Blended SORT-IT for operational research capacity building: the model, its successes and challenges.

The Structured Operational Research Training Initiative (SORT-IT) has been shown to be very effective in strengthening capacity for conducting operational research, publishing in scientific journals and fostering policy and practice change. The 'classic' model includes three face-to-face modules during which, respectively, a study protocol, a data analysis plan, and a manuscript are elaborated. Meanwhile, the lectures of the SORT-IT are available online as YouTube videos. Given the availability of this online material and the experiences with online mentorship of the faculty, we piloted a first blended distance/residential SORT-IT. To inform future implementers of our experience with blended operational research courses, we summarize the model, successes, and challenges of this approach in this perspective paper. The blended SORT-IT consisted of an online phase, covering modules 1 and 2, followed by a face-to-face writing module 3. Four out of six participants successfully completed the course, and submitted a manuscript to a peer-reviewed journal within four weeks of completing module 3. A blended approach may make the SORT-IT course more accessible to future participants and may favour the adoption of the course by other institutions, such as national Ministries of Health

CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance.

Heterozygous mutations in the PRPF31 gene cause autosomal dominant retinitis pigmentosa (adRP), a hereditary disorder leading to progressive blindness. In some cases, such mutations display incomplete penetrance, implying that certain carriers develop retinal degeneration while others have no symptoms at all. Asymptomatic carriers are protected from the disease by a higher than average expression of the PRPF31 allele that is not mutated, mainly through the action of an unknown modifier gene mapping to chromosome 19q13.4. We investigated a large family with adRP segregating an 11-bp deletion in PRPF31. The analysis of cell lines derived from asymptomatic and affected individuals revealed that the expression of only one gene among a number of candidates within the 19q13.4 interval significantly correlated with that of PRPF31, both at the mRNA and protein levels, and according to an inverse relationship. This gene was CNOT3, encoding a subunit of the Ccr4-not transcription complex. In cultured cells, siRNA-mediated silencing of CNOT3 provoked an increase in PRPF31 expression, confirming a repressive nature of CNOT3 on PRPF31. Furthermore, chromatin immunoprecipitation revealed that CNOT3 directly binds to a specific PRPF31 promoter sequence, while next-generation sequencing of the CNOT3 genomic region indicated that its variable expression is associated with a common intronic SNP. In conclusion, we identify CNOT3 as the main modifier gene determining penetrance of PRPF31 mutations, via a mechanism of transcriptional repression. In asymptomatic carriers CNOT3 is expressed at low levels, allowing higher amounts of wild-type PRPF31 transcripts to be produced and preventing manifestation of retinal degeneration

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Jinnah Institute Policy Brief; March 19, 2015

In this issue: “Assessing the future of family planning services in Pakistan after the 18th Amendment"

Yield of facility-based verbal screening amongst household contacts of patients with multi-drug resistant tuberculosis in Pakistan

Background: Household contacts of multidrug-resistant tuberculosis (MDR-TB) patients are at a high risk of getting infected with TB/MDR-TB, therefore symptomatic or vulnerable individuals should be screened and treated early. Methods: A cross-sectional study was conducted among household contacts of MDR-TB patients in three high-burden TB sites in Pakistan from July 2013 to June 2014. MDR-TB index patients were asked to provide a list of all members of their household and were asked whether any of them had TB symptoms such as productive cough, fever, weight loss and night sweat (âfacility-based verbal screeningâ). Symptomatic contacts were defined as presumptive TB cases and were invited for investigations at the facility. Those who did not come were paid a home-visit. Confirmed TB/MDR-TB patients were registered in the nearest treatment facility. Results: Of 209 MDR-TB index patients, 1467 household contacts were identified and screened, 95 of them children <â5 years. Of these 172 (12%) were symptomatic. Most common symptoms were cough 157 (91%) and fever 107 (62%). 58 (34%) presumptive TB contacts were not investigated. Of total contacts, 56 (3.8%) were diagnosed with TB, among them 54(96%) with MDR-TB and 2(4%) with drug-susceptible-TB. The number needed to screen (NNS) to identify a new MDR-TB case among adult household contacts was 27 and among presumptive adult and pediatric TB contacts was three. All 56 confirmed patients were registered for treatment. Conclusion: Screening household contacts of MDR-TB index cases may be considered a feasible and high yield option, in high-burden, low-resource settings within Pakistan. The number of presumptive TB contacts required to screen to identify a new MDR-TB case was unusually low, indicating an effective strategy that could easily be scaled-up. The screening and management of vulnerable adults and children living with patients having TB of any form is a major priority in the combined efforts to end TB. Keywords: MDR-TB, Tuberculosis, Household contacts, Contact tracing, Children, GeneXpert, Index patient

