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Background: Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock., Methods: The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events., Discussion: With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial., Trial Registration: ClinicalTrials.gov NCT05824767. Registered on April 24, 2023., (© 2024. The Author(s).)

Objective: As master of science in health informatics (MSc HI) programs emerge in developing countries, quality assurance of these programs is essential. This article describes a comprehensive comparative analysis of competencies covered by accredited MSc HI programs in the East African common labor and educational zone., Materials and Methods: Two reviewers independently reviewed curricula from 7 of 8 accredited MSc HI university programs. The reviewers extracted covered competencies, coding these based on a template that contained 73 competencies derived from competencies recommended by the International Medical Informatics Association, plus additional unique competencies contained within the MSc HI programs. Descriptive statistics were used to summarize the structure and completion requirements of each MSc HI program. Jaccard similarity coefficient was used to compare similarities in competency coverage between universities., Results: The total number of courses within the MSc HI degree programs ranged from 8 to 22, with 35 to 180 credit hours. Cohen's kappa for coding competencies was 0.738. The difference in competency coverage was statistically significant across the 7 institutions (P = .012), with covered competencies across institutions ranging from 32 (43.8%) to 49 (67.1%) of 73. Only 4 (19%) of 21 university pairs met a cutoff of over 70% similarity in shared competencies., Discussion: Significant variations observed in competency coverage within MSc HI degree programs could limit mobility of student, faculty, and labor., Conclusions: Comparative analysis of MSc HI degree programs across 7 universities in East Africa revealed significant differences in the competencies that were covered., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The International Medical Informatics Association (IMIA) has provided recommendations on Education in Biomedical and Health Informatics (BMHI) as guidance on competencies relevant to education of BMHI specialists. However, it remains unclear how well these competencies have been adopted to guide emerging degree programs in low- and middle-income countries (LMICs). We evaluated comprehensiveness of IMIA-recommended competency coverage by Masters in Health Informatics (MSc HI) programs in East Africa., Materials and Methods: Two investigators independently reviewed curricula for seven accredited MSc HI university programs in the East Africa region to extract covered competencies using an instrument based on the IMIA education recommendations. Descriptive statistics were used to determine competency coverage by institution and across institutions and by IMIA-defined competency domains. Duplication of competency coverage in courses within each curriculum was also evaluated. Multivariable logistic regression was used to test whether coverage of IMIA-recommended competencies differed between institutions., Results: Cohen's Kappa for coding competencies within courses was 0.738 (95% CI, 0.713-0.764). Coverage of the 40 recommended required IMIA competencies by institutional curricula ranged from 25 (62.5%) to 39 (97.5%) (p < 0.0001), with only 18 (45%) of these competencies covered by all seven institutions. No significant variations in competency coverage were observed between the domains of information sciences (83.7%), health sciences (71.4%), and core BMHI competencies (83.5%) (p = 0.13). On average, each competency was covered by 3.06 courses in each curriculum (range 0 - 14). Curricula also contained 25 additional competencies not part of the IMIA recommendations, 15 of which were found only within the curriculum of a single institution., Discussion: There is significant variability in coverage of IMIA-recommended competencies across MSc HI curricula evaluated, with observed duplication of competency coverage within each curriculum. The additional competencies uncovered that were not part of the IMIA-recommendations were not universally shared across institutions., Conclusion: The IMIA education recommendations provide a relevant, comprehensive reference guide for developing and improving health informatics degree programs within LMIC settings. Variability in competency coverage needs to be addressed for institutions within similar educational and labor regions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Colonic mast cells have been proposed to be related to the pathophysiology of irritable bowel syndrome (IBS). Whether mast cell counts are altered in the small intestine, a less-explored region in patients with IBS is not completely clear., Methods: PubMed and EMBASE were searched for case-control studies on mast cell count/density in the small intestine of patients with IBS vs controls through February 2019. Mast cell counts were separately analyzed in the duodenum, jejunum, and ileum. Data were pooled using the standardized mean difference (SMD) method. When zero was not within the 95% confidence interval (CI), the SMD was considered significant., Key Results: Data from 344 patients with IBS and 229 healthy controls from three studies in the duodenum, six in the jejunum, and five in the ileum were pooled in this meta-analysis. The number of mast cells was significantly higher in the ileum (SMD: 1.78 [95% CI: 0.89, 2.66]) of patients with IBS. Mast cell counts were not significantly different in the duodenum (SMD: 0.81 [-0.06, 1.67]) or the jejunum (SMD: 0.58 [-0.03, 1.19]) of patients with IBS vs healthy controls., Conclusions and Inferences: Mast cells are increased in the small intestine of IBS vs controls, mainly in the ileum. Future studies should address whether such findings are IBS subtype or gender-dependent. Methodological variations, single-center bias, and the limited number of studies included in this meta-analysis may affect the final results., (© 2019 John Wiley & Sons Ltd.)

