Post-Overdose Extended-Release Buprenorphine Initiation Facilitated by a Partnership Between Emergency Medical Services and an Outpatient Substance Use Disorder Observation Unit.

BACKGROUND: People who experience a nonfatal opioid overdose and receive naloxone are at high risk of subsequent overdose death but experience gaps in access to medications for opioid use disorder. The immediate post-naloxone period offers an opportunity for buprenorphine initiation. Limited data indicate that buprenorphine administration by emergency medical services (EMS) after naloxone overdose reversal is safe and feasible. We describe a case in which a partnership between a low-barrier substance use disorder (SUD) observation unit and EMS allowed for buprenorphine initiation with extended-release injectable buprenorphine after naloxone overdose reversal. CASE: A man in his 40's with severe opioid use disorder and numerous prior opioid overdoses experienced overdose in the community. EMS was activated and he was successfully resuscitated with intranasal naloxone, administered by bystanders and EMS. He declined emergency department (ED) transport and consented to transport to a 24/7 SUD observation unit. The patient elected to start buprenorphine due to barriers attending opioid treatment programs daily. His largest barrier was unsheltered homelessness. His severe opioid withdrawal symptoms were successfully treated with 16/4 mg sublingual buprenorphine/naloxone and 300 mg extended-release injectable buprenorphine (XR-buprenorphine), without precipitated withdrawal. Two weeks later, he reported no interval fentanyl use. DISCUSSION: We describe the case of a patient successfully initiated onto XR-buprenorphine in the immediate post-naloxone period via a partnership between an outpatient low-barrier addiction programs and EMS. Such partnerships offer promise in expanding buprenorphine access and medication choice, particularly for the high-risk population of patients who decline ED transport.

How Would You Manage HIV Pre-exposure Prophylaxis in This Patient With Medical Comorbidities? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Despite advances in treatment, HIV infection remains an important cause of morbidity and mortality, with more than 30 000 new cases diagnosed in the United States each year. There are several interventions traditionally used to prevent HIV transmission, but these vary in effectiveness and there are challenges to their implementation. In 2014, the Centers for Disease Control and Prevention published initial guidance on the use of antiretroviral pre-exposure prophylaxis (PrEP) to prevent transmission of HIV infection in persons at risk based on multiple studies that showed it to be highly efficacious in various populations. It was updated in 2021 to reflect new drug options. The U.S. Preventive Services Task Force also recently updated its recommendations for PrEP, which strongly support its use in persons at risk. Despite its well-established effectiveness, the implementation of PrEP in clinical practice has been variable, especially among populations underserved by the medical system and marginalized by society. Fewer than one third of persons in the United States who are eligible for PrEP currently receive it. Here, 2 physicians experienced in HIV PrEP debate how best to identify patients who might benefit from PrEP, how to decide what regimen to use, and how to monitor therapy.

Obesity and Associated Outcomes for Blunt vs Penetrating Mechanism in Trauma Laparotomy Patients.

Obesity in trauma patients is an established risk factor contributing to postoperative complications, but the relationship between body mass index (BMI) and trauma patient outcomes is not well-defined, especially when stratified by mechanism of injury. We surveyed the trauma laparotomy registry at an academic level 1 trauma center over a 3-year period to identify mortality, injury severity score, and hospital length of stay (hLOS) outcome measures across BMI classes, with further stratification by mechanism of injury: blunt vs penetrating trauma. A total of 442 patients were included with mean age 44.6 (SD = 18.7) and mean BMI 28.55 (SD = 7.37). These were subdivided into blunt trauma (n = 313) and penetrating trauma (n = 129). Within the blunt trauma subgroup, the hLOS among patients who survived hospitalization significantly increased 9% for each successive BMI class (P = .022, 95% CI = 1.29-17.5). We conclude that successive increase in BMI class is associated with longer hospital stay for blunt trauma patient survivors requiring laparotomy, though additional analysis is needed to establish this relationship to other outcome measures and among penetrating trauma patients.

