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Hospitals in low- and middle-income countries (LMICs) could benefit from decision support technologies to reduce time to triage, diagnosis, and surgery for patients with traumatic brain injury (TBI). Corticosteroid Randomization after Significant Head Injury (CRASH) and International Mission for Prognosis and Clinical Trials in Traumatic Brain Injury (IMPACT) are robust examples of TBI prognostic models, although they have yet to be validated in Sub-Saharan Africa (SSA). Moreover, machine learning and improved data quality in LMICs provide an opportunity to develop context-specific, and potentially more accurate, prognostic models. We aim to externally validate CRASH and IMPACT on our TBI registry and compare their performances to that of the locally derived model (from the Kilimanjaro Christian Medical Center [KCMC]). We developed a machine learning-based prognostic model from a TBI registry collected at a regional referral hospital in Moshi, Tanzania. We also used the core CRASH and IMPACT online risk calculators to generate risk scores for each patient. We compared the discrimination (area under the curve [AUC]) and calibration before and after Platt scaling (Brier, Hosmer-Lemeshow Test, and calibration plots) for CRASH, IMPACT, and the KCMC model. The outcome of interest was unfavorable in-hospital outcome defined as a Glasgow Outcome Scale score of 1-3. There were 2972 patients included in the TBI registry, of whom 11% had an unfavorable outcome. The AUCs for the KCMC model, CRASH, and IMPACT were 0.919, 0.876, and 0.821, respectively. Prior to Platt scaling, CRASH was the best calibrated model (χ

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Introduction Data describing atrial fibrillation (AF) care in emergency centres (ECs) in sub-Saharan Africa is lacking. We sought to describe the prevalence and outcomes of AF in a Tanzanian EC. Methods In a prospective, observational study, adults presenting with chest pain or shortness of breath to a Tanzanian EC were enrolled from January through October 2019. Participants underwent electrocardiogram testing which were reviewed by two independent physician judges to determine presence of AF. Participants were asked about their medical history and medication use at enrollment, and a follow-up questionnaire was administered via telephone thirty days later to assess mortality, interim stroke, and medication use. Results Of 681 enrolled patients, 53 (7.8%) had AF. The mean age of participants with AF was 68.1, with a standard deviation (sd) of 21.1 years, and 23 of the 53 (43.4%) being male. On presentation, none of the participants found to have AF reported a previous history of AF. The median CHADS-VASC score among participants was 4 with an interquartile range (IQR) of 2-4. No participants were taking an anticoagulant at baseline. On index presentation, 49 (92.5%) participants with AF were hospitalised with 52 (98.1%) participants completing 30-day follow-up. 18 (34%) participants died, and 5 (9.6%) suffered a stroke. Of the surviving 31 participants with AF and a CHADS-VASC score ≥ 2, none were taking other anti-coagulants at 30 days. Compared to participants without AF, participants with AF were more likely to be hospitalised (OR 5.25, 95% CI 2.10-17.95, p, Highlights • In a Tanzanian emergency centre, atrial fibrillation was common but patient awareness of their condition was low • Use of anticoagulants among patients with atrial fibrillation was rare both before and after hospital presentation • Following hospital presentation, thirty-day mortality and stroke rates among patients with atrial fibrillation were high

OBJECTIVES To describe knowledge, attitudes, and practices (KAP) regarding ischemic heart disease (IHD) among adults with HIV in Tanzania. METHODS Adults presenting for routine HIV care at a clinic in northern Tanzania were consecutively enrolled and were administered a standardised KAP survey. For each participant, an IHD knowledge score was calculated by tallying correct answers to the IHD knowledge questions, with maximum score 10. Individual 5-year risk of cardiovascular event was calculated using the Harvard NHANES model. Associations between participant characteristics and IHD knowledge scores were assessed via Welch's t-test. RESULTS Among the 500 participants, the mean (SD) age was 45.3 (11.4) years and 139 (27.8%) were males. Most participants recognised high blood pressure (n = 313, 62.6%) as a risk factor for IHD, but fewer identified diabetes as a risk factor (n = 241, 48.2%), or knew that aspirin reduces the risk of a secondary cardiovascular event (n = 73, 14.6%). Higher IHD knowledge score was associated with post-primary education (mean 6.27 vs. 5.35, p = 0.001) and with >10% 5-year risk of cardiovascular event (mean 5.97 vs. 5.41, p = 0.045). Most participants believed there were things they could do to reduce their chances of having a heart attack (n = 361, 72.2%). While participants indicated that they adhered to their prescribed medications (n = 488, 97.6%), only 106 (21.2%) attended regular health check-ups. CONCLUSION Efforts are needed to improve gaps in IHD knowledge, and increase uptake of cardiovascular preventative practices among Tanzanian adults with HIV.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

