Preoperative Evaluation for Free Functional Muscle Transfer in Upper Extremity Amyoplasia: A Multicenter Report of 3 Cases.

CASE: A multicenter series of 3 patients with amyoplasia of the upper extremity were indicated for gracilis free functional muscle transfer (FFMT) to restore elbow flexion and found to have an absent gracilis. A final case is discussed detailing standardized evaluation with ultrasound to confirm gracilis before surgical intervention. CONCLUSION: In amyoplasia, the gracilis muscle may be absent or have fatty infiltration, making this donor muscle inadequate. Preoperative ultrasound to determine the presence of the gracilis is noninvasive and recommended in patients with amyoplasia of the upper extremity being considered for FFMT.

The use of acupuncture for addressing neurological and neuropsychiatric symptoms in patients with long COVID: a systematic review and meta-analysis.

Importance: Acupuncture has been used to treat neurological and neuropsychiatric symptoms in China and other parts of the world. These symptoms, such as fatigue, headache, cognitive impairment, anxiety, depression, and insomnia, are common in people experiencing long COVID. Objective: This study aims to explore the feasibility of acupuncture in the treatment of neurological and neuropsychiatric symptoms in long COVID patients. Data Sources: A systematic search was conducted in four English and four Chinese databases from inception to 23 June 2023. Literature selection and data extraction were conducted by two pairs of independent reviewers. Study Selection: Randomized controlled trials (RCTs) that explored the effect of acupuncture on fatigue, depression, anxiety, cognitive abnormalities, headache, and insomnia were included. Data Extraction and Synthesis: RCTs that explored the effect of acupuncture on fatigue, depression, anxiety, cognitive abnormalities, headache, and insomnia were included. A meta-analysis was performed using R software. Heterogeneity was measured using I2. Subgroup analyses were performed focusing on the duration of treatment and acupuncture modalities. The systematic review protocol was registered on PROSPERO (registration number: CRD42022354940). Main outcomes and measures: Widely adopted clinical outcome scales included the Fatigue Scale for assessing fatigue, the Hamilton Depression Rating Scale for evaluating depression, the Mini-Mental State Examination for assessing cognitive impairment, the Visual Analog Scale for headache severity, and the Pittsburgh Sleep Quality Index for measuring insomnia. Results: A total of 110 RCTs were included in the systematic review and meta-analysis. Overall, acupuncture was found to improve the scores of the Fatigue Scale (vs. medication: mean differences (MD): -2.27, P < 0.01; vs. sham acupuncture: MD: -3.36, P < 0.01), the Hamilton Depression Rating Scale (vs. medication: MD: -1.62, 95%, P < 0.01; vs. sham acupuncture: MD: -9.47, P < 0.01), the Mini-Mental State Examination (vs. medication: MD: 1.15, P < 0.01; vs. sham acupuncture: MD: 1.20, P < 0.01), the Visual Analog Scale (vs. medication: MD: -1.05, P < 0.01; vs. waitlist: MD: -0.48, P=0.04), and the Pittsburgh Sleep Quality Index (vs. medication: MD: -2.33, P < 0.01; vs. sham acupuncture: MD: -4.19, P < 0.01). Conclusion and relevance: This systematic review suggested acupuncture as a potentially beneficial approach for the treatment of neurological and neuropsychiatric symptoms, as assessed using clinical scales, and it may have applicability in long COVID patients. Further well-designed clinical studies specifically targeting long COVID patients are needed to validate the role of acupuncture in alleviating long COVID symptoms. Systematic Review Registration: PROSPERO, identifier [CRD42022354940].

A potent, broadly neutralizing human monoclonal antibody that efficiently protects hACE2-transgenic mice from infection with the Wuhan, BA.5, and XBB.1.5 SARS-CoV-2 variants.

