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Abstract Background Platelets stored at 1–6 °C are hypothesized to be more hemostatically active than standard room temperature platelets (RTP) stored at 20–24 °C. Recent studies suggest converting RTP to cold-stored platelets (Delayed Cold-Stored Platelets, DCSP) may be an important way of extending platelet lifespan and increasing platelet supply while also activating and priming platelets for the treatment of acute bleeding. However, there is little clinical trial data supporting the efficacy and safety of DCSP compared to standard RTP. Methods This protocol details the design of a multicentre, two-arm, parallel-group, randomized, active-control, blinded, internal pilot trial to be conducted at two cardiac surgery centers in Canada. The study will randomize 50 adult (≥ 18 years old) patients undergoing at least moderately complex cardiac surgery with cardiopulmonary bypass and requiring platelet transfusion to receive either RTP as per standard of care (control group) or DCSP (intervention group). Patients randomized to the intervention group will receive ABO-identical, buffy-coat, pathogen-reduced, platelets in platelet additive solution maintained at 22 °C for up to 4 days then placed at 4 °C for a minimum of 24 h, with expiration at 14 days after collection. The duration of the intervention is from the termination of cardiopulmonary bypass to 24 h after, with a maximum of two doses of DCSP. Thereafter, all patients will receive RTP. The aim of this pilot is to assess the feasibility of a future RCT comparing the hemostatic effectiveness of DCSP to RTP (defined as the total number of allogeneic blood products transfused within 24 h after CPB) as well as safety. Specifically, the feasibility objectives of this pilot study are to determine (1) recruitment of ≥ 15% eligible patients per center per month); (2) appropriate platelet product available for ≥ 90% of patients randomized to the cold-stored platelet group; (3) Adherence to randomization assignment (> 90% of patients administered assigned product). Discussion DCSP represents a promising logistical solution to address platelet supply shortages and a potentially more efficacious option for the management of active bleeding. No prospective clinical studies on this topic have been conducted. This proposed internal pilot study will assess the feasibility of a larger definitive study. Trial registration NCT 06147531 (clinicaltrials.gov).

Key Clinical Message In a patient with de novo AML, co‐existing BCR::ABL1 p190 isoform and RUNX1::MECOM rearrangement is accompanied by a very poor prognosis including limited response to treatment and no molecular remission. It is essential to develop a consensus on the therapeutic modalities different from the current regimen. Abstract Acquisition of BCR::ABL1 fusion as a primary or secondary event and RUNX1::MECOM fusion independently is reported in de novo and therapy‐related MDS/AML, albeit with low frequency (

Background. Dyslipidaemia and hypertension care have not been reported in large samples of community-based participants with known diabetes (KD) nor compared with individuals at high risk for diabetes. Objectives. To describe the management and associations of dyslipidaemia and hypertension in adults with KD, newly diagnosed diabetes (NDD) and normoglycaemia. Methods. This urban population-based cross-sectional study comprised participants with KD, NDD and normoglycaemia. Participants at high risk for diabetes but without KD underwent oral glucose tolerance tests; those who were subsequently classified as NDD or normoglycaemic were included in this study. Data collection comprised administered questionnaires, clinical measurements and biochemical analyses. Multivariable logistic regressions determined the associations with hypertension and dyslipidaemia management in separate models. Results. Among 618 participants (82% women), aged median 58 years, there were 339 participants with KD, 70 with NDD and 209 with normoglycaemia. Prevalence of hypertension (BP ≥140/90 mmHg or on treatment) and dyslipidaemia (raised low-density lipoprotein cholesterol >3 mmol/L or on treatment) was highest in KD (89% and 83%) compared with NDD (64% and 74%) and normoglycaemia (66% for both) (p

Summary: Background: Lymphedema affects one in six breast cancer survivors making it a global healthcare challenge. There is considerable debate about the efficacy of different treatments for lymphedema. We aimed to summarize the current evidence for treatments for lymphedema in breast cancer survivors. Methods: In this overview of systematic reviews with meta-analyses (SRMAs), five databases were searched for SRMAs of randomised controlled trials (RCTs) reporting effects of medications, surgery, exercise, laser therapy, acupuncture, kinesio taping, or complex decongestive physiotherapy (CDP) for breast cancer-related lymphedema published from database inception up to March 7, 2023. Data extraction was performed for the SRMAs and RCTs, and SRMAs were appraised with AMSTAR2. Random effects meta-analyses of the RCTs provided estimates of the pooled effects sizes (Hedges’ g) for each treatment modality. This study is registered with PROSPERO, CRD42020184813. Findings: 1569 studies were identified by the search and eighteen SRMAs with 51 RCTs were included, investigating manual lymphatic drainage (MLD), compression pump, exercise, kinesio taping, laser, and acupuncture. Overall, the methodological quality of the SRMAs was low. SRMAs reached different conclusions for all treatment modalities, except for kinesio taping where the two SRMAs found no effect. The analysis of 40 RCTs with 1970 participants revealed a small effect across all interventions compared to any control (g = 0.20, p = 0.047, I2 = 0.79), corresponding to volume reductions of 119.7 ml (95% CI 135–104) and 88.0 ml (95% CI 99–77) in the intervention and control groups, respectively, and a small effect of exercise (g = 0.26, p = 0.022, I2 = 0.44). The between-group differences in volume reduction were small and did not reach statistical significance for any one treatment modality. Interpretation: Based on the available data, there is no evidence of superiority of any one treatment on volume reduction nor any solid research refuting these treatments. Thus, definitive conclusions to inform clinical practice about the efficacy of these treatments cannot be drawn. Due to poor-quality evidence, more research is needed to untangle the efficacy of each treatment component for different stages of lymphedema. Funding: Danish Cancer Society.

Key Clinical Message In an adolescent patient with severe yew intoxication and consecutive cardiac arrest, non‐responsive to conventional resuscitation necessitating extracorporeal life support, Levosimendan has been implemented in the early acute phase of hemodynamic stabilization, without obvious side effects. However, the additive value of this treatment in severe yew intoxication remains speculative.