Addressing Unmet PrEP Needs in Women: Impact of a Laboratory-Driven Protocol at an Urban, Essential Hospital.

Background: HIV pre-exposure prophylaxis (PrEP) uptake in women remains low. We developed a laboratory result-driven protocol to link women with a positive bacterial sexually transmitted infection (STI) to HIV PrEP at an urban safety-net hospital. Methods: Electronic health records of women with positive chlamydia, gonorrhea, and/or syphilis tests were reviewed, and those eligible for PrEP were referred for direct or primary care provider-driven outreach. We assessed the proportion of women with STIs who received PrEP offers, acceptance, and prescriptions before (July 1, 2018-December 31, 2018) and after (January 1, 2019-June 30, 2020) implementation to evaluate changes in the delivery of key elements of the PrEP care cascade (ie, PrEP offers, acceptance, and prescribing) for women with STIs after protocol implementation. Results: The proportion of women who received PrEP offers increased from 7.6% to 17.6% (P < .001). After multivariable adjustment, only the postintervention period was associated with PrEP offers (odds ratio [OR], 2.49; 95% CI, 1.68-3.68). In subgroup analyses, PrEP offers increased significantly among non-Hispanic Black (OR, 2.75; 95% CI, 1.65-4.58) and Hispanic (OR, 5.34; 95% CI, 1.77-16.11) women but not among non-Hispanic White women (OR, 1.49; 95% CI, 0.54-4.05). Significant changes in PrEP acceptance and prescriptions were not observed in the sample overall. Conclusions: A laboratory result-driven protocol was associated with a significant increase in PrEP offers to Black and Hispanic women with STI. These results provide concrete suggestions for health systems seeking to increase PrEP access and equity among women.

Feasibility of paying people who use drugs cash to distribute naloxone within their networks.

INTRODUCTION: Immediate access to naloxone is needed to prevent fatal opioid-related overdoses in the presence of fentanyl analogs saturating the opioid supply. Peer models engage impacted populations who are not accessing naloxone through standard venues, yet compensating peers who utilize syringe service programs with cash stipends to distribute naloxone within networks of people who use drugs is not well described. METHODS: As part of the HEALing Communities Study, syringe service program-based interventions were developed in Holyoke and Gloucester, MA, which paid people who use drugs ("peers") cash to distribute naloxone. Early program outcomes were evaluated for the time each program was funded within the HCS study period. RESULTS: During 22 study-months of observation, peers in two communities distributed 1104 naloxone kits. The total cost of peer compensation for program delivery was $10,510. The rate of peer-distributed naloxone per 100 K population reached 109 kits/mo and 222 kits/mo in the two communities. Participating peers addressed gaps in harm reduction outreach and distributed naloxone and other harm reduction equipment to individuals who were not syringe service program participants, expanding organizational reach. Being compensated with unrestricted cash stipends supported dignity and acknowledged peers' work in overdose prevention. CONCLUSION: The underutilization of compensated peer models is often attributed to funding and organizational barriers. These programs demonstrate that providing cash stipends to peers is feasible and expanded naloxone distribution at two existing syringe service programs. Providing cash stipends for peers who engage in secondary naloxone distribution offers promise in delivering naloxone to people not accessing syringe services.

Novel Uses of Methadone Under the "72-Hour Rule" to Facilitate Transitions of Care and Low-Dose Buprenorphine Induction in an Outpatient Bridge Clinic.