Engagement of public and private medical facilities in tuberculosis care in Myanmar: contributions and trends over an eight-year period

Abstracts Background As part of the WHO End TB strategy, national tuberculosis (TB) programs increasingly aim to engage all private and public TB care providers. Engagement of communities, civil society organizations and public and private care provider is the second pillar of the End TB strategy. In Myanmar, this entails the public-public and public-private mix (PPM) approach. The public-public mix refers to public hospital TB services, with reporting to the national TB program (NTP). The public-private mix refers to private general practitioners providing TB services including TB diagnosis, treatment and reporting to NTP. The aim of this study was to assess whether PPM activities can be scaled-up nationally and can be sustained over time. Methods Using 2007–2014 aggregated program data, we collected information from NTP and non-NTP actors on 1) the number of TB cases detected and their relative contribution to the national case load; 2) the type of TB cases detected; 3) their treatment outcomes. Results The total number of TB cases detected per year nationally increased from 133,547 in 2007 to 142,587 in 2014. The contribution of private practitioners increased from 11% in 2007 to 18% in 2014, and from 1.8% to 4.6% for public hospitals. The NTP contribution decreased from 87% in 2007 to 77% in 2014. A similar pattern was seen in the number of new smear (+) TB cases (31% of all TB cases) and retreatment cases, which represented 7.8% of all TB cases. For new smear (+) TB cases, adverse outcomes were more common in public hospitals, with more patients dying, lost to follow up or not having their treatment outcome evaluated. Patients treated by private practitioners were more frequently lost to follow up (8%). Adverse treatment outcomes in retreatment cases were particularly common (59%) in public hospitals for various reasons, predominantly due to patients dying (26%) or not being evaluated (10%). In private clinics, treatment failure tended to be more common (8%). Conclusions The contribution of non-NTP actors to TB detection at the national level increased over time, with the largest contribution by private practitioners involved in PPM. Treatment outcomes were fair. Our findings confirm the role of PPM in national TB programs. To achieve the End TB targets, further expansion of PPM to engage all public and private medical facilities should be targeted

Before the bombing: High burden of traumatic injuries in Kunduz Trauma Center, Kunduz, Afghanistan.

BACKGROUND:Médecins Sans Frontières (MSF) has been providing healthcare in Afghanistan since 1981 including specialized health services for trauma patients in Kunduz Trauma Center (KTC) from 2011. On October 3rd, 2015, a US airstrike hit the KTC, killing 42 people including 14 MSF staff. This study aims to demonstrate the impact on healthcare provision, after hospital destruction, by assessing the extent of care provided for trauma and injuries by the MSF KTC and to report on treatment outcomes from January 2014 to June 2015, three months prior to the bombing. METHODS:This is a descriptive, retrospective review of hospital records. All patients with traumatic injuries registered in the Emergency Department (ED) or hospitalized in In-Patients Department (IPD) and/or Intensive Care Unit (ICU) of KTC between January 2014 and June 2015 were included in the study. RESULTS:A total of 35647 patients were registered in KTC during the study period. 3199 patients registered in the ED were children aged <5 years and 310 of them were admitted including 47 to the ICU. 77.5% patients were from Kunduz province and the remaining were from other provinces. The average length of stay was 7.3 days and 3.3 days while the bed occupancy rate was an average 91.1% and 75.8% in IPD and ICU, respectively. Of 4605 IPD patients, 105 (2.3%) developed complications. Among those admitted to the ICU, 12.6% patients died. About one-third surgical interventions were carried out on an urgent basis and the major proportion (45.8%) of surgical procedures was wound surgery followed by orthopedic surgery (27.0%). CONCLUSIONS:This study highlights the high burden of traumatic injuries in Kunduz province and MSF Trauma Center's contribution to saving lives, preventing disabilities and alleviating suffering among adults and children within the region. The bombing and destruction of KTC has resulted in a specific gap in critical healthcare services for the local communities in the health system of this war-ravaged region. This suggests the urgent need for reconstruction and re-opening of the center

Six early-warning indicators of stock-out and overstocking of the Procurement and Supply Management System (PSM) for MDR-TB drugs in Nigeria.

<p>Adapted from reference 4</p><p>Six early-warning indicators of stock-out and overstocking of the Procurement and Supply Management System (PSM) for MDR-TB drugs in Nigeria.</p