The COVID-19 pandemic has uncovered the high genetic variability of the SARS-CoV-2 virus and its ability to evade the immune responses that were induced by earlier viral variants. Only a few monoclonal antibodies that have been reported to date are capable of neutralizing a broad spectrum of SARS-CoV-2 variants. Here, we report the isolation of a new broadly neutralizing human monoclonal antibody, iC1. The antibody was identified through sorting the SARS-CoV-1 RBD-stained individual B cells that were isolated from the blood of a vaccinated donor following a breakthrough infection. In vitro, iC1 potently neutralizes pseudoviruses expressing a wide range of SARS-CoV-2 Spike variants, including those of the XBB sublineage. In an hACE2-transgenic mouse model, iC1 provided effective protection against the Wuhan strain of the virus as well as the BA.5 and XBB.1.5 variants. Therefore, iC1 can be considered as a potential component of the broadly neutralizing antibody cocktails resisting the SARS-CoV-2 mutation escape.

A novel kinetic model to demonstrate the independent effects of ATP and ADP/Pi concentrations on sarcomere function.

Understanding muscle contraction mechanisms is a standing challenge, and one of the approaches has been to create models of the sarcomere-the basic contractile unit of striated muscle. While these models have been successful in elucidating many aspects of muscle contraction, they fall short in explaining the energetics of functional phenomena, such as rigor, and in particular, their dependence on the concentrations of the biomolecules involved in the cross-bridge cycle. Our hypothesis posits that the stochastic time delay between ATP adsorption and ADP/Pi release in the cross-bridge cycle necessitates a modeling approach where the rates of these two reaction steps are controlled by two independent parts of the total free energy change of the hydrolysis reaction. To test this hypothesis, we built a two-filament, stochastic-mechanical half-sarcomere model that separates the energetic roles of ATP and ADP/Pi in the cross-bridge cycle's free energy landscape. Our results clearly demonstrate that there is a nontrivial dependence of the cross-bridge cycle's kinetics on the independent concentrations of ATP, ADP, and Pi. The simplicity of the proposed model allows for analytical solutions of the more basic systems, which provide novel insight into the dominant mechanisms driving some of the experimentally observed contractile phenomena.

Superficial Branch of the Radial Nerve Versus Sural Nerve Grafting After Traumatic Adult Brachial Plexus Injury.

The purpose of this study was to compare two sources of nerve graft for brachial plexus reconstruction: the denervated superficial branch of the radial nerve (SBRN) and the sural nerve. Ninety-seven patients who underwent brachial plexus reconstruction with denervated SBRN nerve (24 patients with 24 grafts) or with sural nerve grafting (73 patients with 83 nerve grafts) were included. The two groups were compared with respect to postoperative muscle reinnervation, disabilities of the arm, shoulder, and hand (DASH) scores. In the SBRN group, only four (17%) of the nerve grafts provided grade III or higher muscle function. In the sural nerve group, 31 (37%) of the nerve grafts provided grade III or higher muscle function. Smoking had a negative impact on muscle recovery. Denervated SBRN grafts are associated with inferior outcomes when compared with sural nerve grafts in the treatment of traumatic adult brachial plexus injuries. (Journal of Surgical Orthopaedic Advances 33(2):080-083, 2024).

Triceps-to-Biceps Tendon Transfer Technique for Restoration of Elbow Flexion in Adult Brachial Plexus Injury.

Restoration of elbow flexion is a priority in treating adult traumatic brachial plexus injuries. A tendon transfer is an ideal option for patients not candidates for reconstructive nerve surgery or free-functioning muscle transfer. For patients with a partial brachial plexus injury or a pan plexus injury with adequate recovered triceps function and loss of elbow flexion, a triceps-to-biceps tendon transfer is a nonmicrosurgical option to restore elbow flexion. The technique of triceps-to-biceps transfer in which the complete triceps tendon is transferred laterally, secured lateral to the radial tuberosity, and reinforced with suture to the biceps tendon is described.

Diversity, Methane Oxidation Activity, and Metabolic Potential of Microbial Communities in Terrestrial Mud Volcanos of the Taman Peninsula.

