Prescribed safer supply during dual public health emergencies: a qualitative study examining service providers perspectives on early implementation.

BACKGROUND: Within North America and worldwide, drug related overdoses have increased dramatically over the past decade. COVID-19 escalated the need for a safer supply to replace unregulated substances and to reduce toxicity and overdoses. Service providers play an integral role in the delivery of safer supply but there is little empirical evidence that conceptualizes effective safer supply from their perspectives. This study explored early implementation and impacts of a safer supply program, capturing the perspectives of an interdisciplinary team of service providers on tensions and issues encountered in the development of the SAFER program. METHODS: Using a community-based participatory approach, we conducted individual interviews with program providers (n = 9). The research team was composed of researchers from a local drug user organization, a local harm reduction organization, and academic researchers. The Consolidated Framework for Implementation Research (CFIR) informed the interview guide. Data was analyzed using thematic analysis. RESULTS: There are six themes describing early implementation: (1) risk mitigation prescribing as context for early implementation; (2) developing SAFER specific clinical protocols; (3) accessibility challenges and program innovations; (4) interdisciplinary team and wraparound care; (5) program tensions between addiction medicine and harm reduction; (6) the successes of safer supply and future visions. CONCLUSION: Early implementation issues and tensions included prescriber concerns about safer supply prescribing in a highly politicized environment, accessibility challenges for service users such as stigma, encampment displacement, OAT requirements, program capacity and costs, and tensions between addiction medicine and harm reduction. Navigating these tensions included development of clinical protocols, innovations to reduce accessibility challenges such as outreach, wraparound care, program coverage of medication costs and prescribing safer supply with/without OAT. These findings contribute important insights for the development of prescribed safer supply programs.

A Systematic Review of Qualitative Research in Hand Surgery.

No formal review of qualitative research in hand surgery has been previously performed. The primary objective of this study was to evaluate the reporting quality of hand surgery qualitative research with the Standards for Reporting Qualitative Research (SRQR), a 21-item checklist. The secondary objectives were to describe qualitative research in hand surgery by domain, determine differences in reporting quality based on use of a reporting guideline, publication of SRQR and journal of publication, and to identify important outcomes in hand surgery conditions. Fifty-five studies were included from MEDLINE, Embase, PsycINFO, and Emcare. The median SRQR score was 16. The lowest reported sections were context, data collection methods, and data analysis. Qualitative research was found in multiple domains of hand surgery. There was a significant difference between papers that used a reporting guideline and studies published after the publication of the SRQR. Clinical/medical/basic science journals had the highest median SRQR score. Outcomes identified were pain for carpal tunnel syndrome and pain, function, unintentional harm, recurrence, and recovery time for Dupuytren disease. To further improve reporting quality in hand surgery qualitative research, we recommend that investigators ensure they provide rationale for their methodology and become familiar with the SRQR guidelines.

Metachronous colorectal cancer metastasis: Who, what, when and what to do about it.

Metachronous colorectal cancer (CRC) metastasis occurs due to micrometastatic disease, in up to 23% of patients who have undergone curative-intent treatment. Metachronous metastasis tends to occur within 2 years of initial treatment. Diagnosis relies on posttreatment surveillance strategies. Care for patients with metachronous CRC metastasis is complex and requires careful multidisciplinary consideration. Those with isolated and technically resectable diseases are recommended to undergo metastasectomy with adjunct chemotherapy, however, survival, even after curative-intent resection, is poor.

A filter-rectify-filter model of the tactile perception of 3D-printed, texture-defined form.

We show that a two-stage filter-rectify-filter (FRF) model, previously used to explain the visual perception of texture-defined form, can also account for the tactile perception of texture-defined form. This result is interesting because, first, relatively little is known about the neural mechanisms of tactile form perception, and second, the generalization of the model may reflect a canonical computation at work in both visual and somatosensory cortex. We 3D-printed test objects comprising a regular, rectangular array of raised, oriented bars measuring 0.75 × 0.75 × 3 mm (width × height × length) that were centre-to-centre spaced by 4 mm. Bars on the left-hand-side of a test object were horizontal, and those on the right were vertical, thus defining a texture boundary. We independently jittered the orientations of bars by drawing random numbers from a uniform distribution; across trials, we systematically increased jitter from 0° (i.e., no jitter) to ±90° (i.e., no boundary). Blindfolded participants (n = 25) used the preferred index finger pad to actively scan objects for 10 seconds before reporting the texture boundary's orientation (vertical or horizontal; randomised across trials). Results showed a threshold jitter of ±52.7° (i.e., the jitter at which the boundary orientation was only just discriminable). Computational modelling indicated that the first stage of the FRF model is a Gabor function tuned to spatial frequency = 0.23 cycles per mm with extent = 2.53 mm (full-width at half-maximum). We discuss this result with regard to neuronal receptive field structure in non-human primate somatosensory cortex.

