Impact of an alcohol withdrawal screening and treatment protocol for hospitalized patients.

INTRODUCTION: Alcohol Withdrawal Syndrome (AWS) is a potentially life-threatening complication of alcohol use disorder (AUD) that can be challenging to recognize in hospitalized patients. Our institution implemented universal AUD screening for all patients admitted to a non-critical care venue using the Prediction of Alcohol Withdrawal Severity Scale (PAWSS). At risk patients were then further assessed, utilizing the Glasgow Modified Alcohol Withdrawal Scale (GMAWS), and medicated according to a predetermined protocol. This study sought to determine whether this protocol decreased hospital length of stay, lowered the total benzodiazepine dose administered, and decreased adverse events attributable to AWS. METHODS: This retrospective cohort study was conducted over a 6-year period from 2014 to 2020. The study included patients with an ICD-10 code diagnosis of AWS and subsequently divided them into two groups: pre- and post-protocol introduction. Outcome measures were compared pre- versus post-protocol introduction. RESULTS: There were 181 patient encounters pre- and 265 patient encounters post-protocol. There was no statistically significant difference in median length of stay between the two groups (2.956 days pre and 3.250 days post-protocol, p = 0.058). Post-protocol, there was a statistically significant reduction in median total benzodiazepine dose (13.5 mg and 9 mg lorazepam equivalents pre- and post-protocol, p < 0.001) and in occurrence of delirium tremens (7.7 % pre and 2.3 % post-protocol, p = 0.006). CONCLUSION: Protocol implementation did not reduce length of stay in patients with AUD but was associated with a significant reduction in total benzodiazepine dose and, when adjusted, a non-statistically significant decrease in progression to delirium tremens in hospitalized patients, after applying Bonferroni adjustment.

Identification of brain-enriched proteins in CSF as biomarkers of relapsing remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a clinically and biologically heterogenous disease with currently unpredictable progression and relapse. After the development and success of neurofilament as a cerebrospinal fluid (CSF) biomarker, there is reinvigorated interest in identifying other markers of or contributors to disease. The objective of this study is to probe the predictive potential of a panel of brain-enriched proteins on MS disease progression and subtype. METHODS: This study includes 40 individuals with MS and 14 headache controls. The MS cohort consists of 20 relapsing remitting (RR) and 20 primary progressive (PP) patients. The CSF of all individuals was analyzed for 63 brain enriched proteins using a method of liquid-chromatography tandem mass spectrometry. Wilcoxon rank sum test, Kruskal-Wallis one-way ANOVA, logistic regression, and Pearson correlation were used to refine the list of candidates by comparing relative protein concentrations as well as relation to known imaging and molecular biomarkers. RESULTS: We report 30 proteins with some relevance to disease, clinical subtype, or severity. Strikingly, we observed widespread protein depletion in the disease CSF as compared to control. We identified numerous markers of relapsing disease, including KLK6 (kallikrein 6, OR = 0.367, p < 0.05), which may be driven by active disease as defined by MRI enhancing lesions. Other oligodendrocyte-enriched proteins also appeared at reduced levels in relapsing disease, namely CNDP1 (carnosine dipeptidase 1), LINGO1 (leucine rich repeat and Immunoglobin-like domain-containing protein 1), MAG (myelin associated glycoprotein), and MOG (myelin oligodendrocyte glycoprotein). Finally, we identified three proteins-CNDP1, APLP1 (amyloid beta precursor like protein 1), and OLFM1 (olfactomedin 1)-that were statistically different in relapsing vs. progressive disease raising the potential for use as an early biomarker to discriminate clinical subtype. CONCLUSIONS: We illustrate the utility of targeted mass spectrometry in generating potential targets for future biomarker studies and highlight reductions in brain-enriched proteins as markers of the relapsing remitting disease stage.

Medium-Term Outcomes of Concomitant Aortic Valve Repair in Patients with Continuous-Flow Left Ventricular Assist Device.