Microbial communities of terrestrial mud volcanoes are involved in aerobic and anaerobic methane oxidation, but the biological mechanisms of these processes are still understudied. We have investigated the taxonomic composition, rates of methane oxidation, and metabolic potential of microbial communities in five mud volcanoes of the Taman Peninsula, Russia. Methane oxidation rates measured by the radiotracer technique varied from 2.0 to 460 nmol CH4 cm-3 day-1 in different mud samples. This is the first measurement of high activity of microbial methane oxidation in terrestrial mud volcanos. 16S rRNA gene amplicon sequencing has shown that Bacteria accounted for 65-99% of prokaryotic diversity in all samples. The most abundant phyla were Pseudomonadota, Desulfobacterota, and Halobacterota. A total of 32 prokaryotic genera, which include methanotrophs, sulfur or iron reducers, and facultative anaerobes with broad metabolic capabilities, were detected in relative abundance >5%. The most highly represented genus of aerobic methanotrophs was Methyloprofundus reaching 36%. The most numerous group of anaerobic methanotrophs was ANME-2a-b (Ca. Methanocomedenaceae), identified in 60% of the samples and attaining relative abundance of 54%. The analysis of the metagenome-assembled genomes of a community with high methane oxidation rate indicates the importance of CO2 fixation, Fe(III) and nitrate reduction, and sulfide oxidation. This study expands current knowledge on the occurrence, distribution, and activity of microorganisms associated with methane cycle in terrestrial mud volcanoes.

Study of the RNA splicing kinetics via in vivo 5-ethynyl uridine labelling.

Splicing, a process of intron removal from eukaryotic RNA transcripts, is an important step of gene expression in all eukaryotes. Splice sites might be used with different efficiency giving rise to alternative splicing products. At the same time, splice sites might be utilised at a variable rate. We used 5-ethynyl uridine labelling to sequence a nascent transcriptome of HeLa cells and deduce the rate of splicing for each donor and acceptor splice site. The following correlation analysis allowed us to assess a correspondence of primary transcript features with the rate of splicing. Some dependencies we revealed were anticipated, such as splicing rate decrease with a decreased complementarity of donor splice site to U1 and acceptor sites to U2 snRNAs, or an acceleration of donor site usage if an upstream acceptor site is located at a shorter distance. Other dependencies were more surprising, like a negative influence of a distance to the 5' end on the rate of acceptor splicing site utilization, or the differences in splicing rate between long, short and RBM17-dependent introns. We also observed a deceleration of last intron splicing with an increase of the distance to the polyA site, which might be explained by a cooperativity of the splicing and polyadenylation. In addition, we performed the analysis of splicing kinetics of SF3B4 knockdown cells which suggested the impairment of U2 snRNA recognition step. As a result, we deconvoluted the effects of several examined features on the splicing rate into a single regression model. The data obtained here are useful for further studies in the field as it provides general splicing rate dependencies as well as helps justify the existence of slowly removed splice sites, e.g. to ensure alternative splicing.

Medication for Opioid Use Disorder After Serious Injection-Related Infections in Massachusetts.

Importance: Serious injection-related infections (SIRIs) cause significant morbidity and mortality. Medication for opioid use disorder (MOUD) improves outcomes but is underused. Understanding MOUD treatment after SIRIs could inform interventions to close this gap. Objectives: To examine rehospitalization, death rates, and MOUD receipt for individuals with SIRIs and to assess characteristics associated with MOUD receipt. Design, Setting, and Participants: This retrospective cohort study used the Massachusetts Public Health Data Warehouse, which included all individuals with a claim in the All-Payer Claims Database and is linked to individual-level data from multiple government agencies, to assess individuals aged 18 to 64 years with opioid use disorder and hospitalization for endocarditis, osteomyelitis, epidural abscess, septic arthritis, or bloodstream infection (ie, SIRI) between July 1, 2014, and December 31, 2019. Data analysis was performed from November 2021 to May 2023. Exposure: Demographic and clinical factors potentially associated with posthospitalization MOUD receipt. Main Outcomes and Measures: The main outcome was MOUD receipt measured weekly in the 12 months after hospitalization. We used zero-inflated negative binomial regression to examine characteristics associated with any MOUD receipt and rates of treatment in the 12 months after hospitalization. Secondary outcomes were receipt of any buprenorphine formulation, methadone, and extended-release naltrexone examined individually. Results: Among 8769 individuals (mean [SD] age, 43.2 [12.0] years; 5066 [57.8%] male) who survived a SIRI hospitalization, 4305 (49.1%) received MOUD, 5919 (67.5%) were rehospitalized, and 973 (11.1%) died within 12 months. Of those treated with MOUD in the 12 months after hospitalization, the mean (SD) number of MOUD initiations during follow-up was 3.0 (1.7), with 956 of 4305 individuals (22.2%) receiving treatment at least 80% of the time. MOUD treatment after SIRI hospitalization was significantly associated with MOUD in the prior 6 months (buprenorphine: adjusted odds ratio [AOR], 16.51; 95% CI, 13.81-19.74; methadone: AOR, 28.46; 95% CI, 22.41-36.14; or naltrexone: AOR, 2.05; 95% CI, 1.56-2.69). Prior buprenorphine (incident rate ratio [IRR], 1.17; 95% CI, 1.11-1.24) or methadone (IRR, 1.89; 95% CI, 1.79-2.01) use was associated with higher treatment rates after hospitalization, and prior naltrexone use (IRR, 0.86; 95% CI, 0.77-0.95) was associated with lower rates. Conclusions and Relevance: This study found that in the year after a SIRI hospitalization in Massachusetts, mortality and rehospitalization were common, and only half of patients received MOUD. Treatment with MOUD before a SIRI was associated with posthospitalization MOUD initiation and time receiving MOUD. Efforts are needed to initiate MOUD treatment during SIRI hospitalizations and subsequently retain patients in treatment.

