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Reading Through the Nonsense: Gentamicin and ELX-02 as Rescuing Therapies for Epidermolysis Bullosa
No full textHigh Retention Among Key Populations Initiated on HIV Pre-Exposure Prophylaxis in Kigali City, Rwanda
No full textIntroduction: Key populations (KPs) including female sex workers (FSWs) and men who have sex with men (MSM) in sub-Saharan Africa are disproportionately impacted by HIV. Despite the increasing availability of pre-exposure prophylaxis (PrEP), data on retention remain limited. This study assessed PrEP retention at 1 and 12 months among Rwandan FSWs and MSM. Methods: We analysed routine clinical data on adult FSWs and MSM receiving PrEP care from 11 health facilities in Kigali, Rwanda between 2019 and 2022. Retention was defined as attendance at regularly scheduled appointments for a PrEP refill. We used logistic regression to assess associations between demographic and clinical characteristics and retention at 1 and 12 months. Results: Among 2043 PrEP initiators, 1343 (66%) were FSWs and 700 (34%) were MSM. FSWs reported a median number of eight sexual partners in the prior 7 days, 70% reported condomless sex and 94% considered themselves at high HIV risk. About 1239 (92%) and 1032 (77%) were retained at 1 and 12 months, respectively. One-month retention was lower among FSWs living with others (OR 0.59, 95% CI: 0.35−0.99; ref: living alone) or with low HIV risk perception (OR 0.12, 95% CI: 0.04−0.29). At 12 months, low HIV risk perception remained statistically significant (aOR 0.20, 95% CI: 0.12−0.32). At PrEP initiation, MSM reported a median of four sexual partners in the prior 12 months, 88% reported condomless sex and 72% considered themselves at high HIV risk. Retention rates were 96% at 1 month and 82% at 12 months. At 1 month, retention was higher among MSM with some education (OR 12.74, 95% CI: 2.74−70.93; ref: no education). At 12 months, retention was lower among MSM with part-time employment (aOR 0.29, 95% CI: 0.11, 0.76), students (aOR 0.12, 95% CI: 0.04, 0.37) and unemployed (aOR 0.12, 95% CI: 0.05, 0.28); ref: full-employed) and those unaware of PrEP at baseline (aOR 0.15, 95% CI: 0.10, 0.23). Conclusions: We observed very high rates of PrEP retention among Rwandan FSWs and MSM. Predictors of retention included living situation, employment status, HIV risk perception and low PrEP awareness, but differed between FSWs and MSM. These findings suggest that targeted awareness campaigns tailored to different KPs could improve PrEP retention in care
Follicular Skin Disorders, Inflammatory Bowel Disease, and the Microbiome: A Systematic Review
No full textFollicular skin disorders, including hidradenitis suppurativa (HS), frequently coexist with systemic autoinflammatory diseases, such as inflammatory bowel disease (IBD) and its subtypes, Crohn’s disease and ulcerative colitis. Previous studies suggest that dysbiosis of the human gut microbiome may serve as a pathogenic link between HS and IBD. However, the role of the microbiome (gut, skin, and blood) in the context of IBD and various follicular disorders remains underexplored. Here, we performed a systematic review to investigate the relationship between follicular skin disorders, IBD, and the microbiome. Of the sixteen included studies, four evaluated the impact of diet on the microbiome in HS patients, highlighting a possible link between gut dysbiosis and yeast-exclusion diets. Ten studies explored bacterial colonization and HS severity with specific gut and skin microbiota, including Enterococcus and Veillonella. Two studies reported on immunological or serological biomarkers in HS patients with autoinflammatory disease, including IBD, and identified common markers including elevated cytokines and T-lymphocytes. Six studies investigated HS and IBD patients concurrently. Our systematic literature review highlights the complex interplay between the human microbiome, IBD, and follicular disorders with a particular focus on HS. The results indicate that dietary modifications hold promise as a therapeutic intervention to mitigate the burden of HS and IBD. Microbiota analyses and the identification of key serological biomarkers are crucial for a deeper understanding of the impact of dysbiosis in these conditions. Future research is needed to more thoroughly delineate the causal versus associative roles of dysbiosis in patients with both follicular disorders and IBD
Acute Coronary Syndrome Due to Coronary Vasospasm: A Case Report
No full textCoronary vasospasm can lead to decreased cardiac perfusion and result in acute coronary syndrome. Here is a case of a 49-year-old man presented to the emergency department with epigastric pain and nausea with normal initial electrocardiogram. However, 6 h later, the patient experienced severe chest pain prompting a repeat electrocardiogram demonstrating inferior ST-segment elevation with troponin I levels peaked at 1.2 ng/ml (normal range: 0.00–0.02 ng/ml). Coronary angiography revealed angiographic stenosis in the left circumflex territory of a left dominant system which resolved with intracoronary nitroglycerin administration indicating ischemia with nonobstructive coronary arteries secondary to coronary vasospasm. He was discharged on isosorbide mononitrate and amlodipine therapy and had no recurrence of symptoms during follow-up
Acute Myocardial Injury in Spontaneous Intracerebral Hemorrhage: A Secondary Observational Analysis of the FAST Trial
No full textBACKGROUND: Acute myocardial injury is associated with poor outcomes in patients with acute ischemic stroke, but its prognostic significance in patients with spontaneous intracerebral hemorrhage remains unclear. We investigated whether acute myocardial injury and the direction of the cardiac troponin I (cTnI) change (rising versus falling) affect post-intracerebral hemorrhage outcomes. METHODS AND RESULTS: We re-analyzed the FAST (Factor-Seven-for-Acute-Hemorrhagic-Stroke) trial. Acute myocardial injury was defined as at least 1 cTnI value above the upper reference limit with a rise/fall of \u3e20%. Logistic regression tested for associations (1) between acute myocardial injury (presence versus absence) and poor outcome (modified Rankin Scale 4–6) and mortality at 15 and 90 days; (2) among 3 groups (rising versus falling versus no acute myocardial injury) and outcomes. Among the 841 FAST participants, 785 patients were included. Acute myocardial injury was detected in 29% (n=227); 170 had rising cTnI. At 15 and 90 days, respectively, those with acute myocardial injury had higher odds of poor outcome (adjusted odds ratio) ([aOR] 2.3 [95% CI, 1.3–3.9]); and adjusted odds ratio 2.5 [95% CI, 1.6–3.9];, and higher odds of mortality (adjusted odds ratio 2.4 [95% CI, 1.4–4.3]; and adjusted odds ratio 2.2 [CI, 1.3–3.6]) than patients without. There was no interaction between FAST group assignment and myocardial injury, and associations between myocardial injury and outcomes were consistent across group assignments. Rising cTnI was associated with the highest risk of poor outcomes and mortality. CONCLUSIONS: In this secondary analysis of the FAST trial, acute myocardial injury was common and associated with poor outcomes. The direction of the cTnI change might provide additional risk stratification after intracerebral hemorrhage
The IL-6 Hypothesis in COVID-19: A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Free IL-6 Sequestration by the Monoclonal Antibody Sirukumab in Severe and Critical COVID-19
No full textBackground: Upregulation of IL-6 has been associated with worse prognosis in COVID-19 patients. Impact on IL-6 signalling has mostly been limited to clinical outcomes in IL-6 receptor antagonist trials. Methods: We performed a phase 2, randomised, double-blind, placebo-controlled trial (NCT04380961) of US-based hospitalised adults (\u3c85 years) with laboratory-confirmed SARS-CoV-2 infection and severe (low levels of supplemental oxygen) or critical disease (high levels of oxygen supplementation). Patients received sirukumab 5 mg/kg or placebo single dose IV on Day 1 plus standard of care. The primary endpoint was time to sustained clinical improvement up to Day 28 based on an ordinal scale. Secondary endpoints included clinical improvement, all-cause mortality, and safety. Following an interim analysis, the protocol was amended to only recruit patients with critical COVID-19. Findings: From May 2020 to March 2021, 209 patients were randomised; 112 had critical disease (72 sirukumab, 40 placebo) at baseline. Median time to sustained clinical improvement in critical patients was 17 and 23 days in the sirukumab and placebo groups (HR, 1∙1; 95% CI, 0∙66–1∙88; p \u3e 0∙05). At Day 28, 59∙4% versus 55∙0% of patients achieved clinical improvement with sirukumab versus placebo and rates of all-cause mortality were 24∙6% versus 30∙0%, respectively. Rates of grade ≥3 adverse events were comparable between the sirukumab and placebo groups (25∙9% vs 32∙9%; all patients). Interpretation: In critical COVID-19 patients who received sirukumab, there was no statistically significant difference in time to sustained clinical improvement versus placebo despite objective sequestration of circulating IL-6, questioning IL-6 as a key therapeutic target in COVID-19
Code-ICH: A New Paradigm for Emergency Intervention
No full textPurpose of review: Intracerebral hemorrhage (ICH) is the most devastating type of stroke, causing widespread disability and mortality. Unfortunately, the acute care of ICH has lagged behind that of ischemic stroke. There is an increasing body of evidence supporting the importance of early interventions including aggressive control of blood pressure and reversal of anticoagulation in the initial minutes to hours of presentation. This review highlights scientific evidence behind a new paradigm to care for these patients called Code-ICH. Recent findings: While numerous trials aimed at decreasing hematoma expansion through single interventions had failed to show statistically significant effects on primary outcomes, time-sensitive, multifaceted, bundled care approaches have recently shown substantial promise in improving functional outcomes in patients with ICH. Summary: The concept of Code-ICH can serve as a structural platform for the practice of acute care neurology to continuously measure its performance, reflect on best practices, advance care, and address disparities
Myelomodulatory Treatments Augment the Therapeutic Benefit of Oncolytic Viroimmunotherapy in Murine Models of Malignant Peripheral Nerve Sheath Tumors
No full textIntroduction: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy’s antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation
Vertical Transmission of SARS-Cov-2 Delta-Variant in a Preterm Infant
No full textBackground: As SARS-CoV-2 continues to be relevant and cause illnesses, the effect of emerging virus variants on perinatal health remains to be elucidated. It was demonstrated that vertical transmission of SARS-CoV-2 is a relatively rare event in the original SARS-CoV-2 strain. However, very few reports describe vertical transmission related to the delta-variant. Case presentation: We report a case of a preterm male neonate born to a mother with positive SARS-CoV-2 and mild respiratory complications. The neonate was born by cesarean section due to fetal distress. The rupture of the amniotic membrane was at delivery. The neonate had expected prematurity-related complications. His nasopharyngeal swabs for RT-PCR were positive from birth till three weeks of age. RT-ddPCR of the Placenta showed a high load of the SARS-CoV-2 virus with subgenomic viral RNA. RNAscope technique demonstrated both the positive strand of the S gene and the orf1ab negative strand. Detection of subgenomic RNA and the orf1ab negative strand indicats active viral replication in the placenta. Conclusions: Our report demonstrates active viral replication of the SARS-CoV-2 delta-variant in the placenta associated with vertical transmission in a preterm infant