Food Insecurity and Undernutrition Are Associated With Distinct Immunologic Profiles in People With Tuberculosis and Advanced HIV Starting Antiretroviral Therapy.

BACKGROUND: Food insecurity and undernutrition are related but distinct concepts contributing to poor HIV and tuberculosis outcomes. Pathways linking them with immunologic profile, which may relate to clinical outcomes, remain understudied. METHODS: We analyzed data from a cohort study of 165 antiretroviral therapy (ART)-naïve adults with advanced HIV and newly diagnosed tuberculosis in Botswana from 2009 to 2013. Twenty-nine plasma biomarkers were measured pre-ART and 4 weeks post-ART initiation. We used principal components analysis (PCA) and multivariable linear regression models to assess relationships between immunological profiles and food insecurity (based on the Household Food Insecurity Access Scale), undernutrition (body mass index <18.5 kg/m 2 ), and clinical outcomes. RESULTS: PCA identified 5 principal components with eigenvalues >1. After adjustment, food insecurity was associated with PC3 pre-ART (0.19 per increased category of severity, 95% CI: 0.02 to 0.36) and post-ART (0.24, 95% CI: 0.07 to 0.41). PC3 was driven by higher levels of IFN-α, IFN-γ, interleukin (IL)-12p40, vascular endothelial growth factor, IL-1α, and IL-8 and decreased concentrations of IL-3. Undernutrition was associated with PC5 post-ART (0.49, 95% CI: 0.16 to 0.82). PC5 was driven by higher levels of IL-8, MIP-1α, IL-6, and IL-10 and decreased concentrations in IP-10 and IFN-α. Post-ART PC3 (4.3 percentage point increased risk per increased score of 1, 95% CI: 0.3 to 8.9) and post-ART PC5 (4.8, 95% CI: 0.6 to 8.9) were associated with death in adjusted models. DISCUSSION: We identified 2 distinct immunologic profiles associated with food insecurity, undernutrition, and clinical outcomes in patients with advanced HIV and tuberculosis. Different pathophysiologic processes may link food insecurity and undernutrition with poor outcomes in this vulnerable patient population. Future studies should assess the impact of improving food access and intake on immune function and clinical outcomes.

National Institutes of Health Funding for Tuberculosis Comorbidities Is Disproportionate to Their Epidemiologic Impact.

Tuberculosis (TB) is a leading infectious killer worldwide. We systematically searched the National Institutes of Health Research, Portfolio Online Reporting Tools Expenditures and Results (RePORTER) website to compare research funding for key TB comorbidities-undernutrition, alcohol use, human immunodeficiency virus, tobacco use, and diabetes-and found a large mismatch between the population attributable fraction of these risk factors and the funding allocated to them.

Comparing COVID-19-related Morbidity and Mortality Between Patients With and Without Substance Use Disorders: A Retrospective Cohort Study.

Objectives: People with substance use disorders (SUD) are suggested to have higher risk of hospitalization, intubation, or death from coronavirus disease 2019 (COVID-19), although data are mixed. Little is known about other COVID-19-related complications in this group. We compared morbidity and mortality among individuals with and without SUD who were admitted to an urban safety net hospital with COVID-19 early in the pandemic, contemporaneous to other published studies on this subject. Methods: We performed a retrospective study of patients ⩾18 years old admitted with COVID-19 from March 16th to April 8th, 2020. SUD included alcohol, opioid, cocaine, amphetamine, and benzodiazepine use disorders and was identified using diagnostic codes, free text clinical documentation, and urine drug screens. The primary outcome was inpatient mortality. Secondary outcomes included clinical complications (eg, secondary infections, venous thromboembolism) and resource utilization (eg, mechanical ventilation, length of stay). We used multivariable regression to assess the relationship between SUD and mortality. Results: Of 409 patients, the mean age was 56 years and 13.7% had SUD. Those with SUD were more likely to be male, have experienced homelessness, have pulmonary disease or hepatitis C, or use tobacco or cannabis. After multivariable analysis, SUD was not associated with mortality (aOR 1.03; 95% CI, 0.31-3.10). Secondary outcomes were also similar between groups. Conclusions: Our findings suggest that persons with and without SUD have similar COVID-19-related outcomes. Previously reported increased COVID-19 complications may be from medical comorbidities.