BACKGROUND: Federal regulations restrict methadone for opioid use disorder (OUD) treatment to licensed opioid treatment programs (OTPs). However, providers in other settings can administer methadone for opioid withdrawal under the "72-hour rule" while linking to further care. Prior work has demonstrated that methadone initiation in a low-barrier bridge clinic is associated with high OTP linkage and 1-month retention rates. We describe 2 other novel applications of the 72-hour rule in which methadone withdrawal management facilitated linkage to inpatient hospitalization and outpatient buprenorphine induction. CASE PRESENTATIONS: Patient 1 was a 46-year-old woman with OUD complicated by serious injection-related infections. Severe opioid withdrawal limited her ability to tolerate emergency department wait times and receive inpatient care. We administered methadone for opioid withdrawal in an outpatient bridge clinic immediately before emergency department referral; this enabled hospital admission for intravenous antibiotics and anticoagulation. Patient 2 was a 36-year-old man with OUD desiring buprenorphine treatment. He had been unable to complete traditional buprenorphine induction without experiencing precipitated withdrawal. Thus, we recommended a low-dose buprenorphine induction overlapping with a full opioid agonist. Given the patient's preference to stop using fentanyl immediately, he received 72 hours of methadone for withdrawal treatment during the induction phase and successfully transitioned to buprenorphine without significant concomitant fentanyl use. CONCLUSION: In addition to facilitating OTP linkage, on-demand 72-hour methadone administration for opioid withdrawal can reduce barriers to acute medical care and buprenorphine treatment.

Understanding the Strengths and Limitations of Current Methods for Surveying Partner Nation Medical Facilities.

INTRODUCTION: During exercises or operations, there may be times when U.S. medical capabilities are not available and the next best or only option may be to use partner nation (PN) or host nation capabilities. Joint Publication 4-02 Joint Health Services states that "medical planners should always consider the quality, suitability, and availability of multinational and host-nation support." It is normal practice for medical planners to survey PN medical capabilities as part of the pre-deployment planning process. Currently, medical capability surveys are not conducted in a consistent and systematic manner across the DoD global health engagement enterprise. The lack of a systematic approach undermines medical operations planners' ability to conduct efficient and adequate pre-deployment surveys. MATERIALS AND METHODS: The article presents the results of a descriptive analysis of 62 unclassified medical capability surveys of PN or host nation facilities from the U.S. Africa Command (USAFRICOM) area of responsibility that were conducted by U.S. DoD personnel. The team characterized the content and formats of surveys with respect to what medical capabilities were described, how the capabilities were described, and how the information was presented. These analyses focused on determining if a surveyor obtained information about a capability, not whether or not the facility had a capability. RESULTS: Approximately 75-80% of surveys included information describing the presence or absence of five key capabilities: Emergency department/trauma care, surgical services, intensive care unit, laboratory, and imaging. Conversely, 30-50% of surveys did not include any information describing the presence or absence of five other key capabilities: Pharmacy, blood bank, mass casualty plans, land evacuation, or air evacuation. Information on key capabilities and administrative information was not consistently reported across the sample of surveys. There was substantial variation in how capabilities were characterized, including number of staff, staff training, and available equipment. Additionally, the order in which information was presented in surveys varied within and across components. CONCLUSIONS: There are significant inconsistencies in the types of capabilities and services documented and how the quality of the capabilities and services is characterized. These inconsistencies can be attributed, in part, to the absence of information that explicitly confirmed whether or not the facility had a capability. Such variation results in obscured or incomplete depictions of facility capabilities, thereby undermining the ability of medical planners to coordinate effective medical readiness for engagements, exercises, or real-life operations. Guidance and survey templates could support better-informed decision-making by including information about survey methods and documenting the lack of confirmatory information. The DoD enterprise should consider how guidance and a standard survey template could improve the relevance, accuracy, and efficiency of data collection and reporting.

Review of terrestrial temporarily conserved areas in Canada, the United States, and Mexico.