Summary A 32-year-old Caucasian male presented to the emergency department with a one-day history of acute severe bilateral lower limb weakness, three days after competing in a bodybuilding competition. He consumed large quantities of carbohydrate-rich foods following the competition. His past medical history was significant for anxiety, and family history was non-contributory. Examination was normal except for reduced power and hyporeflexia in both legs, despite his muscular physique. He was noted to have severe hypokalaemia (K+= 1.9 mmol/L). His thyroid function tests were consistent with thyrotoxicosis. He reported taking thyroxine and several other agents to facilitate muscle mass generation before the bodybuilding competition. His presentation was reminiscent of thyrotoxic periodic paralysis, albeit uncommon with Caucasian ethnicity. He also had transient hyperglycaemia at presentation with concomitant hyperinsulinaemia, which could be attributed to the carbohydrate load and may have exacerbated his hypokalaemia through a transcellular shift. Urine toxicology screen subsequently ruled out the use of diuretics but confirmed the presence of a long-acting beta agonist (clenbuterol) which, along with other substances, may have aggravated the hypokalaemia further. After 12 h of i.v. replacement, the potassium level normalised and leg weakness resolved. The patient agreed to stop taking thyroxine and beta agonists and was well during the clinic visit at one month follow-up. This case highlights the potential for thyrotoxicosis factitia to exacerbate hypokalaemia and muscle weakness from other causes in bodybuilders presenting with acute severe weakness, irrespective of ethnicity. Learning points In patients presenting with muscle weakness and hypokalaemia, early consideration of thyrotoxicosis is essential, even in the absence of a past history of thyroid disease or specific symptoms of thyrotoxicosis, in order to allow prompt initiation of appropriate treatment and to prevent recurrence. Bodybuilders may constitute a uniquely ‘at-risk’ group for thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia, especially where there is concomitant use of beta-adrenergic agonists, even in the absence of diuretic use. Although rare and usually described in patients of Asian or Polynesian ethnicity, this case highlights that thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia can also occur in patients with Caucasian ethnicity. We speculate that consuming large quantities of carbohydrates may induce hyperinsulinaemia, which could theoretically contribute to worse hypokalaemia, though mechanistic studies would be needed to explore this further.

We report a case of a 66-year-old male who presented with a locally advanced primary mucinous adenocarcinoma arising from a fistula-in-ano. The presentation was typical for perianal sepsis and fistula-in-ano with anal pain and chronic discharge. Initial treatments with fistula debridement and seton were performed. Subsequent review of histology revealed underlying adenocarcinoma, while magnetic resonance imaging (MRI) showed local invasion into the prostate. The patient received neoadjuvant chemoradiotherapy followed by pelvic exenteration to maximize the chance of achieving cure. Features of this case are discussed together with its implications, including treatment guidelines and typical MRI findings.

PURPOSE: To determine the unique contributions from elevated voiding and storage pressures in the development of fibrosis and the epithelial-to-mesenchymal transition (EMT) in urothelial cells, and how progressive BOO pressure cycling is an important mechanical cue leading to these pathological changes. MATERIALS AND METHODS: Urothelial cells isolated from control, SHAM, 2 (acute)- or 6 (chronic)-week BOO rats treated with an inflammasome inhibitor or no drug. Total RNA was isolated and RT-PCR was conducted with custom primers for pro-fibrotic and EMT genes. In separate experiments, a rat urothelial cell line was exposed to cyclic pressure regimes characteristic of acute and chronic BOO in the presence or absence of an inflammasome inhibitor. Following exposure, RT-PCR was conducted, collagen content was determined and intracellular caspase-1 activity was measured. RESULTS: Urothelial cells isolated from acute and chronic BOO rat models demonstrated expression of pro-fibrotic and EMT genes. Similarly, MYP3 rat urothelial cells subjected to pressure cycling regimes that reflect intravesical pressures in the acute or chronic BOO bladder also demonstrated increased expression of pro-fibrotic and EMT genes, along with elevated soluble collagen. Treatment with inflammasome inhibitors reduced expression of pro-fibrotic genes in the rat model and pressure cycling model but had a limited effect on EMT. CONCLUSION: These results indicate that acute and chronic BOO pressure cycling are essential in the initiation and progression of fibrosis in the bladder via the NLRP3 inflammasome, but also provide new evidence that there is also an alternative NLRP3-independent pathway leading to EMT and fibrosis.