Intra-arterial Pressure Enabled Drug Delivery Significantly Increases Penetration of Glass Microspheres in a Porcine Liver Tumor Model.

PURPOSE: To test the hypothesis that Pressure Enabled Drug Delivery (PEDD) with a TriNav device (TNV-21120-35, TriSalus Life Sciences, Westminster, CO) would improve the delivery of surrogate therapeutic glass microspheres (GM) via hepatic artery infusion (HAI) to liver tumors when compared to a conventional endhole microcatheter. MATERIALS AND METHODS: The study was conducted in transgenic pigs (Oncopigs) with induced liver tumors. Tumors were infused intra-arterially with fluorescently labeled GM. PEDD with a TriNav device was compared to conventional endhole delivery in both lobar and selective infusions. Near-Infrared (nearIR) imaging was used to detect GM fluorescent signal in tumors. Image analysis with a custom Deep Learning algorithm (Visiopharm A/S) was used to quantitate signal intensity in relation to the tumor border. RESULTS: With lobar infusions, significant increases in GM signal intensity were observed in and around tumors after PEDD (n=10) when compared to conventional delivery (n=7), with PEDD increasing penetration into the tumor by 117% (p = 0.004). In selective infusions, PEDD (n=9) increased penetration into the tumor by 39% relative to conventional delivery (n=8, p =0.032). Lobar PEDD delivery of GM to the tumor was statistically equivalent to conventional selective delivery (p=0.497). CONCLUSIONS: PEDD with a TriNav device significantly improved GM uptake in liver tumors relative to conventional infusion in both lobar and selective procedures. Lobar GM delivery with PEDD was equivalent to conventional selective delivery with an endhole device, suggesting that proximal PEDD infusions may enable effective delivery without selection of distal target vessels.

Multilevel Factors Impacting Substance Use Treatment Access, Engagement, and Racial Equity Among Opioid Overdose Survivors in Boston, MA.

BACKGROUND: There are well-documented racial/ethnic inequities in drug-related overdoses and access to evidence-based opioid use services nationally and in Boston, MA. OBJECTIVE: To qualitatively explore the drivers of racial/ethnic inequities in access to opioid use disorder treatment and services in Boston. DESIGN: Semi-structured qualitative interviews. PARTICIPANTS: Using purposive sampling, researchers recruited 59 opioid overdose survivors in Boston who self-identified as Black, Hispanic or Latino/a/x, and/or White. APPROACH: Interviewers administered a socio-demographic and drug use survey, and used a semi-structured interview guide to explore experiences with and perspectives on substance use treatment and services. KEY RESULTS: Participants' racial/ethnic identities were distributed across three subgroups: non-Hispanic Black (n = 18; 31%), non-Hispanic White (n = 18; 31%), and Latino/a/x (n = 23; 39%). Qualitative analysis identified multiple themes that were organized into four social-ecological levels after analysis. At the individual level, some participants emphasized the importance of personal responsibility and individual motivation in determining access to services. Participants expressed a range of perspectives about using medication for opioid use disorder treatment; Black and Latino/a/x participants were more likely than White participants to have critical perspectives. At the interpersonal level, experiences of bias, stigma, and racism from staff in healthcare and treatment settings were common. At the program/process level, participants described challenges connecting to services following overdose and barriers within specific programs, with Black and Latino/a/x participants experiencing particular gaps. At the systems level, the limited availability of housing, employment, and mental health care negatively impacted treatment access and engagement. CONCLUSION: A racism lens was used during data interpretation to apply the themes at a broader population level. Through this lens, the identified barriers can be understood to have a disproportionate impact on people of color. Findings call for programmatic and policy solutions that address racism, break down stigma, and ensure equitable access to evidence-based services and social supports.