The establishment of protected areas is a cornerstone of conservation, but permanent protection could be inefficient or even impossible in some situations. We synthesized the literature on temporarily conserved areas (TCAs) across Canada, the United States, and Mexico. We used a comprehensive search string to retrieve peer-reviewed articles published from 2000 to 2021 from the Web of Science. We identified 27 relevant peer-reviewed articles that examined the potential benefits of TCAs in the study area, indicating TCA is a relatively understudied area of research in the peer-reviewed literature. The TCA studies were highly clustered; 77% of studies focused on protecting a single life stage of migratory species and 61% of studies related to temporary conservation of breeding or staging habitats for migratory birds. Ninety-three percent of studies focused on preventing human-driven threats, mainly on public lands of coastal areas, the Great Plains, and the Mississippi Valley in the central United States. Short-term and experimental studies were the dominant study types. TCAs have the potential to complement permanently protected areas and provide protection when permanent protection is difficult. Some included studies examined their conservation value, but the ecological, social, and economic outcomes of TCAs are unclear. More TCA research is needed to determine the role they could play in conservation worldwide. Embracing the concept of TCAs as conservation tool could lead to more comprehensive and consistent reporting of the outcomes of temporary area-based conservation measures. However, a global review and analysis of effectiveness of TCAs will be required if they are to play a formal role in meeting international targets for biodiversity conservation.

Revisión de áreas terrestres conservadas temporalmente en Canadá, Estados Unidos y México Resumen La creación de áreas protegidas es una piedra angular de la conservación, aunque en algunos casos la protección permanente podría ser ineficiente o incluso imposible. Condensamos la literatura sobre las áreas de conservación temporal (ACT) en Canadá, Estados Unidos y México. Usamos una cadena completa de búsqueda para obtener artículos revisados por pares publicados del 2000 al 2021 en Web of Science. Identificamos 27 artículos relevantes que analizaban el potencial de las ACT en el área de estudio, lo que indica que las ACT es un área poco estudiada en la literatura revisada por pares. Los estudios sobre ACT estaban muy agrupados: el 77% se enfocaban en la protección de un solo estadio de vida de las especies migratorias y el 61% se relacionaban con la conservación temporal de los hábitats de reproducción o de descanso de las aves migratorias. El 93% de los estudios se enfocó en la prevención de amenazas causadas por humanos, principalmente en los terrenos públicos de las áreas costeras, las Grandes Llanuras y el valle del Mississippi en el centro de los Estados Unidos. Los estudios experimentales y a corto plazo fueron el tipo de estudio dominante. Las áreas de conservación temporal tienen el potencial para complementar las áreas de protección permanente y proporcionar protección cuando es complicado proporcionarla permanentemente. Algunos de los estudios incluidos analizaron el valor para la conservación de las ACT, pero aún no están claros sus resultados ecológicos, sociales y económicos. Se necesita más investigación sobre las ACT para determinar el papel que podrían tener en la conservación mundial. Si se acepta el concepto de ACT como una herramienta de conservación, se podrían reportar los resultados de las medidas de conservación basadas en las ACT de forma más completa y consistente. Sin embargo, se requerirá una revisión y análisis global de la eficiencia de las ACT si se espera que tengan un papel formal en el cumplimiento de los objetivos internacionales de la conservación de la biodiversidad.

Mobile treatment for opioid use disorder: Implementation of community-based, same-day medication access interventions.

BACKGROUND: Medications for Opioid Use Disorder (MOUD) are lifesaving, but <20 % of individuals in the US who could benefit receive them. As part of the NIH-supported HEALing Communities Study (HCS), coalitions in several communities in Massachusetts and Ohio implemented mobile MOUD programs to overcome barriers to MOUD receipt. We defined mobile MOUD programs as units that provide same-day access to MOUD at remote sites. We aimed to (1) document the design and organizational structure of mobile programs providing same-day or next-day MOUD, and (2) explore the barriers and facilitators to implementation as well as the successes and challenges of ongoing operation. METHODS: Program staff from five programs in two states (n = 11) participated in semi-structured interviews. Two authors conducted thematic analysis of the transcripts based on the domains of the social-ecological model and the semi-structured interview guide. RESULTS: Mobile MOUD units sought to improve immediate access to MOUD ("Our answer is pretty much always, 'Yes, we'll get you started right here, right now,'"), advance equity ("making sure that we have staff who speak other languages, who are on the unit and have some resources that are in different languages,"), and decrease opioid overdose deaths. Salient program characteristics included diverse staff, including staff with lived experience of substance use ("She just had that personal knowledge of where we should be going"). Mobile units offered harm reduction services, broad medical services (in particular, wound care), and connection to transportation programs and incorporated consistency in service provision and telemedicine access. Implementation facilitators included trusting relationships with partner organizations (particularly pharmacies and correctional facilities), nuanced understanding of local politics, advertising, protocol flexibility, and on-unit prescriber hours. Barriers included unclear licensing requirements, staffing shortages and competing priorities for staff, funding challenges due to inconsistency in grant funding and low reimbursement ("It's not really possible that billing in and of itself is going to be able to sustain it"), and community stigma toward addiction services generally. CONCLUSIONS: Despite organizational, community, and policy barriers, participants described mobile MOUD units as an innovative way to expand access to life-saving medications, promote equity in MOUD treatment, and overcome stigma.

