Tübingen model study: large-scale introduction of rapid antigen testing in the population and the viral dynamics of SARS-CoV-2.

Despite of contact restrictions, population mobility remains the main reason for the spread of SARS-CoV-2. The state of Baden-Württemberg (BW), Germany, approved a model study in Tübingen (TÜMOD) to evaluate how mandatory rapid diagnostic tests (RDT) could reduce transmission. Between 16 March and 24 April 2021, approximately 165,000 residents and visitors to the city were screened for SARS CoV-2 infection using Abbott Panbio™ COVID-19 Antigen rapid test device. We assessed incidences and recorded epidemiological characteristics in a subset of 4,118 participants recruited at three of the nine testing stations. PCR tests were performed in RDT-positives to determine the positive predictive value (PPV), and circulating variants of SARS-CoV-2 were identified by whole-genome sequencing. 2,282 RDT-negative samples were tested by pooled PCR to calculate the false negative rate (FNR). Viral load was compared between variants. 116 (3%) participants were positive by RDT, and of these, 57 (49%) were positive by PCR, 55 (47%) were negative. This resulted in a PPV of 51%. Of the 57 positives, 52 SARS-CoV-2 genomes were successfully sequenced. Of these, 50 belonged to the B.1.1.7 lineage, which had a high viral load (average Ct = 19). Of the 2,282 RDT negatives tested, all were PCR negative (FNR 0%). At the end of TÜMOD, the incidence in Tübingen, which was initially lower, had reached the incidence in the state of BW. While it is difficult to assess the impact of TÜMOD on incidence independent of confounding factors, further studies are needed to identify the effect of close-meshed testing on infection rates.

Improved clinical and laboratory skills after team-based, malaria case management training of health care professionals in Uganda.

BACKGROUND: Deployment of highly effective artemisinin-based combination therapy for treating uncomplicated malaria calls for better targeting of malaria treatment to improve case management and minimize drug pressure for selecting resistant parasites. The Integrated Management of Malaria curriculum was developed to train multi-disciplinary teams of clinical, laboratory and health information assistants. METHODS: Evaluation of training was conducted in nine health facilities that were Uganda Malaria Surveillance Programme (UMSP) sites. From December 2006 to June 2007, 194 health professionals attended a six-day course. One-hundred and one of 118 (86%) clinicians were observed during patient encounters by expert clinicians at baseline and during three follow-up visits approximately six weeks, 12 weeks and one year after the course. Experts used a standardized tool for children less than five years of age and similar tool for patients five or more years of age. Seventeen of 30 laboratory professionals (57%) were assessed for preparation of malaria blood smears and ability to interpret smear results of 30 quality control slides. RESULTS: Percentage of patients at baseline and first follow-up, respectively, with proper history-taking was 21% and 43%, thorough physical examination 18% and 56%, correct diagnosis 51% and 98%, treatment in compliance with national policy 42% and 86%, and appropriate patient education 17% and 83%. In estimates that adjusted for individual effects and a matched sample, relative risks were 1.86 (95% CI: 1.20,2.88) for history-taking, 2.66 (95%CI: 1.60,4.41) for physical examination, 1.77 (95%CI: 1.41,2.23) for diagnosis, 1.96 (95%CI: 1.46,2.63) for treatment, and 4.47 (95%CI: 2.68,7.46) for patient education. Results were similar for subsequent follow-up and in sub-samples stratified by patient age. Quality of malaria blood smear preparation improved from 21.6% at baseline to 67.3% at first follow-up (p < 0.008); sensitivity of interpretation of quality control slides increased from 48.6% to 70.6% (p < 0.199) and specificity increased from 72.1% to 77.2% (p < 0.736). Results were similar for subsequent follow-up, with the exception of a significant increase in specificity (94.2%, p < 0.036) at one year. CONCLUSION: A multi-disciplinary team training resulted in statistically significant improvements in clinical and laboratory skills. As a joint programme, the effects cannot be distinguished from UMSP activities, but lend support to long-term, on-going capacity-building and surveillance interventions.

Polymorphisms in the apoptotic pathway gene BCL-2 and survival in small cell lung cancer.