Biphasic co-detection of melanoma aneuploid tumor cells and tumor endothelial cells in guidance of specifying the field cancerized surgical excision margin and administering immunotherapy.

An optimum safety excision margin (EM) delineated by precise demarcation of field cancerization along with reliable biomarkers that enable predicting and timely evaluating patients' response to immunotherapy significantly impact effective management of melanoma. In this study, optimized biphasic "immunofluorescence staining integrated with fluorescence insitu hybridization" (iFISH) was conducted along the diagnosis-metastasis-treatment-cellular MRD axis to longitudinally co-detect a full spectrum of intact CD31- aneuploid tumor cells (TCs), CD31+ aneuploid tumor endothelial cells (TECs), viable and necrotic circulating TCs (CTCs) and circulating TECs (CTECs) expressing PD-L1, Ki67, p16 and Vimentin in unsliced specimens of the resected primary tumor, EM, dissected sentinel lymph nodes (SLNs) and peripheral blood in an early-stage melanoma patient. Numerous PD-L1+ aneuploid TCs and TECs were detected at the conventional safety EM (2 cm), quantitatively indicating the existence of a field cancerized EM for the first time. Contrary to highly heterogeneous PD-L1 expression and degrees of Chr8 aneuploidy in TCs and TECs in the primary lesions as well as CTCs and CTECs in peripheral blood, almost all TCs and TECs in SLNs and EM were homogeneously PD-L1+ haploid cells. Dynamic monitoring and cellular MRD assessment revealed that, in contrast to PD-L1+ CTCs being responsive to the immune checkpoint inhibitor (ICI-anti-PD-1), multiploid (≥pentasomy 8) PD-L1+ and Ki67+ CTECs were respectively resistant to ICI-sensitized T cells. In therapeutically stressed lymphatic and hematogenous metastatic cascades, stratified phenotypic and karyotypic profiling of iFISH tissue and liquid biopsied TCs, TECs, CTCs and CTECs in future large-cohort studies will enable appropriate re-specification of the optimal safety EM and distribution mapping of in-depth characterized, subcategorized target cells to help illustrate their metastatic relevance, ultimately improving risk stratification and clinical intervention of tumor progression, metastases, therapy resistance and cancer relapse.

Neoadjuvant Immunotherapy Effectiveness in Patients With Microsatellite Instability-High (MSI-H) Gastric Cancer.

Purpose This research work evaluates monotherapy with checkpoint inhibitors (CPI). as a neoadjuvant treatment for patients with Microsatellite Instability-High (MSI-H) locally advanced gastric cancer. Methods Here we present the results of the retrospective study from Napalkov Cancer Center over 4.5 years on patients with MSI-H locally advanced gastric cancer. A total of 566 patients were analyzed, 18 of whom were included in the research, focusing on clinical response rate, surgical pathology, 'watch and wait' strategy, and safety outcomes on an exploratory basis. Patients were assigned to four to eight neoadjuvant cycles of CPI, followed by surgery. Results The objective response to neoadjuvant CPI in patients with MSI-H gastric cancer was 77.8%. Complete response was achieved in five (27.8%) and partial response in nine (50%) patients, accordingly. Surgery was performed on 14 patients. Complete margin-free (R0) resection rates were 100%. Downstaging was observed in 12 out of 14 patients. Histopathologic complete response rates (pathologic complete response or Tumor Regression Grade-major response (TRG1)) were achieved in eight (57.1%) patients. No disease progression was detected with a median follow-up of 33.7 months (4.4-55.7 months). Clinically significant adverse events were not observed. Conclusion CPI in a neoadjuvant setting for patients with MSI-H locally advanced gastric cancer is highly effective and safe.