ABSTRACTBackground Craniofacial pain (CFP) poses a burden on patients and health care systems. It is hypothesized that ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can reverse central sensitization associated with causation and propagation of CFP. This systematic review aims to assess the role of ketamine for CFP.Methods Databases were searched for studies published up to September 26, 2022, investigating the efficacy of ketamine for adults with CFP. Primary outcome was the change in pain intensity at 60 min postintervention. Two reviewers screened and extracted data. Registration with PROSPERO was performed (CRD42020178649).Results Twenty papers (six randomized controlled trials [RCTs], 14 observational studies) including 670 patients were identified. Substantial heterogeneity in terms of study design, population, dose, route of administration, treatment duration, and follow-up was noted. Bolus dose ranged from 0.2–0.3 mg/kg (intravenous) to 0.4 mg/kg (intramuscular) to 0.25–0.75 mg/kg (intranasal). Ketamine infusions (0.1–1 mg/kg/h) were given over various durations. Follow-up was short in RCTs (from 60 min to 72 h) but longer in observational studies (up to 18 months). Ketamine by bolus treatment failed to reduce migraine intensity but had an effect by reducing intensity of aura, cluster headache (CH), and trigeminal neuralgia. Prolonged ketamine infusions showed sustainable reduction of migraine intensity and frequency of CH attacks, but the quality of the evidence is low.Conclusion Current evidence remains conflicting on the efficacy of ketamine for CFP owing to low quality and heterogeneity across studies. Ketamine infusions are suggested to provide sustained improvement, possibly because of prolonged duration and higher dosage of administration. RCTs should focus on the dose–response relationship of prolonged ketamine infusions on CFP.

Abstract Multi‐omics analyses are used in microbiome studies to understand molecular changes in microbial communities exposed to different conditions. However, it is not always clear how much each omics data type contributes to our understanding and whether they are concordant with each other. Here, we map the molecular response of a synthetic community of 32 human gut bacteria to three non‐antibiotic drugs by using five omics layers (16S rRNA gene profiling, metagenomics, metatranscriptomics, metaproteomics and metabolomics). We find that all the omics methods with species resolution are highly consistent in estimating relative species abundances. Furthermore, different omics methods complement each other for capturing functional changes. For example, while nearly all the omics data types captured that the antipsychotic drug chlorpromazine selectively inhibits Bacteroidota representatives in the community, the metatranscriptome and metaproteome suggested that the drug induces stress responses related to protein quality control. Metabolomics revealed a decrease in oligosaccharide uptake, likely caused by Bacteroidota depletion. Our study highlights how multi‐omics datasets can be utilized to reveal complex molecular responses to external perturbations in microbial communities.

Key Clinical Message Complete molecular remission in a “variant APL” patient with short isoform of PML‐RARα and FLT3‐ITD mutation was achieved in response to ATRA and ATO plus IDA instead of standard treatment protocol. The use of FLT3 inhibitor in APL induction management is implicated to prevent differentiation syndrome and coagulopathy experienced in in patients with FLT3‐ITD. Abstract FLT3‐ITD mutations are the most common activating mutations in FLT3 gene, occurring in about 12 to 38% of acute promyelocytic leukemia cases, and are mainly associated with high white blood cell counts and poor clinical outcomes. Here, we present a case of APL variant with adverse prognostic features who showed short isoform [bcr3] of PML‐RARα and FLT3‐ITD mutation at diagnosis. The patient received all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO) plus idarubicin (IDA) instead of standard treatment protocol, and achieved a complete morphological, cytogenetic and molecular response. However, the patient experienced differentiation syndrome, and coagulopathy that was subsequently resolved by continuous oxygen therapy, dexamethasone, and enoxaparin. The use of FLT3 inhibitor in APL induction management is implicated to prevent differentiation syndrome and coagulopathy in patients with FLT3‐ITD mutation.

Background: Economic restrictions and workforce cuts have continually challenged conventional autopsies. Recently, the COVID-19 pandemic has added tissue quality and safety requirements to the investigation of this disease, thereby launching efforts to upgrade autopsy strategies. Methods: In this proof-of-concept study, we performed bedside ultrasound-guided minimally invasive autopsy (US-MIA) in the ICU of critically ill COVID-19 patients using a structured protocol to obtain non-autolyzed tissue. Biopsies were assessed for their quality (vitality) and length of biopsy (mm) and for diagnosis. The efficiency of the procedure was monitored in five cases by recording the time of each step and safety issues by swabbing personal protective equipment and devices for viral contamination. Findings: Ultrasound examination and tissue procurement required a mean time period of 13 min and 54 min, respectively. A total of 318 multiorgan biopsies were obtained from five patients. Quality and vitality standards were fulfilled, which not only allowed for specific histopathological diagnosis but also the reliable detection of SARS-CoV-2 virions in unexpected organs using electronic microscopy and RNA-expressing techniques. Interpretation: Bedside multidisciplinary US-MIA allows for the fast and efficient acquisition of autolytic-free tissue and offers unappreciated potential to overcome the limitations of research in postmortem studies.

Abstract A small but significant proportion of COVID‐19 patients develop life‐threatening cytokine storm. We have developed a new anti‐inflammatory drug, EXO‐CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF‐kB pathway and the production of cytokines/chemokines. EXO‐CD24 discriminates damage‐from pathogen‐associated molecular patterns (DAMPs and PAMPs) therefore does not interfere with viral clearance. EXO‐CD24 was produced and purified from CD24‐expressing 293‐TREx™ cells. Exosomes displaying murine CD24 (mCD24) were also created. EXO‐CD24/mCD24 were characterized and examined, for safety and efficacy, in vitro and in vivo. In a phase Ib/IIa study, 35 patients with moderate–high severity COVID‐19 were recruited and given escalating doses, 108–1010, of EXO‐CD24 by inhalation, QD, for 5 days. No adverse events related to the drug were observed up to 443–575 days. EXO‐CD24 effectively reduced inflammatory markers and cytokine/chemokine, although randomized studies are required. EXO‐CD24 may be a treatment strategy to suppress the hyper‐inflammatory response in the lungs of COVID‐19 patients and further serve as a therapeutic platform for other pulmonary and systemic diseases characterized by cytokine storm.