Intranasal Naloxone for Opioid Overdose.

This JAMA Insights describes indications for naloxone use in preventing opioid overdoses and benefits vs barriers to its availability following FDA approval of its availability without a prescription.

Sustained long-term disease correction in a murine model of MPSII following stem cell gene therapy.

Mucopolysaccharidosis type II (MPSII) is a pediatric lysosomal storage disease caused by deficiencies in the IDS (iduronate-2-sulfatase) gene resulting in accumulation of glycosaminoglycans, multisystem disease, and profound neurodegeneration in severe forms. Although enzyme replacement therapy is available for somatic forms of disease, the inability of native IDS to pass the blood-brain barrier renders it ineffective for the brain. We previously demonstrated the short-term efficacy of a brain-targeted hematopoietic stem cell gene therapy approach to treat MPSII mice using lentiviral IDS fused to the blood-brain-barrier-crossing peptide ApoEII (IDS.ApoEII) in comparison with a lentivirus expressing native IDS and an unmanipulated bone marrow transplant. Here we evaluated the longevity of disease correction for 12-16 months following treatment. We observed sustained IDS enzyme activity in organs of long-term IDS.ApoEII-treated MPSII mice, similar to those analyzed 6 months post-treatment, with continued clearance of storage material in the brain and peripheral organs, maintained correction of astrogliosis, microgliosis, and correction of altered cytokines and chemokines. IDS.ApoEII also significantly reduced retinal atrophy, characteristic of MPSII. Overall, IDS.ApoEII resulted in systemic prevention of the MPSII phenotype, with no observed toxicity following treatment. This provides evidence of the sustained efficacy and safety of this treatment ahead of a recently opened clinical trial.

Facilitating exit from encampments: combining low-barrier transitional housing with stabilizing treatment for substance related problems.

BACKGROUND: Tent encampments in the neighborhood surrounding Boston Medical Center (BMC) grew to include 336 individuals at points between 2019 and 21, prompting public health concerns. BMC, the City of Boston, and Commonwealth of Massachusetts partnered in 2/2022 to offer low-barrier transitional housing to encampment residents and provide co-located clinical stabilization services for community members with substance use disorders (SUDs) experiencing homelessness. METHODS: To meet the needs of some of the people who had been living in encampments, BMC established in a former hotel: 60 beds of transitional housing, not contingent upon sobriety; and a low-barrier SUD-focused clinic for both housing residents and community members, offering walk-in urgent care, SUD medications, and infection screening/prevention; and a 24/7 short-stay stabilization unit to manage over-intoxication, withdrawal, and complications of substance use (e.g., abscesses, HIV risk, psychosis). A secure medication-dispensing cabinet allows methadone administration for withdrawal management. Housing program key metrics include retention in housing, transition to permanent housing, and engagement in SUD treatment and case management. Clinical program key metrics include patient volume, and rates of initiation of medication for opioid use disorder. RESULTS: Housing: Between 2/1/22-1/31/2023, 100 people entered the low-barrier transitional housing (new residents admitted as people transitioned out); 50 former encampment residents and 50 unhoused people referred by Boston Public Health Commission. Twenty-five residents transferred to permanent housing, eight administratively discharged, four incarcerated, and four died (two overdoses, two other substance-related). The remaining 59 residents remain housed; none voluntarily returned to homelessness. One hundred residents (100%) engaged with case management, and 49 engaged with SUD treatment. CLINICAL: In the first 12 months, 1722 patients (drawn from both the housing program and community) had 7468 clinical visits. The most common SUDs were opioid (84%), cocaine (54%) and alcohol (47%) and 61% of patients had a co-occurring mental health diagnosis in the preceding 24-months. 566 (33%) patients were started on methadone and accepted at an Opioid Treatment Program (OTP). CONCLUSIONS: During the 1st year of operation, low-barrier transitional housing plus clinical stabilization care was a feasible and acceptable model for former encampment residents, 49% of whom engaged with SUD treatment, and 25% of whom transitioned to permanent housing.

