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To evaluate whether patients with HIV enrolled in Linkage to Care (hospital-based only) or Linkage to Care Plus (nurse-led hospital-to-community transitional care) programmes fare better on clinical outcomes; and to investigate how factors such as substance use, mental health or health-related social needs contribute to these outcomes.Social determinants of health contribute to poor HIV outcomes such that only 57% of people living with HIV have achieved the goal of viral suppression nationally, and 50% are retained in clinical care. The programmes evaluated here aimed to increase HIV appointment attendance, retention in care, viral suppression and decrease acute care utilization and mitigate social needs via hospital-to-community transitional support.A retrospective observational cohort study.We conducted a retrospective patient chart review abstracting data over three time periods between 2017 and 2020 to conduct this longitudinal programme evaluation.Both programmes had meaningful effects on increasing HIV appointment attendance and viral suppression; Linkage to Care Plus experienced the largest gains. Older age was associated with viral suppression, and housing insecurity and mental health conditions were associated with increased emergency department utilization.Hospital-only and nurse-led hospital-to-community transitional care programmes can positively influence HIV care outcomes. There is a need for enhanced attention and accountability related to health-related social needs, especially housing, and mental and behavioural health, to end the HIV epidemic.Globally, we are striving to end the HIV epidemic with evidence-informed interventions. The nurse-led hospital-to-community and the hospital-only interventions evaluated here improved HIV outcomes with most gains realized by the nurse-led transitional care model. Integrating lessons from these programmes, with increased attention and accountability for addressing social needs, can improve practice and policies to achieve programmatic and national goals related to HIV and other diseases, and more critically, to meet the goals of the people we serve.Patients, staff and leadership at the University of Maryland Institute of Human Virology JACQUES Initiative and University of Maryland Medical Center THRIVE clinic contributed to the design and implementation of the programmes and informed the programme evaluation study.

Multimodality treatment improves survival for gastric cancer (GC). However, the effect of treatment sequence by stage remains unclear. We aim to compare outcomes between patients receiving neoadjuvant(neoadj) and adjuvant chemotherapy (adj).Nonmetastatic GC patients with clinical stage ≥ T2N0 who underwent both resection and neoadj or adj were identified using the National Cancer Database (2005-2014). Multivariable Cox regression analyses were performed on propensity score-matched (PSM) cohorts stratified by stage to compare overall survival (OS).We identified 11 984 patients; 55% stage I (SI), 76% stage II (SII) and 57% stage III (SIII) received neoadj. Unadjusted analysis showed worse survival among SI neoadj patients (hazard ratio [HR] 1.195, confidence interval [CI] 1.04-1.38) and improved survival for SII (HR 0.93 CI 0.87-0.998) and SIII (HR 0.75, CI 0.68-0.84). After PSM, SI patients with neoadj had worse OS with increased risk of death compared to Adj (HR 1.186, CI 1.004-1.402). SII patients had no difference in OS (HR 0.98, CI 0.91-1.07) and SIII patients had improved OS (HR 0.78, CI 0.69-0.90).In patients who received surgery and chemotherapy, the benefit of neoadj was limited to SIII with worse survival for SI. A clinical trial to examine the optimal sequence of chemotherapy is warranted.

Overdose is a leading cause of death among people who use drugs (PWUDs), but policies to reduce fatal overdose have had mixed results. Summaries of naloxone access and Good Samaritan Laws (GSLs) in prior studies provide limited information about local context. Witnessing overdoses may also be an important consideration in providing services to PWUDs, as it contributes to post traumatic stress disorder (PTSD) symptoms, which complicate substance use disorder treatment.We aim to estimate the prevalence and correlates of witnessing and responding to an overdose, while exploring overdose context among rural PWUD. The Drug Injection Surveillance and Care Enhancement for Rural Northern New England (DISCERNNE) mixed-methods study characterized substance use and risk behaviors in 11 rural Massachusetts, Vermont, and New Hampshire counties between 2018 and 2019. PWUD completed surveys (n = 589) and in-depth interviews (n = 22).Among the survey participants, 84% had ever witnessed an overdose, which was associated with probable PTSD symptoms. Overall, 51% had ever called 911 for an overdose, though some experienced criminal legal system consequences despite GSL. Although naloxone access varied, 43% had ever used naloxone to reverse an overdose.PWUD in Northern New England commonly witnessed an overdose, which they experienced as traumatic. Participants were willing to respond to overdoses, but faced barriers to effective overdose response, including limited naloxone access and criminal legal system consequences. Equipping PWUDs with effective overdose response tools (education and naloxone) and enacting policies that further protect PWUDs from criminal legal system consequences could reduce overdose mortality.