Objective: Antimicrobial Resistance (AMR) happens when microbes, infections, organisms, and parasites change over the long run, becoming resistant to any drug, as well as making contaminations harder to treat and expanding the danger of the disease spreading, severity, and death. Because of medication obstruction and anti-infection agents, antimicrobial drugs become ineffectual, and diseases become progressively troublesome or difficult to treat. AMR keeps on representing a public health concern because of high mortality rate and expensive treatments. Food assumes a significant part in the transmission of commensal microorganisms yet in addition, food-borne microbes include zoonotic organic entities. The aim of this meta-analysis review is to report the predominance of antimicrobial resistance in food from animals and a few vegetables from India and to compare the data with countries like Switzerland and Taiwan. Material and Methods: To evaluate AMR pervasiveness in retail food a literature review survey of information distributed in the range of 2013 to 2020 was done. The research articles were identified through Google scholar, PubMed, and ResearchGate. The Keywords AMR, INDIA, food source like seafood, goat meat, chicken meat, pork, raw eggs, milk, and vegetables were used for the search. Results: Out of the 63 eligible studies, 10 articles (all articles from India) were included in this review. A total of 2,126 AMR tests were collected for various bacteria found in various food products. Nine distinct bacteria and resistance to about 13 different antimicrobial agents/drugs were identified. The sample sources, bacterial species, and their proportion are displayed in Tables 1. In these 9 distinct microorganisms, 1800 microorganism isolates of which 611 samples and 698 isolates were AMR positive. A middle AMR commonness of >50% was noticed for meat and fish with Escherichia coli, Staphylococcus aureus, Enterococci, Salmonella, Enterobacter, Klebsiella, Streptococci, Vibrio spp, and Shigella. Conclusions: AMR potential for Gram-negative foodborne bacteria was found in raw meat, milk, fish, and certain matured dairy products. To enable an expanded AMR hazard appraisal for customers, AMR genetics attributes are suggested to be better coordinated into regulated One Health AMR observation and alleviation systems.

Summary: A major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers. We propose a harmonized terminology and a uniform concept that stratifies biomarkers according to clinical context of use and evidence levels, adapted from existing frameworks in oncology with a strong focus on (epi)genetic markers and treatment context. We demonstrate that this framework allows for a consistent assessment of clinical validity across disease entities and that sufficient evidence for many clinical applications of protein biomarkers is lacking. Our framework may help to identify promising biomarker candidates and classify their applications by clinical context, aiming for routine clinical use of (protein) biomarkers in neurology.

Plain English summary Some topics of research are considered ‘sensitive’ or ‘risky’. This includes topics such as suicide and violence. Some groups of people are also considered ‘sensitive’ or ‘risky’. This includes prisoners. Because of this, there is little research done with prisoners on topics such as suicide and violence. This study aimed to explore the experiences of prisoners who took part in a study about suicide and violence. Eighty male prisoners took part in either a questionnaire study or an interview study (or both). At the beginning of the session people were asked to rate their mood from 0 to 10. Zero was the worst possible imaginable mood and 10 was the best possible imaginable mood. People were asked to do this again at the end of the session. People were also asked to give three words to describe their experience of the session. The people who took part in the questionnaire study had a significant improvement in mood after the session. The people who took part in the interview study had no difference in mood after the session. Most people gave positive words to describe the session. People said the session was satisfying, calming, interesting, enlightening and beneficial. A smaller number of people gave negative words. They described the session as stressful, challenging, saddening, uncomfortable and bizarre. This study therefore contrasts the idea that prisoners will become upset if they take part in research about suicide and violence. Therefore, we should continue to research this area.

BackgroundThe COVID-19 pandemic led to transformations in healthcare infrastructures and increased use of (innovative) telemedicine (TM) tools. Comparison of the use of video consultation (VC) in rheumatology in the pre-pandemic period and during the pandemic might allow for evaluating this new form of consultancy in healthcare due to changing conditions and possibilities.Materials and methodsCross-sectional nationwide online survey among German rheumatologists and rheumatologists in training between March and May 2021 promoted by newsletters and Twitter posts.ResultsResults refer to 205 participants. The majority was male (59%), older than 40 years (90%). Thirty-eight percent stated to have employed TM before (“digital users”), 27% were using VC as part of their TM expertise (“VC-users”), 10% stated to have experience with TM but not VC (“TM-users”). Those negating the use of any TM (62%) were designated as “digital non-users.” TM-Knowledge was self-rated as 4 [median on a Likert Scale 1 (very high) to 6 (very low)] with a significant difference between digital users (VC-user 2.7 ± 1.2, TM-user 3.2 ± 1.1) and digital non-users (4.4 ± 1.3). The reported significant increase of VC use during the lockdown periods and between the lockdowns compared to the pre-pandemic phase was regarded as a proxy for VC acceptance in the pandemic. Reasons for VC non-use were administrative/technical efforts (21%), lack of technical equipment (15%), time constraints (12%), time required for individual VC sessions (12%), inadequate reimbursement (11%), lack of demand from patients (11%), data security concerns (9%), poor internet connection (8%), and lack of scientific evaluation/evidence (5%). Physicians considered the following clinical situations to be particularly suitable for VC: follow-up visits (VC-user 79%, TM-user 62%, digital non-user 47%), emergency consultations (VC-user 20%, TM-user 33%, digital non-user 20%), and patients presenting for the first time (VC-user 11%, TM-user 19%, digital non-user 8%).ConclusionEven though the pandemic situation, with social distancing and several lockdowns, provides an ideal environment for the implementation of new remote care forms as VC, its use and acceptance remained comparatively low due to multiple reasons. This analysis may help identify hurdles in employing innovative digital care models for rheumatologic healthcare.

Congenital high airway obstruction syndrome (CHAOS) is a rare condition that can be diagnosed antenatally by ultrasound. It is usually lethal without immediate intervention at delivery. A 24-year-old woman was diagnosed with fetal CHAOS at 27 weeks’ gestation. The couple declined termination of pregnancy. A multidisciplinary team including obstetricians, geneticists, paediatric surgeons, neonatologists and anaesthetists was constituted to plan an ex utero intrapartum treatment (EXIT) procedure. After several simulations, a caesarean section was performed at 38 weeks’ gestation under deep inhalational anaesthesia. The fetus was fully delivered with placenta remaining in utero to maintain perfusion. A surgical airway was established via tracheostomy in approximately 5 minutes. The operation was then completed with no maternal complications. The child remains well at 3 years of age. To our knowledge, this is the first EXIT procedure performed for CHAOS in the public sector. This procedure can be lifesaving and is possible with proper planning.