Members of the fungal genus Phyllosticta can colonize a variety of plant hosts, including several Citrus species such as Citrus sinensis (orange), Citrus limon (lemon), and Citrus maxima (pomelo). Some Phyllosticta species have the capacity to cause disease, such as Citrus Black Spot, while others have only been observed as endophytes. Thus far, genomic differences underlying lifestyle adaptations of Phyllosticta species have not yet been studied. Furthermore, the lifestyle of Phyllosticta citrichinaensis is ambiguous, as it has been described as a weak pathogen but Koch’s postulates may not have been established and the presence of this species was never reported to cause any crop or economic losses. Here, we examined the genomic differences between pathogenic and endophytic Phyllosticta spp. colonizing Citrus and specifically aimed to elucidate the lifestyle of Phyllosticta citrichinaensis. We found several genomic differences between species of different lifestyles, including groups of genes that were only present in pathogens or endophytes. We also observed that species, based on their carbohydrate active enzymes, group independent of their phylogenetic association, and this clustering correlated with trophy prediction. Phyllosticta citrichinaensis shows an intermediate lifestyle, sharing genomic and phenotypic attributes of both pathogens and endophytes. We thus present the first genomic comparison of multiple citrus-colonizing pathogens and endophytes of the genus Phyllosticta, and therefore provide the basis for further comparative studies into the lifestyle adaptations within this genus.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Ultraprocessed-food manufacturers have proposed product reformulation as a key strategy to tackle obesity. In determining the impact of reformulation on population dietary behaviors, policy makers often depend on data provided by these manufacturers. Where such data are “gifted” to regulators, there may be an implicit expectation of reciprocity that adversely influences nutrition policies. The authors aimed to assess Europe’s industry-led reformulation strategy in five countries deploying critical policy studies as an approach. They found that interim results on industry-led food reformulation did not meet the countries’ targets. Information asymmetries exist between food industry and policy makers: the latter are not privy to marketing intelligence and must instead rely on data that are voluntarily donated by food industry actors, which represent a distorted snippet of the marketing intelligence system from whence they came. Because these data indeed bear all the hallmarks of a gift, regulatory and public health authorities operate within a gift economy. The implications of this “data-gift economy” are strategic delay and the need to set goals when the field is not visible. Ultimately, this could diminish the implementation of public health nutrition policies that run counter to the commercial interests of ultraprocessed-food producers.

Introduction A significant number of climbers on Mount Kilimanjaro are affected by altitude-related disorders. The aim of this study was to determine the main causes of morbidity and mortality in a representative cohort of climbers based on local hospital records. Methods We conducted a 2-y retrospective chart review of all patients presenting to the main referral hospital in the region after a climb on Mount Kilimanjaro, including all relevant records and referrals for postmortem studies. Results We identified 62 climbers who presented to the hospital: 47 inpatients and 15 outpatients. Fifty-six presented with high altitude illness, which included acute mountain sickness (n=8; 14%), high altitude pulmonary edema (HAPE) (n=30; 54%), high altitude cerebral edema (HACE) (n=7; 12%), and combined HAPE/HACE (n=11; 20%). The mean altitude of symptom onset ranged from 4600±750 m for HAPE to 5000±430 m for HAPE/HACE. The vast majority of inpatients (n=41; 87%) were improved on discharge. Twenty-one deceased climbers, most having died while climbing (n=17; 81%), underwent postmortem evaluation. Causes of death were HAPE (n=16; 76%), HAPE/HACE (n=3; 14%), trauma (1), and cardiopulmonary (1). Conclusions HAPE was the main cause of death during climbing as well as for hospital admissions. The vast majority of climbers who presented to hospital made a full recovery.