To evaluate outcomes following salvage microsurgery (MS) and salvage stereotactic radiosurgery (SRS) after failure of primary treatment for vestibular schwannomas (VS).Retrospective chart review.Tertiary referral center.Patients with more than 1 intervention for their VS were divided into 4 groups: MS followed by SRS (n = 61), MS followed by MS (n = 9), SRS followed by MS (n = 7), and SRS followed by SRS (n = 7), and outcomes were evaluated.A total of 77 patients were included (84 procedures). In group 1 (MS then SRS), 3% developed a decline in facial function, 3% developed trigeminal sensory loss, and 13% patients had gradual improvement of facial nerve function following SRS. Group 2 (MS then MS) had the highest rates of facial nerve deterioration, although all but 1 patient achieved a House-Brackmann score of II or III. Gross-total resection (GTR) was achieved in 56% of patients. When a different approach was used for salvage resection, GTR occurred more commonly, and facial nerve outcomes were similar. In group 3 (SRS then MS), GTR occurred in 43% of cases, and 2 of 7 patients developed worsened facial function. In group 4 (SRS then SRS), no patient developed facial weakness after reirradiation, and 1 developed a trigeminal nerve deficit.For MS recurrences/residuals, SRS is the mainstay of treatment and does not preclude facial function recovery. If salvage microsurgery is required, an alternate approach should be considered. For SRS failures, when MS is required, less-than GTR may be preferable, and reirradiation is a potential safe alternative.

The open-shell iron pentacarbonyl cation [Fe(CO)

OBJECTIVES/HYPOTHESIS The American Academy of Otolaryngology-Head and Neck Surgery has published clinical practice guidelines (CPGs) to guide management of common otolaryngologic (ENT) conditions. While these CPGs have been disseminated within specialty journals, many patients' first presentation of certain ENT complaints is to primary and acute care settings, including the emergency department (ED). It is less clear whether practice in these settings is concordant with specialty CPGs. STUDY DESIGN Retrospective cohort study. METHODS A retrospective review of medical records was performed at an academic tertiary care center with ED diagnoses of 1) Bell's palsy/facial weakness (BP) or 2) acute otitis externa (AOE) from May 2014-June 2018. Individual chart abstraction was performed for all encounters with these diagnoses for the purpose of assessing providers' adherence to CPGs. RESULTS During the study period, 224 patients were diagnosed with BP and 465 patients were diagnosed with AOE. Of the patients diagnosed with BP, 94% (n = 211/224) were prescribed oral steroids, concordant with guidelines, while 36% of these patients received head computed tomography (CT) scans and 43% received laboratory tests, counter to the guidelines. For those with a diagnosis of AOE, 28.6% received topical antibiotics only as primary treatment (n = 133/465) in accordance with guidelines while systemic antibiotics were prescribed in 42.2% (n = 196/465) discordant with the guidelines and 29.2% received both topical and systemic antibiotics (n = 136/465). CONCLUSIONS CPGs developed by subspecialty societies provide evidence-based recommendations for the care of patients with particular conditions, but may not be disseminated broadly outside of the specialty. Further research is required to understand the reasons behind divergent management of such conditions. LEVEL OF EVIDENCE 3 Laryngoscope, 131:1266-1270, 2021.