A descriptive study of the spectrum of dermatological surgery services provided by the University of KwaZulu-Natal Department of Dermatology at Inkosi Albert Luthuli Central Hospital

Background. South Africa (SA) faces multiple health challenges. Quantifying the contribution of modifiable risk factors can be used to identify and prioritise areas of concern for population health and opportunities for health promotion and disease prevention interventions. Objective. To estimate the attributable burden of 18 modifiable risk factors for 2000, 2006 and 2012. Methods. Comparative risk assessment (CRA), a standardised and systematic approach, was used to estimate the attributable burden of 18 risk factors. Risk exposure estimates were sourced from local data, and meta-regressions were used to model the parameters, depending on the availability of data. Risk-outcome pairs meeting the criteria for convincing or probable evidence were assessed using relative risks against a theoretical minimum risk exposure level to calculate either a potential impact fraction or population attributable fraction (PAF). Relative risks were sourced from the Global Burden of Disease, Injuries, and Risk Factors (GBD) study as well as published cohort and intervention studies. Attributable burden was calculated for each risk factor for 2000, 2006 and 2012 by applying the PAF to estimates of deaths and years of life lost from the Second South African National Burden of Disease Study (SANBD2). Uncertainty analyses were performed using Monte Carlo simulation, and age-standardised rates were calculated using the World Health Organization standard population. Results. Unsafe sex was the leading risk factor across all years, accounting for one in four DALYs (26.6%) of the estimated 20.6 million DALYs in 2012. The top five leading risk factors for males and females remained the same between 2000 and 2012. For males, the leading risks were (in order of descending rank): unsafe sex; alcohol consumption; interpersonal violence; tobacco smoking; and high systolic blood pressure; while for females the leading risks were unsafe sex; interpersonal violence; high systolic blood pressure; high body mass index; and high fasting plasma glucose. Since 2000, the attributable age-standardised death rates decreased for most risk factors. The largest decrease was for household air pollution (–41.8%). However, there was a notable increase in the age-standardised death rate for high fasting plasma glucose (44.1%), followed by ambient air pollution (7%). Conclusion. This study reflects the continued dominance of unsafe sex and interpersonal violence during the study period, as well as the combined effects of poverty and underdevelopment with the emergence of cardiometabolic-related risk factors and ambient air pollution as key modifiable risk factors in SA. Despite reductions in the attributable burden of many risk factors, the study reveals significant scope for health promotion and disease prevention initiatives and provides an important tool for policy makers to influence policy and programme interventions in the country.

Background. Ongoing quantification of trends in high blood pressure and the consequent disease impact are crucial for monitoring and decision-making. This is particularly relevant in South Africa (SA) where hypertension is well-established. Objective. To quantify the burden of disease related to high systolic blood pressure (SBP) in SA for 2000, 2006 and 2012, and describe age, sex and population group differences. Methods. Using a comparative risk assessment methodology, the disease burden attributable to raised SBP was estimated according to age, se, and population group for adults aged ≥25 years in SA in the years 2000, 2006 and 2012. We conducted a meta-regression on data from nine national surveys (N=124 350) to estimate the mean and standard deviation of SBP for the selected years (1998 - 2017). Population attributable fractions were calculated from the estimated SBP distribution and relative risk, corrected for regression dilution bias for selected health outcomes associated with a raised SBP, above a theoretical minimum of 110 - 115 mmHg. The attributable burden was calculated based on the estimated total number of deaths and disability-adjusted life years (DALYs). Results. Mean SBP (mmHg) between 2000 and 2012 showed a slight increase for adults aged ≥25 years (127.3 - 128.3 for men; 124.5 - 125.2 for women), with a more noticeable increase in the prevalence of hypertension (31% - 39% in men; 34% - 40% in women). In both men and women, age-standardised rates (ASRs) for deaths and DALYs associated with raised SBP increased between 2000 and 2006 and then decreased in 2012. In 2000 and 2012, for men, the death ASR (339/100 000 v. 334/100 000) and DALYs (5 542/100 000 v. 5 423/100 000) were similar, whereas for women the death ASR decreased (318/100 000 v. 277/100 000) as did age-standardised DALYs (5 405/100 000 v. 4 778/100 000). In 2012, high SBP caused an estimated 62 314 deaths (95% uncertainty interval 62 519 - 63 608), accounting for 12.4% of all deaths. Stroke (haemorrhagic and ischaemic), hypertensive heart disease and ischaemic heart disease accounted for >80% of the disease burden attributable to raised SBP over the period. Conclusion. From 2000 to 2012, a stable mean SBP was found despite an increase in hypertension prevalence, ascribed to an improvement in the treatment of hypertension. Nevertheless, the high mortality burden attributable to high SBP underscores the need for improved care for hypertension and cardiovascular diseases, particularly stroke, to prevent morbidity and mortality.

Background. Low-density lipoprotein cholesterol (LDL-C) is the most important contributor to atherosclerosis, a causal factor for ischaemic heart disease (IHD) and ischaemic stroke. Although raised LDL-C is a key contributor to cardiovascular disease (CVD), the exact attributable disease risk in South Africa (SA) is unknown. The the first SA comparative risk assessment (SACRA1) study assessed the attributable burden of raised total cholesterol, and not specifically LDL-C. Objectives. To estimate the national mean serum LDL-C by age, year and sex and to quantify the burden of disease attributable to LDL-C in SA for 2000, 2006 and 2012. Methods. The comparative risk assessment (CRA) method was used. Estimates of the national mean of LDL-C, representing the 3 different years, were derived from 14 small observational studies using a meta-regression model. A theoretical minimum risk exposure level (TMREL) of 0.7 - 1.3 mmol/L was used. LDL-C estimates together with the relative risks from the Global Burden of Disease Study 2017 were used to calculate a potential impact fraction (PIF). This was applied to IHD and ischaemic stroke estimates sourced from the Second National Burden of Disease Study. Attributable deaths, years of life lost, years lived with disability and disability-adjusted life years (DALYs) were calculated. Uncertainty analysis was performed using Monte Carlo simulation. Results. LDL-C declined from 2.74 mmol/L in 2000 to 2.58 mmol/L in 2012 for males, while in females it declined from 3.05 mmol/L in 2000 to 2.91 mmol/L in 2012. The PIFs for LDL-C showed a slight decline over time, owing to the slight decrease in LDL-C levels. Attributable DALYs increased between 2000 (n=286 712) and 2006 (n=315 125), but decreased thereafter in 2012 (n=270 829). Attributable age-standardised death rates declined between 2000 and 2012 in both sexes: in males from 98 per 100 000 members of the population in 2000 to 78 per 100 000 in 2012, and in females from 81 per 100 000 in 2000 to 58 per 100 000 in 2012. Conclusions. Mean LDL-C levels were close to 3 mmol/L, which is the recommended level at which cholesterol-lowering treatment should be initiated for people at low and moderate risk for cardiovascular outcomes. The decreasing trend in the age-standardised attributable burden due to LDL-C is encouraging, but it can be lowered further with the introduction of additional population-based CVD prevention strategies. This study highlights the fact that high LDL-C concentration in relation to the TMREL in SA is responsible for a large proportion of the emerging CVD, and should be targeted by health planners to reduce disease burden.