13Ccarbene nuclear magnetic resonance chemical shift analysis confirms CeIV[double bond, length as m-dash]C double bonding in cerium(iv)-diphosphonioalkylidene complexes.

Diphosphonioalkylidene dianions have emerged as highly effective ligands for lanthanide and actinide ions, and the resulting formal metal-carbon double bonds have challenged and developed conventional thinking about f-element bond multiplicity and covalency. However, f-element-diphosphonioalkylidene complexes can be represented by several resonance forms that render their metal-carbon double bond status unclear. Here, we report an experimentally-validated 13C Nuclear Magnetic Resonance computational assessment of two cerium(iv)-diphosphonioalkylidene complexes, [Ce(BIPMTMS)(ODipp)2] (1, BIPMTMS = {C(PPh2NSiMe3)2}2-; Dipp = 2,6-diisopropylphenyl) and [Ce(BIPMTMS)2] (2). Decomposing the experimental alkylidene chemical shifts into their corresponding calculated shielding (σ) tensor components verifies that these complexes exhibit Ce[double bond, length as m-dash]C double bonds. Strong magnetic coupling of Ce[double bond, length as m-dash]C σ/π* and π/σ* orbitals produces strongly deshielded σ11 values, a characteristic hallmark of alkylidenes, and the largest 13C chemical shift tensor spans of any alkylidene complex to date (1, 801 ppm; 2, 810 ppm). In contrast, the phosphonium-substituent shielding contributions are much smaller than the Ce[double bond, length as m-dash]C σ- and π-bond components. This study confirms significant Ce 4f-orbital contributions to the Ce[double bond, length as m-dash]C bonding, provides further support for a previously proposed inverse-trans-influence in 2, and reveals variance in the 4f spin-orbit contributions that relate to the alkylidene hybridisation. This work thus confirms the metal-carbon double bond credentials of f-element-diphosphonioalkylidenes, providing quantified benchmarks for understanding diphosphonioalkylidene bonding generally.

Pediatric Peroneal Nerve Palsy Secondary to Fibular Osteochondroma.

Peripheral nerve injuries due to mass effect from bony lesions can occur when the nerve exists in an anatomically constrained location, such as the common peroneal nerve at the fibular head which passes into the tight fascia of the lateral leg compartment. We report a case of a pediatric patient who developed a common peroneal nerve palsy secondary to an osteochondroma of the fibular head and describe the clinical evaluation, radiographic findings, and surgical approach. Rapid diagnosis and nerve decompression after the onset of symptoms restored full motor function at the 8-month postoperative mark.

Gender Equality in Plastic Surgery Training: A Canadian Nationwide Cross-sectional Analysis.

Introduction: One of the important factors in achieving gender equity is ensuring equitable surgical training for all. Previous studies have shown that females get significantly lower surgical exposure than males in certain surgical specialties. Gender gap in surgical exposure has never been assessed in plastic surgery. To that end, the goal of this study was to assess if there are any differences in plastic surgery training between male and female residents. Methods: A survey was sent to all plastic surgery residency programs in Canada to assess the No. of surgeries residents operated on as a co-surgeon or primary assistant during their training. The survey also assessed career goals, level of interest in the specialty, and subjective perception of gender bias. Results: A total of 89 plastic surgery residents (59.3% participation rate) completed the survey and were included in the study. The average No. of reconstructive cases residents operated on as a co-surgeon or primary assistant was 245 ± 312 cases. There was no difference in either reconstructive or aesthetic surgery case logs between male and female residents (p > .05). However, a significantly larger proportion of females (39%) compared to males (4%) felt that their gender limited their exposure to surgical cases and led to a worsening of their overall surgical training (p < .001). Finally, a larger proportion of male residents were interested in academic careers while a larger proportion of female residents were interested in a community practice (p = .024). Conclusion: While there is no evidence of differences in the volume of logged cases between genders, female surgical residents still feel that their respective gender limits their overall surgical training. Gender inequalities in training should be addressed by residency programs.