To report outcomes and follow-up of Baerveldt implant surgery in dogs with primary closed-angle glaucoma (PCAG).Record review of client-owned dogs with PCAG that underwent Baerveldt implant surgery during a 6-year period. Postoperative intraocular pressure (IOP), vision and daily number of anti-glaucoma drops at fixed time points (3, 12, and 24 months) were compared with preoperative values; complications were recorded. Success was defined as IOP20 mm Hg and a positive menace response and navigation/tracking ability.Twenty eyes (17 dogs) were included. Mean follow-up was 575 days (range 30-1767 days) from implant surgery to last examination. Three months postoperatively 15/20 (75%) eyes had IOP20 mm Hg and 14/20 (70%) eyes had vision. Twelve months postoperatively 11/17 (65%) eyes had IOP20 mm Hg and 12/19 (63%) eyes had vision. Twenty-four months postoperatively 8/14 (57%) eyes had IOP20 mm Hg and 7/15 (47%) eyes had vision. Denominators differ between time points as eyes were included when duration after surgery reached the relevant postoperative time point or failure was documented earlier. Within 3 months postoperatively 16/20 (80%) eyes had ≥1 complication, including transient IOP20 mm Hg (14/20; 70% eyes), fibrin (12/20; 60% eyes), and hypotony (4/20; 20% eyes). After 3 months, postoperatively 13/16 (81%) eyes had ≥1 complication, including cataracts (13/16; 81% eyes), bleb fibrosis (3/16; 19% eyes), and conjunctival wound breakdown (1/16; 6% eyes). One patient (1 eye) was euthanized for blindness and 5/20 (25%) eyes were enucleated.The technique was effective in controlling IOP and maintaining vision in most dogs in this study.

Contrast-enhanced voiding urosonography (CEVUS) uses intravesically administered microbubble contrast to detect vesicoureteral reflux (VUR) and urethral anomalies with ultrasound. Multiple studies have suggested CEVUS can replace voiding cystourethrogram (VCUG) as a radiation-free alternative. Analysis of the ureterovesical junction and ureters on VCUG documenting the ureterovesical junction position, ureteral duplication, periureteral diverticula and ureteroceles is important as anatomical variations may affect management and surgical approach. Our purpose was to assess distal ureteral and ureterovesical junction region visualization in children with VUR detected on CEVUS. CEVUS studies performed between June 2018 and March 2019 with reported VUR were retrospectively reviewed by two pediatric radiologists to confirm VUR and to qualitatively assess the ureterovesical junction region for each renal moiety using a 3-point scale for clear, limited or absent visualization of the distal ureter, ureterovesical junction, ureteral duplication, periureteral diverticula and ureteroceles. Thirty-four studies with VUR on CEVUS were identified. Sixty-seven renal moieties were evaluated including a solitary kidney in one child. VUR was detected in 52 moieties by reader 1 and in 53 by reader 2. A single moiety with discrepancy between readers regarding VUR was excluded from statistical analysis. No diverticula were detected by either reader and one ureterocele was detected by both readers. Visualization of the ureterovesical junction was described as clear in 5/52, limited in 14/52 and absent in 33/52 refluxing renal moieties by reader 1 and as clear in 12/52, limited in 20/52 and absent in 20/52 by reader 2. The ureterovesical junction was clearly visualized in 5/52 (9.6%) by reader 1 and 12/52 (23.1%) by reader 2. The Kappa value of −0.29 (confidence interval [CI] −0.25, 0.21) reveals a lack of agreement between the readers for clear versus limited or absent ureterovesical junction visualization. Distal ureteral visualization was described as clear in 14/52, limited in 16/52 and absent in 22/52 refluxing renal moieties by reader 1 and as clear in 27/52, limited in 7/52 and absent in 18/52 by reader 2. The distal ureter was clearly visualized in 14/52 (26.9%) by reader 1 and 27/52 (51.9%) by reader 2. The Kappa of 0.43 (CI 0.22, 0.64) reveals moderate agreement between the readers for clear versus limited or absent distal ureteral visualization. Duplication of the renal collecting system was identified in 13/52 refluxing kidneys by reader 1 and 11/52 refluxing kidneys by reader 2. Visualization of ureteral duplication was described as clear in 9, limited in 4 and absent in 39 of 52 refluxing renal moieties by reader 1 and as clear in 9, limited in 2 and absent in 41 by reader 2. Ureteral duplication was clearly visualized in 9/52 (17.3%) by reader 1 and 9/52 (17.3%) by reader 2. Kappa of 0.87 (CI 0.68, 1) reveals high agreement between the readers for clear versus limited or absent identification of ureteral duplication. The distal ureter and ureterovesical junction region frequently are not clearly visualized in refluxing renal moieties on CEVUS. Awareness of this limitation is important as there may be implications when evaluating patients for surgical management of VUR.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%. A genetic link suggests that interventions that halve the risk of malaria episodes could reduce the prevalence of iron deficiency in African children by nearly 50%.

Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database between 2005 to 2017 to identify studies performing universal screening for LS in unselected CRC, EC, OC, UT and ST. All cases with MSI-H (instability in two or more markers) or missing one or more proteins on IHC testing were considered screening positive. Cases with MLH1 promoter hypermethylation or BRAF mutation positive were considered to have somatic mutations. A total of 3788 articles were identified in MEDLINE yielding 129 study arms from 113 studies. The overall pooled yield of universal LS screening and germline mismatch gene mutation was significantly different across the major LS-associated tumors (Mann Whitney test, p

Little is known about the extent and serotypes of dengue viruses circulating in Africa. We evaluated the presence of dengue viremia during 4 years of surveillance (2014–2017) among children with febrile illness in Kenya. Acutely ill febrile children were recruited from 4 clinical sites in western and coastal Kenya, and 1,022 participant samples were tested by using a highly sensitive real-time reverse transcription PCR. A complete case analysis with genomic sequencing and phylogenetic analyses was conducted to characterize the presence of dengue viremia among participants during 2014–2017. Dengue viremia was detected in 41.9% (361/862) of outpatient children who had undifferentiated febrile illness in Kenya. Of children with confirmed dengue viremia, 51.5% (150/291) had malaria parasitemia. All 4 dengue virus serotypes were detected, and phylogenetic analyses showed several viruses from novel lineages. Our results suggests high levels of dengue virus infection among children with undifferentiated febrile illness in Kenya.

Background The Kilimanjaro region has one of the highest levels of reported alcohol intake per capita in Tanzania. Age at first drink has been found to be associated with alcohol problems in adulthood, but there is less information on the age of first drink in the Kilimanjaro region and its associations with alcohol-related consequences later in life. Furthermore, local alcohol cost and availability may influence the prevalence of alcohol use and alcohol use disorders. Method Data on the age of first drink, alcohol use disorder identification tool (AUDIT), number and type of alcohol consequences (DrInC), and perceived alcohol at low cost and high availability for children and adolescents were collected from an alcohol and health behavior survey of injury patients (N = 242) in Moshi, Tanzania. Generalized linear models were used to test age at first drink, perceived alcohol cost and availability, and their association with the AUDIT and DrInC scores, and current alcohol use, respectively. Results Consuming alcohol before age 18 was significantly associated with higher AUDIT and DrInC scores, with odds ratios of 1.22 (CI: 1.004, 1.47) and 1.72 (CI: 1.11, 2.63), respectively. Female gender is strongly associated with less alcohol use and alcohol consequences, represented by an odds ratio of 3.70 (CI: 1.72, 8.33) for an AUDIT score above 8 and an odds ratio of 3.84 (CI: 2.13, 6.67) with the DrInC score. Perceived high availability of alcohol for children is significantly related to higher alcohol use quantity, with the odds ratio of 1.6 (CI: 1.17, 2.20). Conclusions The first use of alcohol before the age of 18 is associated with higher alcohol use and alcohol-related adverse consequences. In Tanzania, age at first drink is an important target for interventions aiming to prevent negative alcohol-related consequences later in life.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel’s recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