Abstract Background People with lived‐experience of the phenomenon under investigation are seldom involved in the analysis of qualitative data, and there exists little guidance for those wishing to involve contributors at this stage of research. Aims To critically reflect on the process of involving people with lived‐experience in a thematic analysis and to offer direction to other researchers. Methods An individual with lived‐experience of residing in prison contributed to a co‐analysis of qualitative data using thematic analysis. This paper reports on involvement at each stage of a thematic analysis and follows an established reporting checklist. Results A number of challenges and benefits were encountered in the process of co‐analysing the data. These are discussed in relation to previous research and how to overcome the challenges encountered. Conclusions The paper concludes by giving recommendations and guidance for future researchers wishing to involve people with lived‐experience in qualitative data analysis.

Abstract Herein, we report a case of VAIHS with atypical clinical presentation of perianal abscess, fistula fever, and bi‐cytopenia including pathogenic ADA2 mutation suggesting that ADA2 deficiency be considered as a differential diagnosis of enlarging cutaneous abscess with no evidence of wound healing in the setting of leukopenia and neutropenia.

Chandra Kumar Elechalawar,1 Md Nazir Hossen,1 Priya Shankarappa,2 Cody J Peer,2 William D Figg,2 J David Robertson,3 Resham Bhattacharya,4 Priyabrata Mukherjee1,5 1Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; 2Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD 20892, USA; 3Department of Chemistry and University of Missouri Research Reactor, University of Missouri, Columbia, MO 65211, USA; 4Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; 5Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USACorrespondence: Priyabrata MukherjeeDepartment of Pathology, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK 73104, USATel +1 405-271-1133Fax +1 405-271-2472Email Priyabrata-Mukherjee@ouhsc.eduIntroduction and Objective: Pancreatic cancer (PC) is characterized by a robust desmoplastic environment, which limits the uptake of the standard first-line chemotherapeutic drug gemcitabine. Enhancing gemcitabine delivery to the complex tumor microenvironment (TME) is a major clinical challenge. Molecular crosstalk between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) plays a critical role in desmoplastic reaction in PCs. Herein, we report the development of a targeted drug delivery system to inhibit the proliferation of PCCs and PSCs in vitro. Using gold nanoparticles as the delivery vehicle, the anti-EGFR antibody cetuximab (C225/C) as a targeting agent, gemcitabine as drug and polyethylene glycol (PEG) as a stealth molecule, we created a series of targeted drug delivery systems.Methods: Fabricated nanoconjugates were characterized by various physicochemical techniques such as UV-Visible spectroscopy, transmission electron microscopy, HPLC and instrumental neutron activation analysis (INAA).Results and Conclusion: Targeted gemcitabine delivery systems containing mPEG-SH having molecular weights of 550 Da or 1000 Da demonstrated superior efficacy in reducing the viability of both PCCs and PSCs as compared to their non-targeted counterparts. EGFR-targeted pathway was further validated by pre-treating cells with C225 followed by determining cellular viability. Taken together, in our current study we have developed a PEGylated targeted nanoconjugate ACG44P1000 that showed enhanced selectivity towards pancreatic cancer cells and pancreatic stellate cells, among others, for gemcitabine delivery. We will investigate the ability of these optimized conjugates to inhibit desmoplasia and tumor growth in vivo in our future studies.Keywords: pancreatic cancer, gold nanoparticles, PEGylation, drug delivery

Background: The role of medication-related osteonecrosis of the jaw (MRONJ) as a dento-maxillo-facial pathology is becoming increasingly important due to its growing prevalence. The success of preventive and therapeutic measures relies mainly on the dentist’s ability to correctly diagnose the disease. Methods: The aim of this study was to evaluate the skills of dental students of different educational levels in choosing the correct stage, diagnostics, and treatment option for MRONJ based on clinical and radiographic imaging (panoramic radiograph, CBCT). The study was designed as a cross-sectional cohort study. Twenty dental students were asked to complete a questionnaire in their third and fifth year of studies in which they had to correctly stage the disease, choose the radiological diagnostics and recommend the treatment. The control group contained experienced oral and maxillofacial surgeons. Results: With an overall performance of 59% (third year: 145.2/248 points; fifth year: 145.3/248 points), no statistically significant difference between the educational levels could be observed. The classification based on CBCT imaging was significantly more often correct compared to panoramic radiographs (p < 0.001). Conclusions: This study highlights students’ lack of knowledge in staging, diagnostics, and treatment of MRONJ, even though the CBCT positively affected decision-making. No significant increase in knowledge could be confirmed through clinical education. This study highlights the need for students to catch up on MRONJ diagnostics and treatment planning. Further expansion of teaching in this disease’s context and X-ray diagnostics is needed.

This longitudinal analysis compares the prevalence of depressive symptoms in patients with psoriatic arthritis in the context of the COVID-19 pandemic. Data from a national patient register in Germany were analyzed regarding the Patient Health Questionnaire 2 (PHQ-2) to identify cases suspicious for depression at two time points, i.e., before and during the COVID-19 pandemic. Only patients with complete concurrent information on the Disease Activity in Psoriatic Arthritis Score (DAPSA) were included in the analysis. The frequency of depressive symptoms in psoriatic arthritis patients during the COVID-19 pandemic did not differ from the prevalence rates measured before. In addition, prevalence rates for depressive symptoms did not differ when stratifying the patient sample for DAPSA levels of disease activity measured before the pandemic. These results were confirmed further in a sensitivity analysis, limiting the second PHQ-2 assessment to lockdown periods only. However, longitudinal data on the prevalence of depressive symptoms in patients with rheumatic diseases, in general, and psoriatic arthritis, in particular, are scarce in the context of the COVID-19 pandemic. For a sensible comparison of prevalence rates for depressive symptoms in the future, underlying SARS-CoV-2 infection rates and resulting local healthcare disruptions need to be taken into account, besides the potential use of different depression screening tools to evaluate resulting numbers sensibly and draw corresponding conclusions for patient care.