OBJECTIVE: Our objective was to analyze the development of aortic insufficiency in patients who received central aortic valve repair when undergoing continuous-flow left ventricular assist device implantation. METHODS: We conducted a retrospective review of patients who underwent HeartMate II or 3 (Abbott Lab) implantation between 2004 and 2022. Ninety-four patients were excluded from analysis for history of aortic valve procedures, a bicuspid aortic valve, baseline trace aortic insufficiency, or other concomitant aortic valve procedure. Patients who had ≥ mild aortic insufficiency had concomitant aortic valve repair. Clinical characteristics, serial echocardiograms, and outcomes were determined. RESULTS: Of the 656 patients who underwent HeartMate II or 3 implantation, 105 patients (59 HeartMate II and 46 HeartMate 3) met study criteria. Median age was 68 years [60-74 years], 91.4% [n=96] were male, 54.4% [n=56] were white, and 68.6% [n=72] received support as destination therapy. Preoperative aortic insufficiency degree was 54.3% (n=57) mild, 23.8% (n=25) mild-to-moderate, 20.0% (n=21) moderate, 1.0% (n=1) moderate-to-severe, 1.0% (n=1) severe. In hospital mortality was 5.7% [n=6]. Freedom from ≥ moderate aortic insufficiency was 96.4% (95%CI: 92.5%-100%), 93.3% (95%CI: 87.6%-99.2%), and 91.0% (95%CI: 84.1%-98.5%) at 1-year, 2-year, and 3-year post-implantation, respectively. One HeartMate II patient experienced severe aortic insufficiency and was treated with a heart transplant. Three-year survival was 63.4% [95%CI: 52.9%-75.9%]. CONCLUSIONS: Central aortic valve repair may be an effective technique to mitigate aortic insufficiency in HeartMate II and 3. A larger cohort study with longer duration of follow up is warranted to further investigate the clinical impact.

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Acquired rifamycin resistance among patients with tuberculosis and HIV in new York City, 2001-2023.

Introduction: Acquired rifamycin resistance (ARR) in tuberculosis (TB) has been associated with HIV infection and can necessitate complicated TB treatment regimens, particularly in people living with HIV (PLWH). This work examines clinical characteristics and treatment outcomes of PLWH who developed ARR from 2001 to 2023 in New York City (NYC) to inform best practices for treating these patients. Methods: PLWH who developed ARR 2001-2023 were identified from the NYC TB registry. Results: Sixteen PLWH developed ARR; 15 were diagnosed 2001-2009 and the 16th was diagnosed in 2017. Median CD4 count was 48/mm3. On initial presentation, 14 had positive sputum cultures; of these, 12 culture-converted prior to developing ARR. Ten patients completed a course of TB treatment but subsequently relapsed; in six of these cases, ARR was discovered upon relapse, triggering treatment with a non-rifamycin-containing regimen, while in the other four, ARR was discovered during a second round of rifamycin-containing treatment. Three patients were lost to follow-up during their initial course of TB treatment and later returned to care; after being restarted on a rifamycin-containing regimen, ARR was discovered. Finally, three patients culture-converted during their first course of treatment but subsequently had cultures that grew rifamycin-resistant Mycobacterium tuberculosis prior to treatment completion, leading to changes in their treatment regimens. Among the 16 patients, eight died before being cured of TB, seven successfully completed treatment, and one was lost to follow-up. Conclusions: PLWH should be monitored closely for the development of ARR during treatment for TB, and sputum culture conversion should be interpreted cautiously in this group. Collecting a final sputum sample may be especially important for PLWH, as treatment failure and relapse were common in this population. The decrease in the number of cases of ARR among PLWH during the study period may reflect the decrease in the total number of PLWH diagnosed with TB in NYC in recent years, improved immune status of PLWH due to increased uptake of antiretroviral drugs, and improvements in the way anti-TB regimens are designed for PLWH (such as recommending daily rather than intermittent rifamycin dosing).

Unacceptable use of substandard metrics in policy decisions which mandate large reductions in animal-source foods.