Protein allostery is a phenomenon involving the long range coupling between two distal sites in a protein. In order to elucidate allostery at atomic resoluion on the ligand-binding WW domain of the enzyme Pin1, multistate structures were calculated from exact nuclear Overhauser effect (eNOE). In its free form, the protein undergoes a microsecond exchange between two states, one of which is predisposed to interact with its parent catalytic domain. In presence of the positive allosteric ligand, the equilibrium between the two states is shifted towards domain-domain interaction, suggesting a population shift model. In contrast, the allostery-suppressing ligand decouples the side-chain arrangement at the inter-domain interface thereby reducing the inter-domain interaction. As such, this mechanism is an example of dynamic allostery. The presented distinct modes of action highlight the power of the interplay between dynamics and function in the biological activity of proteins.

The cystine/glutamate antiporter, system x(c)(-), is essential for the efficient uptake of cystine into cells. Interest in the mechanisms of system x(c)(-)function soared with the recognition that system x(c)(-)presents the most upstream node of ferroptosis, a recently described form of regulated necrosis relevant for degenerative diseases and cancer. Since targeting system x(c)(-)hold the great potential to efficiently combat tumor growth and metastasis of certain tumors, we disrupted the substrate-specific subunit of system x(c)(-), xCT (SLC7A11) in the highly metastatic mouse B16F10 melanoma cell line and assessed the impact on tumor growth and metastasis. Subcutaneous injection of tumor cells into the syngeneic B16F10 mouse melanoma model uncovered a marked decrease in the tumor-forming ability and growth of KO cells compared to control cell lines. Strikingly, the metastatic potential of KO cells was markedly reduced as shown in several in vivo models of experimental and spontaneous metastasis. Accordingly, survival rates of KO tumor-bearing mice were significantly prolonged in contrast to those transplanted with control cells. Analyzing the in vitro ability of KO and control B16F10 cells in terms of endothelial cell adhesion and spheroid formation revealed that xCT expression indeed plays an important role during metastasis. Hence, system x(c)(-)emerges to be essential for tumor metastasis in mice, thus qualifying as a highly attractive anticancer drug target, particularly in light of its dispensable role for normal life in mice.

The focus of this work is to assess the long-term progression of degeneration in the ovine lumbar spine following a minimally invasive model injury comparable to the damage of an intervertebral disc (IVD) herniation. A partial nucleotomy was performed on 18 sheep via the percutaneous dorsolateral approach. The animals were culled at 6 and 12 months to evaluate the damaged and neighboring functional spine units (FSUs) for degenerative characteristics via μ-CT and histology. Both quantitative μ-CT and histology investigations demonstrated statistically significant differences between the native and damaged FSUs investigated. Qualitative analysis of μ-CT revealed numerous pathological markers consistent with intervertebral disc degeneration (IDD), with differences in frequency and severity between the native and damaged FSUs. The annulus fibrosus reforms a pressure seal within 6 weeks, but the extent of the trauma is significant enough to initiate IVD degeneration, which is already clearly visible at 6 months and especially so 12 months post-op. IDD pathology consistent with signs of a herniation was seen in both the 6- and 12-month groups. This technique provides a useful model injury for the preclinical evaluation of IDD in large animal models, especially in regards to simulating disc herniation as well as for testing the efficacy of associated therapies in the future. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2376-2388, 2019.

Epigenetic transformations may provide early indicators for cancer and other disease. Specifically, the amount of genomic 5-hydroxymethylcytosine (5-hmC) was shown to be globally reduced in a wide range of cancers. The integration of this global biomarker into diagnostic workflows is hampered by the limitations of current 5-hmC quantification methods. Here we present and validate a fluorescence-based platform for high-throughput and cost-effective quantification of global genomic 5-hmC levels. We utilized the assay to characterize cancerous tissues based on their 5-hmC content, and observed a pronounced reduction in 5-hmC level in various cancer types. We present data for glioblastoma, colorectal cancer, multiple myeloma, chronic lymphocytic leukemia and pancreatic cancer, compared to corresponding controls. Potentially, the technique could also be used to follow response to treatment for personalized treatment selection. We present initial proof-of-concept data for treatment of familial adenomatous polyposis.