Chronic kidney disease (CKD) is a global public health problem, seemingly affecting individuals from low-income and-middle-income countries (LMICs) disproportionately, especially in sub-Saharan Africa. Despite the growing evidence pointing to an increasing prevalence of CKD across Africa, there has not been an Africa-wide concerted effort to provide reliable estimates that could adequately inform health services planning and policy development to address the consequences of CKD. Therefore, we established the CKD in Africa (CKD-Africa) Collaboration. To date, the network has curated data from 39 studies conducted in 12 African countries, totalling 35 747 participants, of which most are from sub-Saharan Africa. We are, however, continuously seeking further collaborations with other groups who have suitable data to grow the network. Although many successful research consortia exist, few papers have been published (with none from Africa) detailing the challenges faced and lessons learnt in setting up and managing a research consortium. Drawing on our experience, we describe the steps taken and the key factors required to establish a functional collaborative consortium among researchers in Africa. In addition, we present the challenges we encountered in building our network, how we managed those challenges and the benefit of such a collaboration for Africa. Although the CKD-Africa Collaboration is focused primarily on CKD research, many of the lessons learnt can be applied more widely in public health research in LMICs.

Abstract Background The effect of extended adjuvant aromatase inhibition in hormone-positive breast cancer after sequential tamoxifen, aromatase inhibitor treatment of 5 years was recently investigated by the DATA study. This study found no statistically significant effect of prolonged aromatase therapy. However, subgroup analysis showed post hoc statistically significant benefits in certain sub-populations. The trans-DATA study is a translational sub-study aiming to identify DNA methylation markers prognostic of patient outcome. Methods Patients from the DATA study are included in the trans-DATA study. Primary breast tumour tissue will be collected, subtyped and used for DNA isolation. A genome-wide DNA methylation discovery assay will be performed on 60 patients that had a distant recurrence and 60 patients that did not have a distant recurrence using the Infinium Methylation EPIC Bead Chip platform. Differentially methylated regions of interest will be selected based on Akaike’s Information Criterion, Gene Ontology Analysis and correlation between methylation and expression levels. Selected candidate genes will subsequently be validated in the remaining patients using qMSP. Discussion The trans-DATA study uses a cohort derived from a clinical randomised trial. This study was designed to avoid common pitfalls in marker discovery studies such as selection bias, confounding and lack of reproducibility. In addition to the usual clinical risk factors, the results of this study may identify predictors of high recurrence risk in hormone receptor-positive breast cancer patients treated with sequential tamoxifen and aromatase inhibitor therapy.

Background: Sex can be an important biological variable in the immune response to infections and the response to vaccines. The magnitude and consistency in age-specific sex differences in the incidence of viral infections remain unclear. Methods: We obtained data from national official agencies on cases of viral meningitis by sex and age group over a period of 6–16 years from five countries: Canada, Czech Republic, Germany, Israel, and Poland. Male to female incidence rate ratios (RR) were computed for each year, by country, and age group. For each age group, we used meta-analysis methodology to combine the incidence RRs. Meta-regression was conducted to the estimate the effects of age, country, and time period on the RR. Findings: In the age groups

The COVID-19 pandemic has presented unique challenges for communities across the globe: affecting everyone, everywhere. With lockdowns and education upended, students and young professionals united worldwide, creating a grassroots movement, #Students_Against_COVID. As a virtual agora for collaboration and innovation, SAC has amplified students’ efforts, elevated their voices, and participated in various community-specific initiatives in the fight against COVID-19. At the core, it has allowed for connection during these trying times, and served as a virtual support network, turning friends into family.

Aim: In the face of increasing tobacco consumption in Sub-Saharan Africa, it is crucial to not only curb the uptake of tobacco, but to ensure that tobacco users quit. Considering the minimal attention that tobacco cessation interventions receive in Sub-Saharan Africa, this review aims to describe studies that evaluated tobacco cessation interventions in the region. Methods: A search of studies published till December 2019 that evaluated tobacco cessation interventions in Sub-Saharan Africa and examined tobacco quit rates was conducted in PubMed-Medline, Web of Science and Scopus. Study designs were not limited to randomised control trials but needed to include a control group. Results: Of the 454 titles and abstracts reviewed, eight studies, all conducted in South Africa, were included. The earliest publication was from 1988 and the most recent from 2019. Five studies were randomised control trials, two were quasi-experimental and one was a case–control study. Populations studied included community-based smokers (four studies) and university students, while the relevant clinic-based studies were conducted in pregnant women, tuberculosis patients and HIV-infected patients. Sample sizes were 23 in the case–control study, 87–561 in randomised control trials, and 979 (pregnant women) and 4090 (three rural communities) in the quasi-experimental studies. Four studies included nicotine replacement therapy in the interventions while four utilised only psychotherapy without adjunct pharmacotherapy. Quit rates were evaluated by exhaled carbon monoxide levels (five studies), blood carbon monoxide, urinary cotinine levels and self-reported quit rates. Four studies (two each with and without pharmacotherapy) reported significantly better outcomes in the intervention versus the control groups while one study findings (without pharmacotherapy) were significant in women but not men. Conclusion: This review highlights that scant attention has been paid to tobacco cessation intervention in Sub-Saharan Africa. The heterogeneity of these studies precluded comparisons across interventions or populations. There is a need for evidence-based low-cost tobacco cessation intervention that target high-risk population in Sub-Saharan Africa.

Abstract Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested. We show that such effects, arising from underlying morphological differences, can skew the outcome of differential expression analysis. We propose a method to detect and normalize morphological effects underlying proteomics data. We demonstrate the applicability of our method to different datasets and biological questions including the analysis of sub‐cellular proteomes in the context of Caenorhabditis elegans aging. Our method provides a complementary perspective to classical differential expression analysis and enables to uncouple overall abundance changes from stoichiometric variations within defined group of proteins.

Recently, there have been significant advances in the battle against tobacco use in Africa, with achievements including ratification of the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) and the passing of tobacco control legislation in several countries. Many African countries have achieved measured success, while Uganda, South Africa and Mauritius have accomplished significantly more in their efforts to curb tobacco use. Nevertheless, few African countries meet the standards of the individual WHO FCTC articles with regard to comprehensive implementation. Africa has lower rates of tobacco taxation, weaker smoke-free policies and fewer restrictions on tobacco advertising compared with other world regions. These shortcomings have enabled the tobacco industry to expand its markets on the continent by capitalising on economic growth, changing social norms and population demographics. Consequently, tobacco use is increasing in Africa, with smoking prevalence having risen 57% between 1990 and 2009 compared with western Europe, where it decreased substantially during the same period. Rapid smoking uptake in Africa has led to tobacco-related conditions emerging as increasingly important public health problems. African nations are unlikely to meet the 2025 goal of a 30% relative reduction in tobacco use, as advocated by the World Health Assembly in 2013 and identified as the ‘most urgent and immediate priority’ intervention to reduce non-communicable diseases (NCDs). While there has been some progress, the current commitment of most African countries to the WHO FCTC has not translated into effective delivery of tobacco control policies and programmes. Strong tobacco control policies, which are among the most effective population-based strategies for NCD prevention, are needed. These include introducing higher tobacco excise taxes, stronger smoke-free policies, graphic warnings on cigarette packages, bans on tobacco advertising, promotion and sponsorship, and anti-smoking mass media campaigns. Furthermore, tobacco industry interference needs to be actively addressed by monitoring its activities and exposing misconducts, thereby changing attitudes to the industry. Technical support, capacity building and adequate financing are needed in Africa to enable countries to competently manage legal challenges to tobacco control and deal with the subversive tactics of the industry. Civil society and the media – major players in holding governments accountable for responsible stewardship – need to educate and pressurise African politicians and governments to implement and enforce effective tobacco control policies. Otherwise, if unchecked, the widespread uptake of tobacco use will be a threat not only to health but also to sustainable human development in Africa.Â