Many recent very influential reports, including those from the Global Burden of Disease (GBD) Risk Factor Collaborators, the EAT-Lancet Commission on Food, Planet, Health, and the Lancet Countdown on Health and Climate Change, have recommended dramatic reductions or total exclusion of animal-source foods, particularly ruminant products (red meat and dairy), from the human diet. They strongly suggest that these dietary shifts will not only benefit planetary health but also human health. However, as detailed in this perspective, there are grounds for considerable concern in regard to the quality and transparency of the input data, the validity of the assumptions, and the appropriateness of the statistical modelling, used in the calculation of the global health estimates, which underpin the claimed human health benefits. The lessor bioavailability of protein and key micronutrients from plant-source foods versus animal-source foods was not adequately recognised nor addressed in any of these reports. Furthermore, assessments of bias and certainty were either limited or absent. Despite many of these errors and limitations being publically acknowledged by the GBD and the EAT-Lancet authors, no corrections have been applied to the published papers. As a consequence, these reports continue to erroneously influence food policy decisions and international dietary guidelines, such as the World Wildlife Fund's Livewell Diet, and the Nordic Nutrition Recommendations 2023.

Exposure and Health Risks Posed by Potentially Toxic Elements in Soils of Metal Fabrication Workshops in Mbarara City, Uganda.

Metal fabrication workshops (MFWs) are common businesses in Ugandan cities, and especially those producing metallic security gates, window and door frames (burglar-proof), and balcony and staircase rails. The objective of this study was to comparatively assess the pollution levels and potential health risks of manganese (Mn), chromium (Cr), cadmium (Cd), lead (Pd) and nickel (Ni) in pooled surface soil samples from four 5-, 7-, 8-, and 10-year-old MFWs (n = 28) and a control site (n = 8) in Mbarara City, Uganda. The concentration of the potentially toxic elements (PTEs) was determined using inductively coupled plasma-optical emission spectrometry. Contamination, ecological, and human health risk assessment indices and models were used to identify any risks that the PTEs could pose to the pristine environment and humans. Our results showed that PTE pollution of soils is occuring in the MFWs than at the control site. The mean concentrations of the PTEs (mg kg-1) in the samples were: Mn (2012.75 ± 0.23-3377.14 ± 0.31), Cr (237.55 ± 0.29-424.93 ± 0.31), Cd (0.73 ± 0.13-1.29 ± 0.02), Pb (107.80 ± 0.23-262.01 ± 0.19), and Ni (74.85 ± 0.25-211.37 ± 0.14). These results indicate that the PTEs could plausibly derive from the fabrication activities in these workshops, which is supported by the high values of contamination factors, index of geoaccumulation, and the overall increase in pollution load indices with the number of years of operation of the MFWs. Human health risk assessment showed that there are non-carcinogenic health risks that could be experienced by children who ingest PTEs in the soils from the 7-, 8- and 10-year-old MFWs. The incremental life cancer risk assessment suggested that there are potential cancerous health effects of Cd and Ni that could be experienced in children (who ingest soils from all the four MFWs) and adults (ingesting soils from the 8- and 10-year-old MFWs). This study underscores the need to implement regulatory guidelines on the operation and location of MFWs in Uganda. Further research should be undertaken to investigate the emission of the PTEs during welding operations in the MFWs.

Left-Ventricular Unloading With Impella During Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis.

OBJECTIVES: Extracorporeal cardiopulmonary resuscitation (ECPR) is the implementation of venoarterial extracorporeal membrane oxygenation (VA-ECMO) during refractory cardiac arrest. The role of left-ventricular (LV) unloading with Impella in addition to VA-ECMO ("ECMELLA") remains unclear during ECPR. This is the first systematic review and meta-analysis to characterize patients with ECPR receiving LV unloading and to compare in-hospital mortality between ECMELLA and VA-ECMO during ECPR. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, and abstract websites of the three largest cardiology societies (American Heart Association, American College of Cardiology, and European Society of Cardiology). STUDY SELECTION: Observational studies with adult patients with refractory cardiac arrest receiving ECPR with ECMELLA or VA-ECMO until July 2023 according to the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. DATA EXTRACTION: Patient and treatment characteristics and in-hospital mortality from 13 study records at 32 hospitals with a total of 1014 ECPR patients. Odds ratios (ORs) and 95% CI were computed with the Mantel-Haenszel test using a random-effects model. DATA SYNTHESIS: Seven hundred sixty-two patients (75.1%) received VA-ECMO and 252 (24.9%) ECMELLA. Compared with VA-ECMO, the ECMELLA group was comprised of more patients with initial shockable electrocardiogram rhythms (58.6% vs. 49.3%), acute myocardial infarctions (79.7% vs. 51.5%), and percutaneous coronary interventions (79.0% vs. 47.5%). VA-ECMO alone was more frequently used in pulmonary embolism (9.5% vs. 0.7%). Age, rate of out-of-hospital cardiac arrest, and low-flow times were similar between both groups. ECMELLA support was associated with reduced odds of mortality (OR, 0.53 [95% CI, 0.30-0.91]) and higher odds of good neurologic outcome (OR, 2.22 [95% CI, 1.17-4.22]) compared with VA-ECMO support alone. ECMELLA therapy was associated with numerically increased but not significantly higher complication rates. Primary results remained robust in multiple sensitivity analyses. CONCLUSIONS: ECMELLA support was predominantly used in patients with acute myocardial infarction and VA-ECMO for pulmonary embolism. ECMELLA support during ECPR might be associated with improved survival and neurologic outcome despite higher complication rates. However, indications and frequency of ECMELLA support varied strongly between institutions. Further scientific evidence is urgently required to elaborate standardized guidelines for the use of LV unloading during ECPR.