Bariatric surgery is known to reduce leptin and increase adiponectin levels, but the influence of sleeve gastrectomy on the leptin: adiponectin ratio (LAR), a measure of insulin sensitivity and cardiovascular risk, has not previously been described. We sought to determine the influence of sleeve gastrectomy on LAR in adults with severe obesity.In a single centre prospective cohort study of adults undergoing laparoscopic sleeve gastrectomy over a four-month period in our unit, we measured LAR preoperatively and 12 months after surgery. Of 22 patients undergoing sleeve gastrectomy, 17 (12 females, 12 with type 2 diabetes) had follow-up LAR measured at 12.1 ± 1 months. Mean body weight decreased from 130.6 ± 30.8 kg to 97.6 ± 21.6 kg, body mass index (BMI) from 46.9 ± 7.8 to 35.3 ± 7.2 kg m−2 and excess body weight from 87.5 ± 31.3 to 41.3 ± 28.8% (all p p = 0.11), but adiponectin increased from 4.49 ± 1.6 to 8.93 ± 6.36 µg/ml (p = 0.005) and LAR decreased from 8.89 ± 4.8 to 5.26 ± 6.52 ng/µg (p = 0.001), equivalent to a 70.9% increase in insulin sensitivity. The correlation with the amount of weight lost was stronger for LAR than it was for leptin or adiponectin alone. In this single-centre, interventional prospective cohort, patients undergoing laparoscopic sleeve gastrectomy had a substantial reduction in their LAR after 12 months which was proportional to the amount of weight lost. This may indicate an improvement in insulin sensitivity and a reduction in cardiovascular risk.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual’s risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology.

O’nyong-nyong virus (ONNV) is a little-known arbovirus causing intermittent, yet explosive, outbreaks in Africa. It is closely related to chikungunya virus, an emerging infectious disease. O’nyong-nyong virus causes a self-limited illness characterized by bilateral polyarthritis, rash, low-grade fever, and lymphadenopathy. In 1959, an extensive outbreak of ONNV occurred in East Africa, and decades later, another large outbreak was documented in Uganda in 1996. Limited evidence for interepidemic transmission is available, although serologic studies indicate a high prevalence of exposure. 1,045 febrile child participants in western and coastal Kenya were tested for the presence of ONNV using a multiplexed real-time reverse transcriptase–PCR assay. More than half of the participants had malaria parasitemia, and there was no evidence of active ONNV viremia in these participants. Further work is required to better understand the interepidemic circulation of ONNV and to reconcile evidence of high serologic exposure to ONNV among individuals in East Africa.

Objectives Cell-free fetal DNA (cfDNA) has been increasingly incorporated into prenatal aneuploidy screening paradigms given its relatively high sensitivity for Down syndrome (DS). This is often the case when fetal ultrasonographic soft markers are present, such as the relatively common echogenic intracardiac focus (EIF). We sought to evaluate the cost-effectiveness of a screening strategy that included cfDNA screening when an isolated EIF is identified in a low-risk population with prior aneuploidy screening. Methods A decision-analytic model was constructed using TreeAge software with probabilities derived from the literature. Our model compared cfDNA screening following isolated EIF detection in women less than 35 years with prior reassuring first trimester screen compared to a strategy of no further aneuploidy screening. Strategies were compared to generate an incremental cost-effectiveness ratio with a threshold of $100 000/quality-adjusted life year (QALY) and applied to a theoretical cohort. Results The cfDNA strategy resulted in 21 fewer DS births and 52 additional QALYs, however, increased costs by $51.3 million. This yielded an incremental cost-effectiveness ratio of $986 503; therefore, it was not a cost-effective strategy. Conclusion In a low-risk population with prior reassuring aneuploidy screening, it is not cost effective to offer cfDNA after identification of an isolated EIF.

"Skin popping" refers to the practice of injecting drugs, most commonly heroin, subcutaneously or into granulation tissue. Pharmaceutical tablets meant for oral consumption are modified into solutions for injection. Excipients-inactive substances that serve as vehicles for medication-are often not filtered out before injection and result in abscess formation, granulomatous inflammation, and scarring. Common excipients used in the production of pharmaceutical tablets include starch, microcrystalline cellulose, magnesium stearate, silica, and polyvinylpyrrolidone (PVP). Identification of these exogenous materials is valuable in confirming the diagnosis of skin popping, especially when patients may not be forthcoming about their drug use. We present a case of subcutaneous oral medication injection in which PVP and cellulose were identified by Fourier transform infrared spectroscopy. Considering the variable cutaneous manifestations of injection drug abuse, recognition of histopathologic and chemical characteristics of exogenous material from oral medications is helpful for diagnosis and intervention.