Receipt of medications for opioid use disorder before and after incarceration in Massachusetts State prisons, 2014-2019.

BACKGROUND: Little is known about how use patterns of medications for opioid use disorder (MOUDs) evolve from pre-incarceration to post-incarceration among incarcerated individuals with opioid use disorder. This article describes pre- and post-incarceration MOUD receipt during a period when naltrexone was the only type of MOUD offered in a state prison system, the Massachusetts Department of Correction (MADOC). METHODS: A retrospective cohort study of individuals with opioid use disorder who had an incarceration episode in MADOC during January 2015 to March 2019. The data source was the Massachusetts Public Health Data Warehouse, a multi-sector data platform that links individual-level data from multiple statewide datasets. We described patterns of MOUD receipt during the four weeks prior to and after an incarceration episode. Multivariable logistic regression models characterized predictors of post-incarceration MOUD receipt. RESULTS: In the male sample (n=691 incarcerations), from the pre- to post-incarceration periods, receipt of buprenorphine increased (14.3 % to 18.3 %), naltrexone increased (5.0 % to 10.5 %), and methadone decreased (4.7 % to 1.7 %). Similarly, in the female sample (n=892 incarcerations), from the pre- to post-incarceration periods, receipt of buprenorphine increased (10.3 % to 12.3 %, naltrexone increased (4.5 % to 9.3 %), and methadone decreased (5.0 % to 2.9 %). Much of the post-release naltrexone receipt occurred among participants in MADOC's pre-release naltrexone program. CONCLUSIONS: MOUD receipt was low but increased slightly in the post-incarceration period. This change was driven by increases in buprenorphine and naltrexone and despite decreases in methadone.

Ignisphaera cupida sp. nov., a hyperthermophilic hydrolytic archaeon from a hot spring of Uzon (Kamchatka), and emended description of the genus Ignisphaera.

A novel strictly anaerobic hyperthermophilic archaeon, strain 4213-coT, was isolated from a terrestrial hot spring in the Uzon Caldera, Kamchatka (Russian Federation). Coccoid cells were present singly, in pairs, or aggregates, and occasionally were motile. The strain grew at 75-100 °C and within a pH range of 5.4-8.2 with the optimum at 92 °C and pH 6.4-6.7. Strain 4213-coT was a chemoorganoheterotroph, growing on proteinaceous substrates and mono-, di- and polysaccharides (starch, guar gum, xanthan gum). It did not require sodium chloride for growth. The complete genome of strain 4213-coT was 1.74 Mbp in size; its G+C content was 36.18 %. Genome analysis allowed to identify 25 genes encoding glycosidases involved in polysaccharide hydrolysis as well as genes of ADP-forming acetate-CoA ligase, lactate dehydrogenase and two [NiFe] hydrogenases responsible for acetate, lactate and hydrogen formation during fermentation. Moreover gene cluster encoding archaellum subunits was found. According to the phylogenomic analysis strain 4213-coT formed a species-level phylogenetic lineage within Ignisphaera genus. Our phylogenomic analysis also supports the delineation of the Ignisphaera genus into a separate family Ignisphaeraceae, as recently published. Here we propose a novel species Ignisphaera cupida, sp. nov. with type strain 4213-coT (=JCM 39446T=VKM B-3715T=UQM 41593T). Ecogenomic analysis showed that representatives of the Ignisphaera are thermophilic archaea, the majority of them were found in terrestrial hot springs and deep-sea hydrothermal vents. This study allowed a better understanding of physiology and ecology of Ignisphaeraceae - a rather understudied archaeal group.

Phosphorylation of (Ser 291) in the linker insert of Syk negatively regulates ITAM signaling in platelets.

