Treatment outcomes of new tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study.

BACKGROUND: In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda. METHODS AND FINDINGS: Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 - 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 - 4.01, P = 0.045). CONCLUSION: Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART

Association of metabolic equivalent of task (MET) score in length of stay in hospital following radical cystectomy with urinary diversion:a multi-institutional study

PURPOSE: The Metabolic equivalent of task (MET) score is used in patients’ preoperative functional capacity assessment. It is commonly thought that patients with a higher MET score will have better postoperative outcomes than patients with a lower MET score. However, such a link remains the subject of debate and is yet unvalidated in major urological surgery. This study aimed to explore the association of patients’ MET score with their postoperative outcomes following radical cystectomy. METHODS: We used records-linkage methodology with unique identifiers (Community Health Index/hospital number) and electronic databases to assess postoperative outcomes of patients who had underwent radical cystectomies between 2015 and 2020. The outcome measure was patients’ length of hospital stay. This was compared with multiple basic characteristics such as age, sex, MET score and comorbid conditions. A MET score of less than four (< 4) is taken as the threshold for a poor functional capacity. We conducted unadjusted and adjusted Cox regression analyses for time to discharge against MET score. RESULTS: A total of 126 patients were included in the analysis. Mean age on date of operation was 66.2 (SD 12.2) years and 49 (38.9%) were female. A lower MET score was associated with a statistically significant lower time-dependent risk of hospital discharge (i.e. longer hospital stay) when adjusted for covariates (HR 0.224; 95% CI 0.077–0.652; p = 0.006). Older age (adjusted HR 0.531; 95% CI 0.332–0.848; p = 0.008) and postoperative complications (adjusted HR 0.503; 95% CI 0.323–0.848; p = 0.002) were also found to be associated with longer hospital stay. Other comorbid conditions, BMI, disease staging and 30-day all-cause mortality were statistically insignificant. CONCLUSION: A lower MET score in this cohort of patients was associated with a longer hospital stay length following radical cystectomy with urinary diversion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11255-021-02813-x

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

Angiogenin protects motoneurons against hypoxic injury.

Cells can adapt to hypoxia through the activation of hypoxia-inducible factor-1 (HIF-1), which in turn regulates the expression of hypoxia-responsive genes. Defects in hypoxic signaling have been suggested to underlie the degeneration of motoneurons in amyotrophic lateral sclerosis (ALS). We have recently identified mutations in the hypoxia-responsive gene, angiogenin (ANG), in ALS patients, and have shown that ANG is constitutively expressed in motoneurons. Here, we show that HIF-1alpha is sufficient and required to activate ANG in cultured motoneurons exposed to hypoxia, although ANG expression does not change in a transgenic ALS mouse model or in sporadic ALS patients. Administration of recombinant ANG or expression of wild-type ANG protected motoneurons against hypoxic injury, whereas gene silencing of ang1 significantly increased hypoxia-induced cell death. The previously reported ALS-associated ANG mutations (Q12L, K17I, R31K, C39W, K40I, I46V) all showed a reduced neuroprotective activity against hypoxic injury. Our data show that ANG plays an important role in endogenous protective pathways of motoneurons exposed to hypoxia, and suggest that loss of function rather than loss of expression of ANG is associated with ALS

Virus Replication Strategies and the Critical CTL Numbers Required for the Control of Infection

Vaccines that elicit protective cytotoxic T lymphocytes (CTL) may improve on or augment those designed primarily to elicit antibody responses. However, we have little basis for estimating the numbers of CTL required for sterilising immunity at an infection site. To address this we begin with a theoretical estimate obtained from measurements of CTL surveillance rates and the growth rate of a virus. We show how this estimate needs to be modified to account for (i) the dynamics of CTL-infected cell conjugates, and (ii) features of the virus lifecycle in infected cells. We show that provided the inoculum size of the virus is low, the dynamics of CTL-infected cell conjugates can be ignored, but knowledge of virus life-histories is required for estimating critical thresholds of CTL densities. We show that accounting for virus replication strategies increases estimates of the minimum density of CTL required for immunity over those obtained with the canonical model of virus dynamics, and demonstrate that this modeling framework allows us to predict and compare the ability of CTL to control viruses with different life history strategies. As an example we predict that lytic viruses are more difficult to control than budding viruses when net reproduction rates and infected cell lifetimes are controlled for. Further, we use data from acute SIV infection in rhesus macaques to calculate a lower bound on the density of CTL that a vaccine must generate to control infection at the entry site. We propose that critical CTL densities can be better estimated either using quantitative models incorporating virus life histories or with in vivo assays using virus-infected cells rather than peptide-pulsed targets

Population size and decadal trends of three penguin species nesting at Signy Island, South Orkney Islands

We report long-term changes in population size of three species of sympatrically breeding pygoscelid penguins: Adélie (Pygoscelis adeliae), chinstrap (Pygoscelis antarctica) and gentoo (Pygoscelis papua ellsworthii) over a 38 year period at Signy Island, South Orkney Islands, based on annual counts from selected colonies and decadal all-island systematic counts of occupied nests. Comparing total numbers of breeding pairs over the whole island from 1978/79 to 2015/16 revealed varying fortunes: gentoo penguin pairs increased by 255%, (3.5% per annum), chinstrap penguins declined by 68% (-3.6% per annum) and Adélie penguins declined by 42% (-1.5% per annum). The chinstrap population has declined steadily over the last four decades. In contrast, Adélie and gentoo penguins have experienced phases of population increase and decline. Annual surveys of selected chinstrap and Adélie colonies produced similar trends from those revealed by island-wide surveys, allowing total island population trends to be inferred relatively well. However, while the annual colony counts of chinstrap and Adélie penguins showed a trend consistent in direction with the results from all-island surveys, the magnitude of estimated population change was markedly different between colony wide and all island counts. Annual population patterns suggest that pair numbers in the study areas partly reflect immigration and emigration of nesting birds between different parts of the island. Breeding success for all three species remained broadly stable over time in the annually monitored colonies. Breeding success rates in gentoo and chinstrap penguins were strongly correlated, despite the differing trends in population size. This study shows the importance of effective, standardised monitoring to accurately determine long-term population trajectories. Our results indicate significant declines in the Adélie and chinstrap penguin populations at Signy Island over the last five decades, and a gradual increase in gentoo breeding pairs

Development of a Standardized Screening Rule for Tuberculosis in People Living with HIV in Resource-Constrained Settings: Individual Participant Data Meta-analysis of Observational Studies

Haileyesus Getahun and colleagues report the development of a simple, standardized tuberculosis (TB) screening rule for resource-constrained settings, to identify people living with HIV who need further investigation for TB disease

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand– foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs