile sensation and regulating blood flow. While previous work has demonstrated the mechanosensitivity of several proteins, the ability to apply precisely defined mechanical forces to cells in a consistent, replicable manner remains a significant challenge. In this work we present a novel 96-well plate-compatible plugin device for generating highly-controlled flow-based mechanical simulation of cells, which enables quantitative assessment of mechanosensitive protein function. The device is used to mechanically stimulate HEK 293T cells expressing the mechanosensitive protein GPR68, a G protein-coupled receptor. By assaying intracellular calcium levels during flow-based cell stimulation, we determine that GPR68 signalling is a function of the applied shear-force. As this approach is compatible with conventional cell culture plates and allows for simultaneous readout in a conventional fluorescence plate reader, this represents a valuable new tool to investigate mechanotransduction.

Rehabilitation via HOMe-Based gaming exercise for the Upper limb post Stroke (RHOMBUS): a qualitative analysis of participants' experience.

OBJECTIVE: To report participants' experiences of trial processes and use of the Neurofenix platform for home-based rehabilitation following stroke. The platform, consisting of the NeuroBall device and Neurofenix app, is a non-immersive virtual reality tool to facilitate upper limb rehabilitation following stroke. The platform has recently been evaluated and demonstrated to be safe and effective through a non-randomised feasibility trial (RHOMBUS). DESIGN: Qualitative approach using semistructured interviews. Interviews were audio recorded, transcribed verbatim and analysed using the framework method. SETTING: Participants' homes, South-East England. PARTICIPANTS: Purposeful sample of 18 adults (≥18 years), minimum 12 weeks following stroke, not receiving upper limb rehabilitation prior to the RHOMBUS trial, scoring 9-25 on the Motricity Index (elbow and shoulder), with sufficient cognitive and communicative abilities to participate. RESULTS: Five themes were developed which explored both trial processes and experiences of using the platform. Factors that influenced participant's decision to take part in the trial, their perceptions of support provided during the trial and communication with the research team were found to be important contextual factors effecting participants' overall experience. Specific themes around usability and comfort of the NeuroBall device, factors motivating persistence and perceived effectiveness of the intervention were highlighted as being central to the usability and acceptability of the platform. CONCLUSION: This study demonstrated the overall acceptability of the platform and identified areas for enhancement which have since been implemented by Neurofenix. The findings add to the developing literature on the interface between virtual reality systems and user experience. TRIAL REGISTRATION NUMBER: ISRCTN60291412.

Synthesis of [11C]BIIB104, an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic-Acid-Positive Allosteric Modulator, and Evaluation of the Bio-Distribution in Non-Human Primate Brains Using Positron Emission Tomography.

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4-5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain.

A phase 3 randomized trial of the safety and immunogenicity of 20-valent pneumococcal conjugate vaccine in adults ≥ 60 years of age in Japan, South Korea, and Taiwan.

BACKGROUND: Pneumococcal infections are associated with high disease burden in older individuals in Japan, South Korea, and Taiwan. The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend protection beyond earlier pneumococcal vaccines. METHODS: This phase 3 randomized, double-blind study investigated the safety and immunogenicity of PCV20 in participants ≥ 60 years of age from Japan, South Korea, and Taiwan. Participants were randomized to receive PCV20 or 13-valent pneumococcal conjugate vaccine (PCV13). One month after vaccination, PCV20 recipients received a saline injection and PCV13 recipients received 23-valent polysaccharide vaccine (PPSV23). Primary immunogenicity objectives were to demonstrate noninferiority of PCV20 to PCV13 (13 matched serotypes) or PPSV23 (7 additional serotypes) for serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after vaccination with PCV20, PCV13, or PPSV23. Noninferiority for each serotype was declared if the lower bound of the 2-sided 95% CI for OPA geometric mean ratio (GMR) was > 0.5. Safety endpoints included local reactions, systemic events, adverse events (AEs), and serious AEs. RESULTS: Overall, 1421‬ participants were vaccinated (median age [range]: 65 [60-85] years). PCV20 was noninferior to PCV13 for all 13 matched serotypes and to PPSV23 for 6 of 7 additional serotypes. Although statistical noninferiority was missed for serotype 8 (lower bound of the 2-sided 95% CI for OPA GMR = 0.5, thus not meeting the statistical noninferiority criterion of > 0.5), secondary immunogenicity endpoints for serotype 8 were supportive of a robust immune response. The incidence of AEs and the frequency and severity of local reactions and systemic events were generally similar after PCV20 and PCV13. No safety concerns were identified. CONCLUSION: PCV20 generated robust immune responses to all vaccine serotypes in older adults in Japan, South Korea, and Taiwan. The safety and tolerability profile was similar to PCV13. PCV20 is expected to help protect against all 20 vaccine serotypes. NCT04875533.

"The Graves Cannot Be Dug Fast Enough": Excess Deaths Among US Amish and Mennonites During the 1918 Flu Pandemic.

Estimating the lethal impact of a pandemic on a religious community with significant barriers to outsiders can be exceedingly difficult. Nevertheless, Stein and colleagues (2021) developed an innovative means of arriving at such an estimate for the lethal impact of COVID-19 on the Amish community in 2020 by counting user-generated death reports in the widely circulated Amish periodical The Budget. By comparing monthly averages of reported deaths before and during the COVID-19 pandemic, Stein and colleagues were able to arrive at a rough estimate of "excess deaths" during the first year of the pandemic. Our research extends the same research method, applying it to the years during and immediately preceding the global influenza pandemic of 1918. Results show similarly robust findings, including three notable "waves" of excess deaths among Amish and conservative Mennonites in the USA in 1918, 1919, and 1920. Such results point to the promise of utilizing religious periodicals like The Budget as a relatively untapped trove of user-generated data on public health outcomes among religious minorities more than a century in the past.