Carbonaceous adsorbents in the removal of aquaculture pollutants: A technical review of methods and mechanisms.

Carbonaceous adsorbents (CAs) are becoming increasingly popular owing to their low-cost, ease of preparation, and versatility. Meanwhile, aquaculture is becoming a fundamental food industry, globally, due to a wide range of advantages such as economic and nutritional benefits, whilst protecting the depletion of natural resources. However, as with any farming, the technique is known to introduce a plethora of chemicals into the surrounding environment, including antibiotics, nutrients, fertilisers and more. Therefore, the treatment of aquaculture effluent is gaining traction to ensure the sustainable growth of the industry. Although the existing mitigation techniques are somewhat effective, they suffer from degradation of the water quality or harm to local environments/organisms. This article aims to identify the sources and impacts of various aquaculture pollutants. After which the authors will provide an environmentally friendly and novel approach to the treatment of aquaculture effluent using carbonaceous adsorbents. The article will detail discussions about the product life span, including, synthesis, activation, modification, applications in aqueous media, regeneration and End-of-Life (EoL) approaches, with a particular focus on the impacts of competitive adsorption between pollutants and environmental matrices. Some research gaps were also highlighted, such as the lack of literature applying real-world samples, the effects of competitive adsorption and the EoL applications and management for CAs.

Elevated tacrolimus levels among COVID-19 kidney transplant recipients are associated with worse disease severity and clinical outcomes.

BACKGROUND: The therapeutic effects of immunosuppressive drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections causing coronavirus disease 2019 (COVID-19) are being actively investigated. However, COVID-19's potential effects on serum calcineurin inhibitor levels have only been described recently. This study aimed to evaluate COVID-19's effect on tacrolimus levels in renal transplant recipients with moderate to severe symptoms and to assess their potential correlation with disease severity. MATERIALS AND METHODS: We retrospectively investigated 50 kidney transplant recipients with moderate to severe COVID-19. Their tacrolimus trough level on admission was compared to baseline levels, and their laboratory measurements and clinical course were reviewed on days 1 (admission), 7, 14, and 28. RESULTS: We found that 90% of patients had admission tacrolimus trough levels above baseline, with a mean increase of 176%. In addition, 71% had tacrolimus trough levels ≥ 50% above baseline, and 40% had supra-therapeutic trough levels of > 15 ng/mL. Supra-therapeutic trough levels were associated with greater hypoxemic respiratory failure, acute kidney injury, and increased 30-day mortality. CONCLUSION: Elevated tacrolimus levels occur in many renal transplant recipients with moderate to severe COVID-19 and are associated with worse clinical outcomes. Close drug monitoring is crucial to avoid toxicities and minimize over-immunosuppression complications.

Opioid use does not limit potent low-dose HIV-1 latency reversal agent boosting.

