Prevention of Organ Failure

Tuberculosis (TB) remains the leading cause of infectious death. The Bacille Calmette-Guerin (BCG) vaccine has been the only licensed vaccine available for TB prevention. Despite BCG being administered intradermally for over a century to >100 million individuals annually, the molecular events in the skin following BCG administration have not been investigated; as a result, measurable correlates of protection that could predict vaccine effectiveness already early after vaccination are lacking. Here we show that BCG immediately (within one day after vaccination) induces dynamic molecular waves that drive the acute human host response across space (layers of the skin and systemically in blood) and time (days). Integration of this data across space and time identified robust networks of interactive modules related to immune surveillance (e.g. Langerhans cells), cell trafficking (e.g. endothelial cells, ITGB5), and trained immunity (e.g. neutrophils, macrophages, gamma-delta T cell). Importantly, not only were we able to identify BCG-activated pathways associated with trained immunity such as mTOR signaling and glycolysis/gluconeogenesis, we were able to pinpoint the time-point and precise location (skin layer) of the initial activation of theses pathways. Combining tissue biopsies of human skin (spatial genomics) with 'liquid biopsies' (cell-free blood plasma RNASeq) following BCG vaccination our data both confirmed known evidence (e.g. prominent gamma-delta T cell induction at the site of BCG administration; negative correlation of blood vs tissue myeloid-derived suppressor cells), but also generated promising new leads such as baseline levels of B cells, platelets and nuocytes in the skin prior to BCG administration predict eventual outcome, and that these predictive differences in baseline cellular composition can be captured non-invasively using high resolution images of the site of injection (dermatoscopy). Given this data represents the first holistic view of the acute molecular response to BCG in the skin in a human population at medium to high TB risk, we anticipate our findings of the immediate/early events following BCG vaccination, including non-invasive predictive assessment will support acceleration of vaccine development in the fight against TB.

The multifaceted interactions among the immune system, cancer cells and microbial components have established a novel concept of the immuno-oncology-microbiome (IOM) axis. Microbiome sequencing technologies have played a pivotal role in not only analyzing how gut microbiota affect local and distant tumors, but also providing unprecedented insights into the intratumor host-microbe interactions. Herein, we discuss the emerging trends of transiting from bulk-level to single cell- and spatial-level analyses. Moving forward with advances in biotechnology, microbial therapies, including microbiota-based therapies and bioengineering-inspired microbes, will add diversity to the current oncotherapy paradigm.

Abstract While every endpointed interval I in a linear order J is, considered as a linear order in its own right, trivially Muchnik‐reducible to J itself, this fails for Medvedev‐reductions. We construct an extreme example of this: a linear order in which no endpointed interval is Medvedev‐reducible to any other, even allowing parameters, except when the two intervals have finite difference. We also construct a scattered linear order which has many endpointed intervals Medvedev‐incomparable to itself; the only other known construction of such a linear order yields an ordinal of extremely high complexity, whereas this construction produces a low‐level‐arithmetic example. Additionally, the constructions here are “coarse” in the sense that they lift to other uniform reducibility notions in place of Medvedev reducibility itself.

Abstract: Background: Gallstones disease is one of the major problem of gastro intestinal tract and surgical removal is usually advised. Surgery is usually laparoscopic but if the dissection is tedious, laparoscopic procedure can be converted into open procedure. Objective: This study aims to assess the reasons and risk factors for the conversion of laparoscopic cholecystectomy (LC) into open cholecystectomy (OC). Materials and Methods: A prospective assessment of medical records of patients who underwent laparoscopic cholecystectomy at ward-2, Jinnah Postgraduate Medical Centre from January 2019 to December 2021 was undertaken to identify indications of all laparoscopic cholecystectomies converted to open cholecystectomy and assess operative time and length of hospital stay of these patients. Results: A total of 984 elective cholecystectomies were performed in which 85.5% (n=841) were females and 14.5% (n=143) were males. Male to female ratio was 1:5.8 with conversion rate 0.40 % (n=04) and 4.36% (n=43) respectively. Laparoscopic cholecystectomy was done in 95.22% (n=937) cases while 4.78% (n=47) patients required conversion to open cholecystectomy with major pre-operative risk factors being acute cholecystitis (p<0.001), history of acute cholecystitis (p=0.012), history of acute pancreatitis (p=0.007), history of previous open surgery (p<0.001) and major per-operative risk factors being severe bleeding (p<0.001), dense adhesions (p=0.755), distorted anatomy (p<0.001), visceral damage (p<0.001) and biliary injury(p<0.001). Conclusion: We have identified some important risk factors for the conversion of surgical approach for acute cholecystitis. However, the open approach should be done by experienced surgeons when necessary. The overall impact of the study is to identify the patients who are the risk of conversion into open preoperatively so that proper arrangement and counseling should be done.

Understanding the epidemiology of long COVID and emerging variants has significant public-health implications as physical interventions and restrictions that help limit viral spread are eased globally. Here, we provide rationales for the necessity of updating current vaccines to improve protection against omicron and emerging variants, as well as more research into understanding the epidemiology and mechanisms of long COVID.

Abstract ImportanceEvidence suggests that early, robust type 1 interferon responses to SARS-CoV-2 are critical determinants for COVID-19 disease outcomes, accelerating viral clearance and limiting viral shedding.ObjectiveWe undertook a ring prophylaxis study to determine whether pegylated IFNβ-1α could reduce SARS-CoV-2 household transmission.DesignA cluster randomized clinical trial of pegylated IFNβ-1α conducted in Santiago, Chile. Recruitment was conducted between December 4th2020, and 31stMay 2021, with the last follow-up completed June 29th2021.SettingThe study was conducted across 341 households in the metropolitan area of Santiago, Chile.ParticipantsIndex cases were identified from databases of those with confirmed SARS-CoV-2 from COVID-19 clinics and emergency room visits in Santiago, Chile. 5,154 index cases were assessed for eligibility, 1,372 index cases were invited to participate, and 341 index cases and their household contacts (n = 831) were enrolled in the study.InterventionHouseholds were cluster randomized to receive 125µg subcutaneous pegylated IFNβ-1α (n = 172 households, 607 participants), or standard care (n = 169 households, 565 participants).Main Outcome(s) and Measure(s)Frequentist and Bayesian analyses were undertaken to determine the effects of treatment on (i) reducing viral shedding in index cases and (ii) reducing viral transmission to treatment-eligible household contacts. Four secondary outcomes were assessed including duration of viral shedding, effects on viral transmission and seroconversion, incidence of hospitalization, and incidence and severity of reported adverse events. A post-hoc ‘at risk population’ was defined as households where the index case was positive at the start of the study and there was at least one treatment eligible contact in a household who tested negative for SARS-CoV-2.ResultsIn total, 1172 participants in 341 households underwent randomization, with 607 assigned to receive IFNβ-1α and 565 to standard care. Based on intention to treat and per protocol analyses, IFNβ-1α treatment was ineffective. However, in the ‘at risk’ population, the relative risk of infection was reduced by 23% in treated individuals and that there was a 95% probability that IFNβ-1α reduced household transmissionConclusions and RelevanceRing prophylaxis with IFNβ-1α reduces the probability of SARS-CoV-2 transmission within a household.Trial RegistrationClinicaltrials.govidentifier:NCT04552379