Long-term autograft dilation and durability after the Ross procedure are similar in infants, children, and adolescents with primary aortic stenosis.

BACKGROUND: Autograft durability and remodeling are thought to be superior in younger pediatric patients after the Ross operation. We sought to delineate the fate of autografts across the pediatric age spectrum in patients with primary aortic stenosis (AS). METHODS: We retrospectively reviewed patients age ≤18 years with primary AS who underwent the Ross operation between 1993 and 2020. Patients were categorized by age. The primary endpoint was autograft dimensional change, and secondary endpoints were severe neo-aortic insufficiency (AI) and autograft reintervention. RESULTS: A total of 119 patients underwent the Ross operation, including 37 (31.1%) in group I (age <18 months), 24 (20.2%) in group II (age 18 months-8 years), and 58 (48.7%) in group III (age 8-18 years). All groups exhibited similar annular growth rates within the first 5 postoperative years, followed by a collective decrease in annulus growth rates from year 5 to year 10. Group III experienced rapid sinus dilation in the first 5 years, followed by stabilization of the sinus z-score from year 5 to year 10, whereas groups I and II demonstrated stable sinus z-scores over 10 years. There were 4 early deaths (3.4%) and 2 late deaths (1.7%) at a median follow-up of 8.1 years (range, 0.01-26.3 years). At 15 years, the incidences of severe neo-AI (0.0 ± 0.0% vs 0.0 ± 0.0% vs 3.9 ± 3.9%; P = .52) and autograft reintervention (8.4 ± 6.0% vs 0.0 ± 0.0% vs 2.4 ± 2.4%; P = .47) were similar in the 3 groups. CONCLUSIONS: Age at the time of Ross operation for primary AS does not influence long-term autograft remodeling or durability. Other physiologic or technical factors are likely greater determinants of autograft fate.

Liberal use of veno-arterial extracorporeal membrane oxygenation in combined sequential heart-liver transplantation.

Combined heart-liver transplantation (CHLT) is a rarely though increasingly performed procedure with evolving indications. Despite CHLT being performed at only a handful of centers, the use of intraoperative mechanical circulatory support to optimize hemodynamics and facilitate dual-organ transplantation varies widely. At our center, we liberally utilize veno-arterial extracorporeal membrane oxygenation (V-A ECMO) when a veno-venous shunt is anticipated to be insufficient in mitigating the hemodynamic perturbations associated with liver reperfusion. In this series, we describe our experience with V-A ECMO in sequential (heart-first) CHLT and demonstrate highly favorable outcomes with this strategy.

Clinical specificity of two assays for immunoglobulin kappa and lambda free light chains.