Addressing the risk of monkeypox exposure during gastrointestinal endoscopy.

The current monkeypox virus (MPV) outbreak is now a global health concern. MPV, a zoonotic double-stranded DNA virus, may be transmitted from human to human or by contaminated surfaces. Understanding the clinical characteristics and risks of MPV transmission are important, especially for health care workers, who may unknowingly encounter the virus while fulfilling their clinical responsibilities. The World Health Organization has recognized this orthopoxvirus outbreak as a public health emergency and the knowledge gaps regarding MPV's transmission are likely to have contributed to its spread. Instituting proper infection controls in all settings, including the endoscopy suite, is critical to stemming this developing epidemic. Direct contact with skin lesions is the primary mode of transmission, and anorectal lesions are the most common skin manifestation. Hence, gastroenterologists and endoscopists are very likely to see patients with MPV infection. In this context, patients may present with symptoms of proctitis, or lesions may be encountered unexpectedly during anoscopy, sigmoidoscopy, or colonoscopy. In consequence, preprocedural exams and endoscopic procedures may increase exposure risk, especially if characteristic lesions go unrecognized. In this review, we provide background epidemiological and virological information, but focus on the potential risk of MPV exposure during gastrointestinal endoscopy and evaluate current practices regarding personal protective equipment and post-procedure instrument and endoscopy suite decontamination.

Cost-effectiveness of second-line therapies in adults with chronic immune thrombocytopenia.

Major options for second-line therapy in adults with chronic immune thrombocytopenia (ITP) include splenectomy, rituximab, and thrombopoietin receptor agonists (TRAs). The American Society of Hematology guidelines recommend rituximab over splenectomy, TRAs over rituximab, and splenectomy or TRAs while noting a lack of evidence on the cost-effectiveness of these therapies. Using prospective, observational, and meta-analytic data, we performed the first cost-effectiveness analysis of second-line therapies in chronic ITP, from the perspective of the U.S. health system. Over a 20-year time-horizon, our six-strategy Markov model shows that a strategy incorporating early splenectomy, an approach at odds with current guidelines and clinical practice, is the cost-effective strategy. All four strategies utilizing TRAs in the first or second position cost over $1 million per quality-adjusted life-year, as compared to strategies involving early use of splenectomy and rituximab. In a probabilistic sensitivity analysis, early use of splenectomy and rituximab in either order was favored in 100% of 10 000 iterations. The annual cost of TRAs would have to decrease over 80% to begin to become cost-effective in any early TRA strategy. Our data indicate that effectiveness of early TRA and late TRA strategies is similar with the cost significantly greater with early TRA strategies. Contrary to current practice trends and guidelines, early use of splenectomy and rituximab, rather than TRAs, constitutes cost-effective treatment in adults with chronic ITP.

Malnutrition leads to increased inflammation and expression of tuberculosis risk signatures in recently exposed household contacts of pulmonary tuberculosis.

Background: Most individuals exposed to Mycobacterium tuberculosis (Mtb) develop latent tuberculosis infection (LTBI) and remain at risk for progressing to active tuberculosis disease (TB). Malnutrition is an important risk factor driving progression from LTBI to TB. However, the performance of blood-based TB risk signatures in malnourished individuals with LTBI remains unexplored. The aim of this study was to determine if malnourished and control individuals had differences in gene expression, immune pathways and TB risk signatures. Methods: We utilized data from 50 tuberculin skin test positive household contacts of persons with TB - 18 malnourished participants (body mass index [BMI] < 18.5 kg/m2) and 32 controls (individuals with BMI ≥ 18.5 kg/m2). Whole blood RNA-sequencing was conducted to identify differentially expressed genes (DEGs). Ingenuity Pathway Analysis was applied to the DEGs to identify top canonical pathways and gene regulators. Gene enrichment methods were then employed to score the performance of published gene signatures associated with progression from LTBI to TB. Results: Malnourished individuals had increased activation of inflammatory pathways, including pathways involved in neutrophil activation, T-cell activation and proinflammatory IL-1 and IL-6 cytokine signaling. Consistent with known association of inflammatory pathway activation with progression to TB disease, we found significantly increased expression of the RISK4 (area under the curve [AUC] = 0.734) and PREDICT29 (AUC = 0.736) progression signatures in malnourished individuals. Conclusion: Malnourished individuals display a peripheral immune response profile reflective of increased inflammation and a concomitant increased expression of risk signatures predicting progression to TB. With validation in prospective clinical cohorts, TB risk biomarkers have the potential to identify malnourished LTBI for targeted therapy.