Objectives: This cross-sectional study examined the distribution and correlates of salivary secretory leukocyte protease inhibitor (SLPI) concentrations within a multinational cohort of men., Methods: Extracellular SLPI was measured in oral gargle cell supernatants of 378 men from three countries using an ELISA-based assay. Risk factor data were collected by a questionnaire. Factors associated with SLPI were assessed using linear and logistic regression for continuous and categorical SLPI, respectively., Results: Among men aged 18-73 years, the median SLPI concentration was 492.0 ng ml -1 (range: 2.3-1919.9). In multivariable modeling, men in Brazil and younger men (18-30 years) were more likely to have higher levels of SLPI [adjusted odds ratio (aOR) 3.84; 95% confidence interval (CI): 1.94-7.59, and aOR 3.84; 95% CI: 1.98-7.43, respectively]. Men with a self-reported sexually transmitted diseases diagnosis in the past 6 months were more likely to have higher SLPI levels (aOR 2.98; 95% CI: 1.1-7.83) and men reporting bleeding/swollen gums were less likely to have higher SLPI (aOR 0.34; 95% CI: 0.15-0.79). Similar results were observed for linear regression models., Conclusions: Secretory leukocyte protease inhibitor concentrations varied significantly by country and decreased with increasing age. The interaction between SLPI, modifiable factors, and oral infections that influence cancer risk warrants further investigation., Competing Interests: Conflict of Interests None to declare., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Human papillomavirus virus type 16 (HPV-16) and HPV-18 cause a large proportion of oropharyngeal cancers, which are increasing in incidence among males, and vaccine efficacy against oral HPV infections in men has not been previously evaluated., Methods: Sera and saliva collected in mouthwash and Merocel sponges at day 1 and month 7 were obtained from 150 men aged 27-45 years from Tampa, Florida, and Cuernavaca, Mexico, who received Gardasil at day 1 and months 2 and 6. Specimens were tested for anti-HPV-16 and anti-HPV-18 immunoglobulin G (IgG) levels by an L1 virus-like particle-based enzyme-linked immunosorbent assay., Results: All participants developed detectable serum anti-HPV-16 and anti-HPV-18 antibodies, and most had detectable antibodies in both oral specimen types at month 7 (HPV-16 was detected in 93.2% of mouthwash specimens and 95.7% of sponge specimens; HPV-18 was detected in 72.1% and 65.5%, respectively). Antibody concentrations in saliva were approximately 3 logs lower than in serum. HPV-16- and HPV-18-specific antibody levels, normalized to total IgG levels, in both oral specimen types at month 7 were significantly correlated with serum levels (for HPV-16, ρ was 0.90 for mouthwash specimens and 0.92 for sponge specimens; for HPV-18, ρ was 0.89 and 0.86, respectively)., Conclusions: This is the first study demonstrating that vaccination of males with Gardasil induces HPV antibody levels at the oral cavity that correlate with circulating levels., (© 2016 World Health Organization; licensee Oxford Journals.)

The phenomenon of kinking in medical tubing remains a problem for some applications, particularly critical ones such as transporting gasses or fluids. Design features are described to prevent its occurrence.

1. The alpha-chymotrypsin-catalysed hydrolysis of N-acetylglycine ethyl and thiolethyl esters was investigated at pH7.90 and 25 degrees over a wide range of substrate concentrations. 2. The Lineweaver-Burk plots for these substrates are markedly curved, and it is shown that the curvature is due solely to the ;enzyme-blank' reaction. The rate of this reaction is proportional to free enzyme concentration in the range 10-100mum, with a pseudo-first-order rate constant of approx. 1x10(-3)sec.(-1). Correction for this reaction by the procedure described leads to linear plots. It is shown that the significance of the enzyme-blank reaction depends on the value of k(0)/K(m) for the substrate under investigation. 3. Interpretation of the curvature in the Lineweaver-Burk plots by previous workers in terms of activation by excess of substrate is shown to be erroneous. 4. Values of K(m) 387mm and k(0) 0.039sec.(-1), and K(m) 41mm and k(0) 0.23sec.(-1), were obtained for the ethyl and thiolethyl esters of N-acetylglycine respectively. The literature values for the methyl esters of N-acetyl- and N-propionyl-glycine have been corrected by the procedure described. The new values agree much better with current theories of alpha-chymotrypsin mechanism and specificity. 5. The kinetic parameters for the ethyl and thiolethyl esters indicate the absence of an electrophilic component in the catalytic mechanism of alpha-chymotrypsin, and the importance of the ester function in substrate binding.

1. The rates of deacylation of acyl-alpha-chymotrypsins in which the hydrogen-bonding capacity of the acylamino group of the substrate has been systematically removed were measured. 2. The ratio of deacylation rates of l- and d-acyl-enzymes is found to depend largely on the existence in the substrate of an amido -NH- group. 3. The data presented agree with the postulate that the stereospecificity of alpha-chymotrypsin is exercised in catalytic rather than binding steps, and that the active site of the enzyme presents three loci to the substrate: the site containing the catalytic functionalities (including serine-195), the hydrophobic area for amino acid side-chain binding, and a hydrogen-bond acceptor site for acylamino group binding. 4. It is noted that, though the hydrogen-bonding site is crucial for the stereospecificity, the free energy of binding of substrates and inhibitors is dominated by the hydrophobic interaction. 5. It is tentatively proposed that alpha-chymotrypsin selects a high-energy conformation of the substrate when the latter binds at the enzyme's active site.

1. The optically pure p-nitrophenyl esters of the d and l enantiomers of N-acetyl-tryptophan, N-acetylphenylalanine and N-acetyl-leucine, and the p-nitrophenyl ester of N-acetylglycine, have been prepared. 2. These materials are all substrates of alpha-chymotrypsin, and the rates of deacylation of the corresponding acyl-alpha-chymotrypsins have been determined. 3. As the size of the amino acid side chain increases, the l series deacylate progressively faster than the N-acetylglycyl-enzyme, and the d series progressively more slowly. 4. The results are interpreted in terms of a three-locus model of the enzyme's active site, which accounts for the interrelationship between substrate specificity and stereospecificity observed. 5. The concepts of negative specificity and of specificity saturation are introduced.