OBJECTIVES: Free light chain (FLC) assays and the ratio of κ/λ are recommended for diagnosis, prognosis and monitoring of plasma cell dyscrasias (PCD). Limited data exists on FLC clinical specificity in patients diagnosed with other conditions. METHODS: We assessed the κ, λ, and κ/λ FLC ratio using the FreeLite assay and the Sebia FLC ELISA assay in 176 patients with clinical presentations of fatigue, anemia, polyclonal hypergammaglobulinemia, joint disorders, kidney disease and non PCD-cancers with no monoclonal protein observed on serum protein electrophoresis or MASS-FIX immunoglobulin isotyping. Manufacturer defined reference intervals (RI) and glomerular filtration rate (GFR) specific RI (renal RI) were utilized. RESULTS: For the κ/λ ratio, 68.7 % (121/176) of specimens on the FreeLite and 87.5 % (154/176) of specimens on the Sebia assay were within RI. For κ, 68.2 % (120/176) and 72.2 % (127/176) of results were outside RI for FreeLite and Sebia respectively. For λ, 37.5 % (66/176) and 84.1 % (148/176) of FreeLite and Sebia results were outside RI. With FreeLite and Sebia, patients with kidney disease (n=25) had the highest κ/λ ratios. 44 patients (25.0 %) had GFR <60 mL/min/BSA. When renal RI were applied, 13.6 % had a FLCr outside the renal RI with FreeLite, and 4.5 % with Sebia. CONCLUSIONS: In a cohort of patients with signs and symptoms suggestive of PCDs, but ultimately diagnosed with other conditions, Sebia FLC had improved clinical specificity relative to FreeLite, if one was using an abnormal κ/λ ratio as a surrogate for monoclonality.

Strategies for the Surgical Management of Highly Aggressive Williams Syndrome Aortopathy: A Three Case Report.

Severe aortopathy in Williams syndrome can sometimes present with an initial ascending aortic pathology, followed in short order by more distal multilevel obstruction and recurrence requiring reintervention. In this series, an early, comprehensive surgical approach using a combination of various access and perfusion strategies yielded excellent long-term results.

Racgap1 knockdown results in cells with multiple cilia due to cytokinesis failure.

Most mammalian cells have a single primary cilium that acts as a signalling hub in mediating cellular functions. However, little is known about the mechanisms that result in aberrant supernumerary primary cilia per cell. In this study, we re-analysed a previously published whole-genome siRNA-based reverse genetic screen for genes mediating ciliogenesis to identify knockdowns that permit multi-ciliation. We identified siRNA knockdowns that caused significant formation of supernumerary cilia, validated candidate hits in different cell-lines and confirmed that RACGAP1, a component of the centralspindlin complex, was the strongest candidate hit at the whole-genome level. Following loss of RACGAP1, mother centrioles were specified correctly prior to ciliogenesis and the cilia appeared normal. Live cell imaging revealed that increased cilia incidence was caused by cytokinesis failure which led to the formation of multinucleate cells with supernumerary cilia. This suggests that the signalling mechanisms for ciliogenesis are unable to identify supernumerary centrosomes and therefore allow ciliation of duplicated centrosomes as if they were in a new diploid daughter cell. These results, demonstrating that aberrant ciliogenesis is de-coupled from cell cycle regulation, have functional implications in diseases marked by centrosomal amplification.

Lack of observed interference by therapeutic monoclonal antibodies in select commonly utilized immunoassays.

BACKGROUND: Therapeutic monoclonal antibodies (tmabs) have been hypothesized to interfere with immunoassay measurements, although studies investigating this potential new class of interference are lacking. This study evaluated the effects of tmabs used in cancers ipilimumab (Bristol Myers Squibb), nivolumab (Bristol Myers Squibb), pembrolizumab (Merck) and autoimmune disorders adalimumab (AbbVie), infliximab (Janssen) and vedolizumab (Takeda) in common immunoassays used in the clinical laboratory. METHODS: Residual sera from 10 randomly chosen patients were split into two tubes and spiked with same volume (approximately 5 % final volume) of either saline (control) or 6 tmabs (final concentration of 100 µg/mL each). Concentrations from sixteen analytes in 19 different assays were assessed: TSH (Roche and Beckman), free thyroxine (Roche and Siemens), cortisol (Beckman), Cancer Antigens (CA): CA19-9 (Beckman), CA15-3 (Roche), CA125 (Roche), and CA27.29 (Siemens), carcinoembryonic antigen (Beckman), alpha-fetoprotein (Beckman), thyroglobulin (Beckman) and thyroglobulin antibodies (Beckman), thyroid peroxidase antibody (Beckman), beta-human chorionic gonadotropin (Roche and Beckman), total prostate-specific antigen (Roche), parathyroid hormone (Roche) and antinuclear antibodies IgG (Werfen). The tmab spiked residual sera were compared with matched saline spiked sera and percent error was assessed against allowable total error defined from biological variation or CLIA limits. RESULTS: None of the tested immunoassays were affected by the presence of the tmabs, in samples within or outside assay reference intervals. The median % error among all immunoassays ranged between -2.0% (for TSH) to 2.7% (for TPO Ab assay). CONCLUSION: These findings demonstrate no detectable tmab interference for the assessed immunoassays using spiked preparations of the tmabs in residual human sera. The findings are limited to the tmabs and immunoassays studied here.