Abstract Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large‐scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture‐independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single‐nucleotide variation clearly indicates the existence of sub‐populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies‐specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro‐inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host.

Oral mucosal melanoma (OMM) represents an extremely rare entity that is associated with a poor prognosis due to late diagnosis and early metastasis. Here, extensive surgical therapy is the therapy of choice. In contrary, for OMM in situ, the respective therapeutical recommendations are lacking. In this case report, treatment modalities of an OMM in situ of the palate, including the maxillary alveolar process, are reported. The tumor relapsed twice despite adequate surgical therapy and reconstruction. Therefore, irradiation was performed as an adjuvant therapy. At a follow-up of two years, the patient was free from recurrences.

Background and Aim: Environmental impacts from carcass management are a significant concern globally. Despite a history of costly, ineffective, and environmentally damaging carcass disposal efforts, large animal carcass disposal methods have advanced little in the past decade. An outbreak today will likely be managed with the same carcass disposal techniques used in the previous decades and will likely result in the same economic, health, and environmental impacts. This article overviews the results of one field test that was completed in Virginia (United States) using the aboveground burial (AGB) technique and the disposal of 111 foot-and-mouth disease (FMD) infected sheep in Tunisia using a similar methodology. Materials and Methods: Researchers in the United States conducted a field test to assess the environmental impact and effectiveness of AGB in decomposing livestock carcasses. The system design included a shallow trench excavated into native soil and a carbonaceous base placed on the bottom of the trenches followed by a single layer of animal carcasses. Excavated soils were subsequently placed on top of the animals, and a vegetative layer was established. A similar methodology was used in Tunisia to manage sheep infected with FMDs, Peste des Petits Ruminants virus, and Bluetongue Virus. Results: The results of the field test in the United States demonstrated a significant carcass degradation during the 1-year period of the project, and the migration of nutrients below the carcasses appears to be limited thereby minimizing the threat of groundwater contamination. The methodology proved practical for the disposal of infected sheep carcasses in Tunisia. Conclusions: Based on the analysis conducted to date, AGB appears to offer many benefits over traditional burial for catastrophic mortality management. Ongoing research will help to identify limitations of the method and determine where its application during large disease outbreaks or natural disasters is appropriate.

Abstract The arrangement of proteins into complexes is a key organizational principle for many cellular functions. Although the topology of many complexes has been systematically analyzed in isolation, their molecular sociology in situ remains elusive. Here, we show that crude cellular extracts of a eukaryotic thermophile, Chaetomium thermophilum, retain basic principles of cellular organization. Using a structural proteomics approach, we simultaneously characterized the abundance, interactions, and structure of a third of the C. thermophilum proteome within these extracts. We identified 27 distinct protein communities that include 108 interconnected complexes, which dynamically associate with each other and functionally benefit from being in close proximity in the cell. Furthermore, we investigated the structure of fatty acid synthase within these extracts by cryoEM and this revealed multiple, flexible states of the enzyme in adaptation to its association with other complexes, thus exemplifying the need for in situ studies. As the components of the captured protein communities are known—at both the protein and complex levels—this study constitutes another step forward toward a molecular understanding of subcellular organization.

Abstract The RNA‐like endoplasmic reticulum kinase (PERK) is genetically associated with the tauopathy progressive supranuclear palsy (PSP). To elucidate the functional mechanisms underlying this association, we explored PERK activity in brains of PSP patients and its function in three tauopathy models (cultured human neurons overexpressing 4‐repeat wild‐type tau or treated with the environmental neurotoxin annonacin, and P301S tau transgenic mice). In vitro, treatment with a pharmacological PERK activator CCT020312 or PERK overexpression reduced tau phosphorylation, tau conformational change and 4‐repeat tau isoforms, and increased cell viability. In vivo, the PERK activator significantly improved memory and locomotor function, reduced tau pathology, and prevented dendritic spine and motoneuron loss in P301S tau mice. Importantly, the PERK substrate EIF2A, mediating some detrimental effects of PERK signaling, was downregulated in PSP brains and tauopathy models, suggesting that the alternative PERK–NRF2 pathway accounts for these beneficial effects in the context of tauopathies. In summary, PERK activation may be a novel strategy to treat PSP and eventually other tauopathies.

Background. Despite supernumerary registrars (SNRs) being hosted in South African (SA) training programmes, there are no reports of their experience. Objectives. To evaluate the experience of SNRs at the University of Cape Town, SA, and the experience of SNRs from the perspective of SA registrars (SARs). Methods. SNRs and SARs completed an online survey in 2012. Results. Seventy-three registrars responded; 42 were SARs and 31 were SNRs. Of the SNRs 47.8% were self-funded, 17.4% were funded through private organisations, and 34.8% were funded by governments. Average annual income was ZAR102 349 (range ZAR680 - 460 000). Funding was considered insufficient by 61.0%. Eighty-seven percent intended to return to their home countries. Personal sacrifices were deemed worthwhile from academic (81.8%) and social (54.5%) perspectives, but not financially (33.3%). Only a small majority were satisfied with the orientation provided and with assimilation into their departments. Almost half experienced challenges relating to cultural and social integration. Almost all SARs supported having SNRs. SNRs reported xenophobia from patients (23.8%) and colleagues (47.8%), and felt disadvantaged in terms of learning opportunities, academic support and on-call allocations. Conclusions. SNRs are fee-paying students and should enjoy academic and teaching support equal to that received by SARs. Both the university and the teaching hospitals must take steps to improve the integration of SNRs and ensure that they receive equal access to academic support and clinical teaching, and also need to take an interest in their financial wellbeing. Of particular concern are perceptions of xenophobia from SA medical colleagues.