Receptor-induced tyrosine phosphorylation of spleen tyrosine kinase (Syk) has been studied extensively in hematopoietic cells. Metabolic mapping and high-resolution mass spectrometry, however, indicate that one of the most frequently detected phosphorylation sites encompassed S297 (S291 in mice) located within the linker B region of Syk. It has been reported that Protein kinase C (PKC) phosphorylates Syk S297, thus influencing Syk activity. However, conflicting studies suggest that this phosphorylation enhances as well as reduces Syk activity. To clarify the function of this site, we generated Syk S291A knock-in mice. We used platelets as a model system as they possess Glycoprotein VI (GPVI), a receptor containing an immunoreceptor tyrosine-based activation motif (ITAM) which transduces signals through Syk. Our analysis of the homozygous mice indicated that the knock-in platelets express only one isoform of Syk, while the wild-type expresses two isoforms at 69 and 66 kDa. When the GPVI receptor was activated with collagen-related peptide (CRP), we observed an increase in functional responses and phosphorylations in Syk S291A platelets. This potentiation did not occur with AYPGKF or 2-MeSADP, although they also activate PKC isoforms. Although there was potentiation of platelet functional responses, there was no difference in tail bleeding times. However, the time to occlusion in the FeCl3 injury model was enhanced. These data indicate that the effects of Syk S291 phosphorylation represent a significant outcome on platelet activation and signaling in vitro but also reveals its multifaceted nature demonstrated by the differential effects on physiological responses in vivo.

What is the context Spleen tyrosine kinase (Syk) is present a number of cells and important in controlling the functions of various cells and organs.Syk is known to exist in two isoforms Syk L (long form or Syk A) and Syk S (short form or Syk B).It is known that phosphorylation events regulate Syk activation and activity.In several inflammatory disease conditions, Syk mutants are known to play a role.Phosphorylation of the Syk residue Serine 291 is known to occur, but its function in the regulation of Syk activation or activity is not known.What is new In this study, we generated a mutant mouse Syk S291A, which cannot be phosphorylated on serine residue. We evaluated the function of platelets isolated from these mice and compared them to platelets isolated from wild type littermates.We observed that the mutation in Syk L unexpectedly caused Syk S to disappear from a number of tissues.Platelet functions are enhanced in mutant mouse platelets compared to those from wild-type mice.What is the impact These studies enhance our understanding of the impact of Serine 291 phosphorylation on the function of Syk in platelets.

PrEP facilitators and barriers in substance use bridge clinics for women who engage in sex work and who use drugs.

BACKGROUND: Women who engage in sex work and use drugs (WSWUD) experience disproportionate HIV risks. Substance use treatment bridge clinics offer an opportunity to increase HIV pre-exposure prophylaxis (PrEP) delivery to WSWUD, but research on best practices is lacking. Therefore, we explored facilitators and barriers to PrEP across the PrEP care continuum in these settings. METHODS: Bridge clinic and affiliated harm reduction health service providers and WSWUD from Boston were recruited using passive and active outreach between December 2021 and August 2022. Participants were invited to take part in semi-structured phone or in-person interviews to explore HIV prevention and PrEP care experiences overall and within bridge clinic settings. Deductive codes were developed based on HIV risk environment frameworks and the Information-Motivation-Behavioral Skills model and inductive codes were added based on transcript review. Grounded content analysis was used to generate themes organized around the PrEP care continuum. RESULTS: The sample included 14 providers and 25 WSWUD. Most WSWUD were aware of PrEP and more than half had initiated PrEP at some point. However, most who initiated PrEP did not report success with daily oral adherence. Providers and WSWUD described facilitators and barriers to PrEP across the steps of the care continuum: Awareness, uptake, adherence, and retention. Facilitators for WSWUD included non-stigmatizing communication with providers, rapid wraparound substance use treatment and HIV services, having a PrEP routine, and service structures to support PrEP adherence. Barriers included low HIV risk perceptions and competing drug use and survival priorities. Provider facilitators included clinical note templates prompting HIV risk assessments and training. Barriers included discomfort discussing sex work risks, competing clinical priorities, and a lack of PrEP adherence infrastructure. CONCLUSION: WSWUD and bridge clinic providers favored integrated HIV prevention and substance use services in harm reduction and bridge clinic settings. Harm reduction and bridge clinic programs played a key role in HIV prevention and PrEP education for WSWUD. Effective behavioral and structural interventions are still needed to improve PrEP adherence for WSWUD.