Rifampin Mono-Resistant Tuberculosis in New York City, 2010-2021: A Retrospective Case Series.

Background: Although relatively rare, rifampin mono-resistant tuberculosis (RMR TB) poses important challenges to effective TB treatment and control. Information on the burden of RMR TB and treatment outcomes is needed to inform diagnosis and management. Methods: Standardized variables were collected from the New York City (NYC) tuberculosis surveillance system for patients treated for RMR TB in NYC during 2010-2021. Results: Of 7097 TB cases reported in 2010-2021, 31 (<1%) were treated clinically as RMR TB. Five (16%) of these patients had HIV. Seventeen patients (55%) had TB that was rifampin-resistant by both molecular and phenotypic drug susceptibility testing; 2 (6%) had rifampin resistance by phenotypic tests, and molecular tests were not done; and 12 (39%) were identified based only on molecular tests. Among these 12, 7 were rifampin-sensitive by phenotypic tests, and phenotypic testing could not be done for the other 5. Ten of the 31 (32%) were diagnosed in 2010-2015; the other 21 (including 10/12 diagnosed by molecular tests alone) were diagnosed in 2016-2021. Of the 31 patients, 21 (68%) completed treatment (median treatment duration of 18 months). Although the interval between tuberculosis treatment initiation and change to a non-rifamycin-containing regimen decreased significantly during the study period, the overall duration of treatment did not decrease significantly between 2010 and 2021. Conclusions: Molecular drug susceptibility tests identified cases of RMR TB that were not detected by phenotypic testing and helped enable timely adjustment of tuberculosis treatment regimens. Short-course regimens are needed to reduce duration of treatment for RMR TB.

Health Risks from Intake and Contact with Toxic Metal-Contaminated Water from Pager River, Uganda.

Pollution of water resources is one of the major impediments to the realization of Sustainable Development Goals, especially in developing countries. The aim of this study was to investigate the physicochemical quality and potentially toxic element (lead and cadmium) concentrations in surface water sampled from Pager River, a tributary of the Nile River in Northern Uganda. Water samples (n = 18) were taken from six different points upstream (A, B, and C) and downstream (D, E, and F) of the river and analyzed following standard methods for their physiochemical properties. Atomic absorption spectroscopy was used to quantify lead and cadmium concentrations. Human health risks from ingestion and dermal contact with potentially toxic metal-contaminated water were calculated. The results obtained indicated that the mean temperature (27.7 ± 0.5-29.5 ± 0.8 °C), turbidity (40.7 ± 2.1-50.1 ± 1.1 NTU), lead (0.296 ± 0.030-0.576 ± 0.163 mg/L) and cadmium (0.278 ± 0.040-0.524 ± 0.040 mg/L) occurred at levels that surpassed their permissible limits as per World Health Organization guidelines for drinking water. Human health risk assessment showed that there are potential non-cancer risks from the ingestion of water from Pager River by adults, as the total hazard quotients were greater than one. These results emphasize the urgency to restrict the dumping of wastes into the river to minimize chances of impacting the Nile River, which flows northwards to the Mediterranean Sea. Further studies should perform routine monitoring of the river during both dry and wet seasons to establish the spatiotemporal variations of physicochemical, microbial, and trace metal profiles of the river and the associated health risks.

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy.

Interleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia, and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7. In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm) which may be important for anti-tumor activities reported with IL-7 treatment. Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide lacks sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur. The properties we report here implicate MDK-703 as a candidate for clinical evaluation in oncology, anti-viral and other infectious disease, vaccine enhancement, and treatment of lymphopenia.