Background. Bacterial meningitis is one of the most common causes of hearing loss. Hearing loss develops within the first few days following the onset of meningitis, highlighting the importance of early audiology referrals. Post-meningitis hearing loss may lead to cochlear ossification, making traditional cochlear implantation impossible.Objectives. To determine the duration of time from meningitis diagnosis to audiology referral. A second objective was to determine the prevalence and severity of meningitis-related sensorineural hearing loss (SNHL) at Red Cross War Memorial Children’s Hospital (RCWMCH), a paediatric tertiary hospital in Cape Town, South Africa (SA).Methods. A retrospective folder review of all children diagnosed with meningitis and referred for audiological evaluation was conducted over an 18-month period between 1 January 2015 and 30 June 2016. Descriptive statistical methods were used for data analysis.Results. The total number of inpatients diagnosed with unspecified meningitis at RCWMCH between January 2015 and June 2016 was 345. The total number diagnosed with bacterial meningitis was 68. Only 16 children with meningitis (23.5%) were referred to the Department of Audiology at RCWMCH over the 18-month period. Twelve children had confirmed bacterial meningitis. All the children had up-to-date immunisations. The mean (standard deviation) time from diagnosis to audiology referral was 17 weeks (16.9; range 1 - 60). The overall prevalence of hearing loss was 42.8%. Four children (28.5%) were diagnosed with severe to profound SNHL.Conclusions. Less than a quarter of all children diagnosed with bacterial meningitis at RCWMCH over the 18-month study period were referred to audiology. Frequent delays in referrals for audiological assessment following meningitis were noted. This may indicate a lack of awareness on the part of doctors. Healthcare practitioners need to be made aware of the need for prompt audiological testing for children with meningitis. In SA, local guidelines for early diagnosis and monitoring of hearing in children who have had meningitis should be developed in order to improve hearing outcomes.Â

Abstract As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid‐β peptide (Aβ) species, which are released from a C‐terminal amyloid precursor protein fragment by γ‐secretase. Mutations in its catalytic subunit presenilin‐1 (PS1) increase the Aβ42 to Aβ40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD. We now show that the very little Aβ generated by PS1 L435F consists primarily of Aβ43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of Aβ43 is not due to a trans‐dominant effect of this mutant on WT presenilin. Furthermore, we found Aβ43‐containing plaques in brains of patients with this mutation. The aberrant generation of Aβ43 by this particular mutant provides a direct objection against the presenilin hypothesis.

The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in studies matched for HIV-1 transmission groups. In two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Barcelona (n = 156) and Stockholm (n = 84), men who have sex with men (MSM) predominantly belonged to the Prevotella-rich enterotype whereas most non-MSM subjects were enriched in Bacteroides, independently of HIV-1 status, and with only a limited contribution of diet effects. Moreover, MSM had a significantly richer and more diverse fecal microbiota than non-MSM individuals. After stratifying for sexual orientation, there was no solid evidence of an HIV-specific dysbiosis. However, HIV-1 infection remained consistently associated with reduced bacterial richness, the lowest bacterial richness being observed in subjects with a virological-immune discordant response to antiretroviral therapy. Our findings indicate that HIV gut microbiome studies must control for HIV risk factors and suggest interventions on gut bacterial richness as possible novel avenues to improve HIV-1-associated immune dysfunction.

Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader–Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

Abstract Identifying all essential genomic components is critical for the assembly of minimal artificial life. In the genome‐reduced bacterium Mycoplasma pneumoniae, we found that small ORFs (smORFs;

Abstract Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC‐associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor‐free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early‐ and late‐stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC‐associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor‐related host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism.

An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms’ tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1+) aldehyde dehydrogenase 1-positive (ALDH1+) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1+ WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.

Abstract Protein post‐translational modifications (PTMs) allow the cell to regulate protein activity and play a crucial role in the response to changes in external conditions or internal states. Advances in mass spectrometry now enable proteome wide characterization of PTMs and have revealed a broad functional role for a range of different types of modifications. Here we review advances in the study of the evolution and function of PTMs that were spurred by these technological improvements. We provide an overview of studies focusing on the origin and evolution of regulatory enzymes as well as the evolutionary dynamics of modification sites. Finally, we discuss different mechanisms of altering protein activity via post‐translational regulation and progress made in the large‐scale functional characterization of PTM function.

Graphical Abstract The computational analysis of the data collected by Tara Oceans represents a formidable challenge that will push the boundaries of our understanding of ecosystems at a planetary scale.

Abstract In pharmacology, it is crucial to understand the complex biological responses that drugs elicit in the human organism and how well they can be inferred from model organisms. We therefore identified a large set of drug‐induced transcriptional modules from genome‐wide microarray data of drug‐treated human cell lines and rat liver, and first characterized their conservation. Over 70% of these modules were common for multiple cell lines and 15% were conserved between the human in vitro and the rat in vivo system. We then illustrate the utility of conserved and cell‐type‐specific drug‐induced modules by predicting and experimentally validating (i) gene functions, e.g., 10 novel regulators of cellular cholesterol homeostasis and (ii) new mechanisms of action for existing drugs, thereby providing a starting point for drug repositioning, e.g., novel cell cycle inhibitors and new modulators of α‐adrenergic receptor, peroxisome proliferator‐activated receptor and estrogen receptor. Taken together, the identified modules reveal the conservation of transcriptional responses towards drugs across cell types and organisms, and improve our understanding of both the molecular basis of drug action and human biology.

Abstract Side effect similarities of drugs have recently been employed to predict new drug targets, and networks of side effects and targets have been used to better understand the mechanism of action of drugs. Here, we report a large‐scale analysis to systematically predict and characterize proteins that cause drug side effects. We integrated phenotypic data obtained during clinical trials with known drug–target relations to identify overrepresented protein–side effect combinations. Using independent data, we confirm that most of these overrepresentations point to proteins which, when perturbed, cause side effects. Of 1428 side effects studied, 732 were predicted to be predominantly caused by individual proteins, at least 137 of them backed by existing pharmacological or phenotypic data. We prove this concept in vivo by confirming our prediction that activation of the serotonin 7 receptor (HTR7) is responsible for hyperesthesia in mice, which, in turn, can be prevented by a drug that selectively inhibits HTR7. Taken together, we show that a large fraction of complex drug side effects are mediated by individual proteins and create a reference for such relations.