The combined effects of the HIV-1 and opioid epidemics on virus reservoir dynamics are less well characterized. To assess the impact of opioid use on HIV-1 latency reversal, we studied forty-seven suppressed participants with HIV-1 and observed that lower concentrations of combination latency reversal agents (LRA) led to synergistic virus reactivation ex vivo, regardless of opioid use. The use of a Smac mimetic or low-dose protein kinase C agonist, compounds that did not reverse latency alone, in combination with low-dose histone deacetylase inhibitors generated significantly more HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin, the maximal known HIV-1 reactivator. This LRA boosting did not differ by sex or race and associated with greater histone acetylation in CD4+ T cells and modulation of T cell phenotype. Virion production and the frequency of multiply spliced HIV-1 transcripts did not increase, suggesting a post-transcriptional block still limits potent HIV-1 LRA boosting.

Survey assessment of HIV pre-exposure prophylaxis availability in student health services in New England colleges and universities.

Objective: To determine HIV pre-exposure prophylaxis (PrEP) availability at student health services (SHS) in New England. Methods: We conducted an electronic survey of medical directors of SHS at New England colleges and universities. We measured the availability and volume of PrEP prescribing, barriers and facilitators to prescribing and provider knowledge. Results: Of 143 institutions surveyed, 39% completed questionnaires; 75% were private and 93% were 4 years. Thirty-six percent of institutions did not offer PrEP. Those offering PrEP started a mean of 2.0 per 1000 students/year. PrEP was available at more schools with higher vs. lower endowments (100 vs. 38%, p = 0.002), 4- vs. 2-year programs (68 vs. 0%, p = 0.042), and private vs. public schools (73 vs. 38%, p = 0.043). Conclusions: PrEP was not available at one in three New England SHS and prescribing rates at institutions that offered PrEP were low. Interventions are needed to improve PrEP access.

Design and Synthesis of Inhibitors of the E3 Ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 as a Treatment for Lung Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating rare disease, which despite currently available treatments, still represents a high unmet medical need. Specific E3 ubiquitin protein ligase 1 (SMURF1) is a HECT E3 ligase that ubiquitinates key signaling molecules from the TGFß/BMP pathways, which are of great relevance in the pathophysiology of PAH. Herein, the design and synthesis of novel potent small-molecule SMURF1 ligase inhibitors are described. Lead molecule 38 has demonstrated good oral pharmacokinetics in rats and significant efficacy in a rodent model of pulmonary hypertension.

Perisplenitis ("Sugar Spleen") Associated With Malrotation of the Intestine in an Elderly Man.

Intestinal non-rotation is an exceedingly rare clinical entity, especially as the etiology for small bowel obstruction following open-heart surgery in an elderly patient. Perisplenitis (also known as "sugar spleen") is also rarely identified during exploratory laparotomy, and is more often encountered post-mortem due to its benign disease course. These two entities were encountered in the same acutely decompensating patient, and while unrelated, serve as a reminder of the importance of recognizing variations in anatomy and understanding subsequent clinical significance.

Peer recovery coaching for comprehensive HIV, hepatitis C, and opioid use disorder management: The CHORUS pilot study.

Introduction: Amidst a surge in HIV and hepatitis C virus (HCV) infections in persons who use drugs, medications that effectively prevent HIV and treat opioid use disorder and HCV remain underutilized. Methods: We developed a 6-month peer recovery coaching intervention (brief motivational interviewing followed by weekly virtual or in-person coaching) and collected data on uptake of medications for opioid use disorder (MOUD), HIV pre-exposure prophylaxis (PrEP), and HCV treatment. The primary outcomes were intervention acceptability and feasibility. Results: At a Boston substance use disorder bridge clinic, we enrolled 31 HIV-negative patients who used opioids. Participants reported high intervention satisfaction at 6 months (95% "satisfied" or "very satisfied"). At study completion, 48% of the participants were on MOUD, 43% who met CDC guidelines were on PrEP, and 22% with HCV were engaged with treatment. Conclusions: A peer recovery coaching intervention is feasible and acceptable, with positive preliminary findings regarding MOUD, PrEP and HCV treatment uptake.

A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome.

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.