Introduction: L'un des facteurs importants pour atteindre l'égalité des genres est d'assurer une formation chirurgicale équitable pour tous. Des études antérieures ont montré que les femmes ont une exposition significativement moindre à la chirurgie que les hommes dans certaines spécialités chirurgicales. L'écart entre genres pour l'exposition à la chirurgie n'a jamais été évalué en chirurgie plastique. À cette fin, la présente étude a eu pour objectif d'évaluer s'il y avait des différences dans la formation à la chirurgie plastique entre les résidents masculins et féminins. Méthodes: Une enquête a été envoyée à tous les programmes canadiens de résidence en chirurgie plastique pour évaluer le nombre d'interventions auxquelles les résidents ont participé en tant que co-chirurgien ou assistant principal au cours de leur formation. L'enquête a également évalué les objectifs de carrière, le niveau d'intérêt dans la spécialité et la perception subjective d'un biais lié au genre. Résultats: En tout, 89 résidents en chirurgie plastique (taux de participation de 59,3 %) ont répondu à l'enquête et ont été inclus dans l'étude. Le nombre moyen de cas de chirurgie reconstructrice au cours desquelles les résidents sont intervenus en tant que co-chirurgien ou principal assistant était de 245 ± 312 cas. Il n'y a pas eu de différence entre les journaux de cas, qu'il s'agisse de chirurgie reconstructrice ou de chirurgie esthétique entre résidents masculins et féminins (P > 0,05). Cependant, un nettement plus grand pourcentage de femmes (39 %) que d'hommes (4 %) estimait que leur genre limitait leur exposition à des cas chirurgicaux et résultait dans une aggravation de leur formation globale à la chirurgie (P < 0,001). Enfin, un plus grand pourcentage de résidents masculins était intéressé par une carrière universitaire alors qu'un plus grand pourcentage de résidentes était intéressé par une pratique dans la communauté (P = 0,024). Conclusion: Bien qu'il n'y ait pas de données probantes étayant des différences de volume des cas consignés entre les genres, les résidentes féminines en chirurgie pensent encore que leur genre limite leur formation chirurgicale. Les inégalités entre genres devraient être abordées par les programmes de résidence.

Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology.

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism.

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.

Pharmacophore Variants of the Macrocyclic Peptide Triazole Inactivator of HIV-1 Env.

Previously we established a family of macrocyclic peptide triazoles (cPTs) that inactivate the Env protein complex of HIV-1, and identified the pharmacophore that engages Env's receptor binding pocket. Here, we examined the hypothesis that the side chains of both components of the triazole Pro - Trp segment of cPT pharmacophore work in tandem to make intimate contacts with two proximal subsites of the overall CD4 binding site of gp120 to stabilize binding and function. Variations of the triazole Pro R group, which previously had been significantly optimized, led to identification of a variant MG-II-20 that contains a pyrazole substitution. MG-II-20 has improved functional properties over previously examined variants, with Kd for gp120 in the nM range. In contrast, new variants of the Trp indole side chain, with either methyl- or bromo- components appended, had disruptive effects on gp120 binding, reflecting the sensitivity of function to changes in this component of the encounter complex. Plausible in silico models of cPT:gp120 complex structures were obtained that are consistent with the overall hypothesisof occupancy by the triazole Pro and Trp side chains, respectively, into the ß20/21 and Phe43 sub-cavities. The overall results strengthen the definition of the cPT-Env inactivator binding site and provide a new lead composition (MG-II-20) as well as structure-function findings to guide future HIV-1 Env inactivator design.

Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels.

The recent determination of cryo-EM structures of voltage-gated sodium (Nav) channels has revealed many details of these proteins. However, knowledge of ionic permeation through the Nav pore remains limited. In this work, we performed atomistic molecular dynamics (MD) simulations to study the structural features of various neuronal Nav channels based on homology modeling of the cryo-EM structure of the human Nav1.4 channel and, in addition, on the recently resolved configuration for Nav1.2. In particular, single Na+ permeation events during standard MD runs suggest that the ion resides in the inner part of the Nav selectivity filter (SF). On-the-fly free energy parametrization (OTFP) temperature-accelerated molecular dynamics (TAMD) was also used to calculate two-dimensional free energy surfaces (FESs) related to single/double Na+ translocation through the SF of the homology-based Nav1.2 model and the cryo-EM Nav1.2 structure, with different realizations of the DEKA filter domain. These additional simulations revealed distinct mechanisms for single and double Na+ permeation through the wild-type SF, which has a charged lysine in the DEKA ring. Moreover, the configurations of the ions in the SF corresponding to the metastable states of the FESs are specific for each SF motif. Overall, the description of these mechanisms gives us new insights into ion conduction in human Nav cryo-EM-based and cryo-EM configurations that could advance understanding of these systems and how they differ from potassium and bacterial Nav channels.

Discovery and design of G protein-coupled receptor targeting antibodies.