INTRODUCTION: We investigated the single-nucleotide polymorphism C-938A in the apoptotic gene BCL-2 to assess the potential impact as a genetic marker for response to chemotherapy and outcome prediction in small cell lung cancer (SCLC) patients. Such a marker might help optimize lung cancer treatment in a tailored approach. METHODS: DNA derived from peripheral blood lymphocytes of 188 Caucasian SCLC patients treated at the Thoraxklinik Heidelberg was genotyped. Chemotherapy response, time to progression (TTP), and overall survival (OS) were evaluated using multivariable regression (unconditional logistic for response and Cox proportional hazard for TTP and OS) with odds ratios and hazard ratios (HRs) and their 95% confidence intervals (CIs) as quantitative outcome measures, respectively. RESULTS: Small cell lung cancer patients carrying the BCL-2 -938CC genotype showed significantly worse TTP than patients carrying the BCL-2 -938AA genotype (HR = 1.86; 95% CI = 1.10-3.13, p = 0.021). The same adverse effect was shown for OS (HR = 2.38; 95% CI = 1.38-4.12, p = 0.002). Also, patients with limited disease (HR = 2.57; 95% CI = 1.18-5.60, p = 0.017) showed worse OS with the BCL-2 -938CC genotype. CONCLUSION: BCL-2 -938CC genotype shows significantly worse outcome in small cell lung cancer patients. This genetic marker might particularly impact on treatment strategies using BCL-2 antisense approaches.

Training needs assessment for clinicians at antiretroviral therapy clinics: evidence from a national survey in Uganda.

BACKGROUND: To increase access to antiretroviral therapy in resource-limited settings, several experts recommend "task shifting" from doctors to clinical officers, nurses and midwives. This study sought to identify task shifting that has already occurred and assess the antiretroviral therapy training needs among clinicians to whom tasks have shifted. METHODS: The Infectious Diseases Institute, in collaboration with the Ugandan Ministry of Health, surveyed health professionals and heads of antiretroviral therapy clinics at a stratified random sample of 44 health facilities accredited to provide this therapy. A sample of 265 doctors, clinical officers, nurses and midwives reported on tasks they performed, previous human immunodeficiency virus training, and self-assessment of knowledge of human immunodeficiency virus and antiretroviral therapy. Heads of the antiretroviral therapy clinics reported on clinic characteristics. RESULTS: Thirty of 33 doctors (91%), 24 of 40 clinical officers (60%), 16 of 114 nurses (14%) and 13 of 54 midwives (24%) who worked in accredited antiretroviral therapy clinics reported that they prescribed this therapy (p<0.001). Sixty-four percent of the people who prescribed antiretroviral therapy were not doctors. Among professionals who prescribed it, 76% of doctors, 62% of clinical officers, 62% of nurses and 51% of midwives were trained in initiating patients on antiretroviral therapy (p=0.457); 73%, 46%, 50% and 23%, respectively, were trained in monitoring patients on the therapy (p=0.017). Seven percent of doctors, 42% of clinical officers, 35% of nurses and 77% of midwives assessed that their overall knowledge of antiretroviral therapy was lower than good (p=0.001). CONCLUSION: Training initiatives should be an integral part of the support for task shifting and ensure that antiretroviral therapy is used correctly and that toxicity or drug resistance do not reverse accomplishments to date.

Improved malaria case management after integrated team-based training of health care workers in Uganda.

Malaria case management in Africa is characterized by presumptive treatment and substantial overtreatment. We evaluated an integrated team-based training program on malaria case management. Surveillance data 120 days before and after training were compared at eight health facilities in Uganda. After training, the proportion of patients with suspected malaria referred for blood smears increased from 38.3% to 54.6% (P=0.04) in persons<5 years of age years and from 34.1% to 53.4% (P=0.02) in those>or=5 years of age. The proportion of patients with negative blood smears prescribed antimalarial drugs decreased from 47.9% to 19.6% (P<0.001) in persons<5 years of age and from 38.8% to 15.6% (P<0.001) in those>or=5 years of age. Training did not improve the proportion of patients with positive blood smears prescribed antimalarial drugs, the proportion of patients prescribed appropriate antimalarial drugs, or the diagnostic accuracy of microscopy. Integrated team-based training may improve malaria case management and reduce the number of unnecessary antimalarial treatments.

Measuring the outcomes of a comprehensive HIV care course: pilot test at the Infectious Diseases Institute, Kampala, Uganda.