The Effect of IL-6 Inhibitors on Mortality Among Hospitalized COVID-19 Patients: A Multicenter Study.

BACKGROUND: The effectiveness of interleukin-6 inhibitors (IL-6i) in ameliorating coronavirus disease 2019 (COVID-19) remains uncertain. METHODS: We analyzed data for patients aged ≥18 years admitted with a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test at 4 safety-net hospital systems with diverse populations and high rates of medical comorbidities in 3 US regions. We used inverse probability of treatment weighting via machine learning for confounding adjustment by demographics, comorbidities, and disease severity markers. We estimated the average treatment effect, the odds of IL-6i effect on in-hospital mortality from COVID-19, using a logistic marginal structural model. RESULTS: Of 516 patients, 104 (20.1%) received IL-6i. Estimate of the average treatment effect adjusted for confounders suggested a 37% reduction in odds of in-hospital mortality in those who received IL-6i compared with those who did not, although the confidence interval included the null value of 1 (odds ratio = 0.63; 95% confidence interval, .29-1.38). A sensitivity analysis suggested that potential unmeasured confounding would require a minimum odds ratio of 2.55 to nullify our estimated IL-6i effect size. CONCLUSIONS: Despite low precision, our findings suggested a relatively large effect size of IL-6i in reducing the odds of COVID-19-related in-hospital mortality.

Early administration of interleukin-6 inhibitors for patients with severe COVID-19 disease is associated with decreased intubation, reduced mortality, and increased discharge.

OBJECTIVE: The aim of this observational study was to determine the optimal timing of interleukin-6 receptor inhibitor (IL6ri) administration for coronavirus disease 2019 (COVID-19). METHODS: Patients with COVID-19 were given an IL6ri (sarilumab or tocilizumab) based on iteratively reviewed guidelines. IL6ri were initially reserved for critically ill patients, but after review, treatment was liberalized to patients with lower oxygen requirements. Patients were divided into two groups: those requiring ≤45% fraction of inspired oxygen (FiO2) (termed stage IIB) and those requiring >45% FiO2 (termed stage III) at the time of IL6ri administration. The main outcomes were all-cause mortality, discharge alive from hospital, and extubation. RESULTS: A total of 255 COVID-19 patients were treated with IL6ri (149 stage IIB and 106 stage III). Patients treated in stage IIB had lower mortality than those treated in stage III (adjusted hazard ratio (aHR) 0.24, 95% confidence interval (CI) 0.08-0.74). Overall, 218 (85.5%) patients were discharged alive. Patients treated in stage IIB were more likely to be discharged (aHR 1.43, 95% CI 1.06-1.93) and were less likely to be intubated (aHR 0.43, 95% CI 0.24-0.79). CONCLUSIONS: IL6ri administration prior to >45% FiO2 requirement was associated with improved COVID-19 outcomes. This can guide clinical management pending results from randomized controlled trials.

A novel interprofessional approach to end-of-life care education: A pilot study.

Navigating the biomedical, emotional, and logistical complexity of end-of-life (EOL) care requires seamless interprofessional teamwork. Unfortunately, EOL care, interprofessional collaboration, and the role of support services such as hospice are not adequately emphasized in nursing and medical curricula. This article describes a student-run program, entitled the "HeArt of Medicine", which was designed to foster a reflective and collaborative approach to EOL care. The program consists of three workshops with a novel blend of art, science, and practical information, highlighting the need for interprofessional teamwork. Participants were surveyed before and after the workshops on their attitudes toward EOL care. Composite participant scores after workshops demonstrated increased comfort with and knowledge of EOL care topics (p = 0.001). The results show that this program has had a positive impact on participants' knowledge, comfort, and collaboration in EOL settings.

Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance.

Little is known about the dynamics of cancer cell death in response to therapy in the tumor microenvironment. Intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor-stroma interactions. We observed associations between vascular leakage and response to doxorubicin, including improved response in matrix metalloproteinase-9 null mice that had increased vascular leakage. Furthermore, we observed CCR2-dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. Thus, live imaging can be used to gain insights into drug responses in situ.