INTRODUCTION: G protein-coupled receptors (GPCRs) are the target of one-third of all approved drugs; however, these drugs only target about one-eighth of the human repertoire of GPCRs. GPCRs regulate a diverse range of critical physiological processes including organ development, cardiovascular function, mood, cognition, multicellularity, cellular motility, immune responses and sensation of light, taste, and odor. However, many GPCRs are expressed poorly, and a significant proportion have unknown ligands and unclear signaling pathways. AREAS COVERED: GPCRs are better suited to be targeted by monoclonal antibodies (mAbs) because of the challenges encountered in small-molecule discoveries such as druggability, selectivity, and distribution. mAbs have better drug-like properties in these respects. Herein, the authors review previously discovered functional mAbs that target GPCRs that are in the clinic and/or in development. They also review the biophysical considerations that make GPCRs so challenging to work with but also provide opportunities for biologic druggability. EXPERT OPINION: GPCRs are proven targets of small molecules yet remain an under-represented target of biologics. We believe that antibody drugs that target GPCRs have the potential to unlock new therapeutic avenues and also uncover previously unappreciated receptor biology, particularly when harnessing next-generation biologic modalities.

Structural and Functional Characterization of Indane-Core CD4-Mimetic Compounds Substituted with Heterocyclic Amines.

The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer on the virion surface interacts with the host receptors, CD4 and CCR5/CXCR4, to mediate virus entry into the target cell. CD4-mimetic compounds (CD4mcs) bind the gp120 Env, block CD4 binding, and inactivate Env. Previous studies suggested that a C(5)-methylamino methyl moiety on a lead CD4mc, BNM-III-170, contributed to its antiviral potency. By replacing the C(5) chain with differentially substituted pyrrolidine, piperidine, and piperazine ring systems, guided by structural and computational analyses, we found that the 5-position of BNM-III-170 is remarkably tolerant of a variety of ring sizes and substitutions, both in regard to antiviral activity and sensitization to humoral responses. Crystallographic analyses of representative analogues from the pyrrolidine series revealed the potential for 5-substituents to hydrogen bond with gp120 Env residue Thr 283. Further optimization of these interactions holds promise for the development of CD4mcs with greater potency.

The Global Task Force for Chronic Pain in People with HIV (PWH): Developing a research agenda in an emerging field.

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward.

Entropic Overcompensation of the N501Y Mutation on SARS-CoV-2 S Binding to ACE2.

Recent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoprotein's receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [Prévost et al. J. Biol. Chem.2021, 297, 101151]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on the enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Furthermore, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intraprotein root mean square fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Y's ability to remodel the inter-residue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein-protein binding affinity is the degree to which fluctuations are distributed throughout the complex and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result in increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.

A concept mapping study of service user design of safer supply as an alternative to the illicit drug market.

BACKGROUND: Within North America and worldwide, drug-related overdoses have increased dramatically over the past decade. COVID-19 escalated the need for a safer supply of illicit substances to reduce overdoses with hopes of replacing substances obtained from the illicit drug market. Drug users1 should be at the centre of program and policy decisions related to the development and implementation of safer supply. Yet, there is little empirical research that conceptualizes effective safer supply from their perspectives. METHOD: Within a community based participatory approach to research, we conducted a concept mapping study to foreground the perspectives of drug users and develop a conceptual model of effective safer supply. Our team was composed of researchers from a local drug user organization, a local harm reduction organization, and academic researchers. The focused prompt developed by the team was: "Safe supply would work well if…" Sixty-three drug users participated in three rounds of focus groups as part of the concept mapping process, involving brainstorming, sorting, rating and naming of themes. RESULTS: The concept mapping process resulted in six clusters of statements: 1) Right dose and right drugs for me; 2) Safe, positive and welcoming spaces; 3) Safer supply and other services are accessible to me; 4) I am treated with respect; 5) I can easily get my safer supply; and 6) Helps me function and improves my quality of life (as defined by me). The statements within each cluster describe key components central to an effective model of safer supply as defined by drug users. CONCLUSION: The results of this study provide insights into key components of effective safer supply to inform planning and evaluation of future safer supply programs informed by drug user perspectives.

Entropic overcompensation of the N501Y mutation on SARS-CoV-2 S binding to ACE2.

Recent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoprotein's receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by a greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [Prévost et al., J. Biol. Chem . (2021) 297;101151]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Further, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intra-protein root-mean squared fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Y's ability to remodel the interresidue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein-protein binding affinity is the degree to which fluctuations are distributed throughout the complex, and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.

Entropic overcompensation of the N501Y mutation on SARS-CoV-2 S binding to ACE2

Recent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoproteins receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by a greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [Prevost et al., J. Biol. Chem. (2021) 297;101151]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Further, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intra-protein root-mean squared fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Ys ability to remodel the interresidue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein-protein binding affinity is the degree to which fluctuations are distributed throughout the complex, and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.

Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)-study protocol for a phase 2, randomized, placebo controlled trial.

BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.