OBJECTIVE: To evaluate the effects of the Infectious Diseases Institute's 4-week course for African doctors on comprehensive management of HIV including antiretroviral therapy on four outcomes: (1) clinical skills, (2) clinical activities, (3) monitoring of HIV patients, and (4) training activities DESIGN: Clinical exam at beginning and end of course and at follow-up 3 to 4 months later, and a cross-section telephone survey. METHODS: Forty-seven doctors attending the course (October 2004, November 2004, March 2005, and April 2005) agreed to participate. A 17-item Clinical Exam Checklist was used to assess clinical skills. A telephone survey was conducted 1 month after the course to collect data in four areas: clinical activities, monitoring of HIV patients, case studies on initiation of ART, and training activities. RESULTS: The course improved the clinical skills of doctors. Between the beginning and end of the course, their clinical skills improved significantly in 11 of 17 areas (n = 34). Between the end of the course and follow-up, their skills improved significantly in three areas (n = 14). The trainees were practicing HIV care and training. The telephone survey (n = 46) showed that 93% of trainees treated HIV patients, 35% provided training on HIV, and 47% monitored the weight of the last HIV patient treated (patient's weight was a clinical end point to measure health status). At follow-up, everyone provided training and trained an average of 20 people per month.

Constitutive mRNA expression of DNA repair-related genes as a biomarker for clinical radio-resistance: A pilot study in prostate cancer patients receiving radiotherapy.

PURPOSE: Repair of radiation-induced DNA damage is believed to play a critical role in the development of adverse reactions in radiotherapy patients. Constitutive mRNA expression of repair genes was investigated in such patients to analyze whether expression patterns are predictive for therapy-related acute side effects. MATERIALS AND METHODS: Prostate cancer patients (n = 406) receiving intensity-modulated radiotherapy were recruited in a prospective epidemiological study. Adverse effects were monitored during therapy using common toxicity criteria. For expression analyses, samples from 58 patients were selected according to their observed grade of clinical side effects to radiotherapy. Expression profiles were generated from peripheral blood lymphocytes using customized cDNA-arrays which carried probes for 143 DNA repair or repair-related genes. In addition, expression of selected genes was confirmed by quantitative real-time reverse transcription PCR (RT-PCR). Constitutive mRNA expression profiles were analyzed for predicting acute clinical radiosensitivity or radio-resistance. RESULTS: Cluster analysis identified 19 differentially expressed genes. Many of these genes are involved in DNA double strand break repair. Expression levels of these genes differed up to 7-fold from the mean of all patients whereas expression levels of housekeeping genes varied only up to 2-fold. High expression of the identified genes was associated with a lack of clinical radiation sensitivity thus indicating radio-resistance. CONCLUSIONS: Constitutive expression of DNA repair-related genes may affect the development of acute side effects in radiotherapy patients, and high expression levels of these genes seem to support protection from adverse reactions.

Gene expression profiles in rat liver slices exposed to hepatocarcinogenic enzyme inducers, peroxisome proliferators, and 17alpha-ethinylestradiol.

Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, alpha-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17alpha-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17alpha-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro.

An epidemiological study of RSV infection in the Gambia.

OBJECTIVE: To describe the epidemiology of respiratory syncytial virus (RSV) infection in a developing country. METHODS: The work was carried out in three hospitals for primary cases and in the community for secondary cases in the western region of the Gambia, West Africa. RSV infection was diagnosed by immunofluorescence of nasopharyngeal aspirate samples in children younger than two years admitted to hospital with acute lower respiratory infection (ALRI). Routine records of all children with ALRI were analysed, and the incidence rates of ALRI, severe RSV-associated respiratory illness and hypoxaemic RSV infections were compared. A community-based study was undertaken to identify secondary cases and to obtain information about spread of the virus. FINDINGS: 4799 children with ALRI who were younger than two years and lived in the study area were admitted to the study hospitals: 421 had severe RSV-associated respiratory illness; 55 of these were hypoxaemic. Between 1994 and 1996, the observed incidence rate for ALRI in 100 children younger than one year living close to hospital was 9.6 cases per year; for severe RSV-associated respiratory illness 0.83; and for hypoxaemic RSV-associated respiratory illness 0.089. The proportion of all ALRI admissions due to RSV was 19%. Overall, 41% of children younger than five years in compounds in which cases lived and 42% in control compounds had evidence of RSV infection during the surveillance period. CONCLUSION: RSV is an important cause of ALRI leading to hospital admission in the Gambia. Morbidity is considerable and efforts at prevention are worthwhile.