Background Globally, pneumonia is the leading cause of death among children. Few data exist regarding the effect of Haemophilus influenzae type b (Hib) vaccine and 13-valent pneumococcal conjugate vaccine (PCV-13) on the burden of childhood pneumonia in African settings. Methods We collected data on children aged 1 to 59 months at 3 hospitals in Botswana. Hib vaccine and PCV-13 were introduced in Botswana in November 2010 and July 2012, respectively. We compared pneumonia hospitalizations and deaths prevaccine (January 2009 to October 2010) with postvaccine (January 2013 to December 2017) using seasonally adjusted, interrupted time-series analyses. Results We identified 6943 pneumonia hospitalizations and 201 pneumonia deaths. In the prevaccine period, pneumonia hospitalizations and deaths increased by 24% (rate, 1.24; 95% CI, .94–1.64) and 59% (rate, 1.59; 95% CI, .87–2.90) per year, respectively. Vaccine introduction was associated with a 48% (95% CI, 29–62%) decrease in the number of pneumonia hospitalizations and a 50% (95% CI, 1–75%) decrease in the number of pneumonia deaths between the end of the prevaccine period (October 2010) and the beginning of the postvaccine period (January 2013). During the postvaccine period, pneumonia hospitalizations and deaths declined by 6% (rate, .94; 95% CI, .89–.99) and 22% (rate, .78; 95% CI, .67–.92) per year, respectively. Conclusions Pneumonia hospitalizations and deaths among children declined sharply following introduction of Hib vaccine and PCV-13 in Botswana. This effect was sustained for more than 5 years after vaccine introduction, supporting the long-term effectiveness of these vaccines in preventing childhood pneumonia in Botswana.

OBJECTIVETraumatic brain injury (TBI) is a leading cause of death and disability worldwide, with a disproportionate burden of this injury on low- and middle-income countries (LMICs). Limited access to diagnostic technologies and highly skilled providers combined with high patient volumes contributes to poor outcomes in LMICs. Prognostic modeling as a clinical decision support tool, in theory, could optimize the use of existing resources and support timely treatment decisions in LMICs. The objective of this study was to develop a machine learning–based prognostic model using data from Kilimanjaro Christian Medical Centre in Moshi, Tanzania.METHODSThis study is a secondary analysis of a TBI data registry including 3138 patients. The authors tested nine different machine learning techniques to identify the prognostic model with the greatest area under the receiver operating characteristic curve (AUC). Input data included demographics, vital signs, injury type, and treatment received. The outcome variable was the discharge score on the Glasgow Outcome Scale–Extended.RESULTSThe AUC for the prognostic models varied from 66.2% (k-nearest neighbors) to 86.5% (Bayesian generalized linear model). An increasing Glasgow Coma Scale score, increasing pulse oximetry values, and undergoing TBI surgery were predictive of a good recovery, while injuries suffered from a motor vehicle crash and increasing age were predictive of a poor recovery.CONCLUSIONSThe authors developed a TBI prognostic model with a substantial level of accuracy in a low-resource setting. Further research is needed to externally validate the model and test the algorithm as a clinical decision support tool.

Background Prevention and treatment of malaria during pregnancy is crucial in dealing with maternal mortality and adverse fetal outcomes. The World Health Organization recommendation to treat all pregnant women with sulfadoxine-pyrimethamine (SP) through antenatal care structures was implemented in Kenya in the year 1998, but concerns about its effectiveness in preventing malaria in pregnancy has arisen due to the spread of SP resistant parasites. This study aimed to determine the prevalence of SP resistance markers in Plasmodium falciparum parasites isolated from pregnant women seeking antenatal care at Msambweni County Referral Hospital, located in coastal Kenya, between the year 2013 and 2015. Methods This hospital-based study included 106 malaria positive whole blood samples for analysis of SP resistance markers within the Pfdhfr gene (codons 51, 59 and 108) and Pfdhps gene (codons 437 and 540). The venous blood collected from all pregnant women was tested for malaria via light microscopy, then the malaria positive samples were separated into plasma and red cells and stored in a − 86° freezer for further studies. Archived red blood cells were processed for molecular characterization of SP resistance markers within the Pfdhfr and Pfdhps genes using real time PCR platform and Sanger sequencing. Results All samples had at least one mutation in the genes associated with drug resistance; polymorphism prevalence of Pfdhfr51I, 59R and 108N was at 88.7%, 78.3% and 93.4%, respectively, while Pfdhps polymorphism accounted for 94.3% and 91.5% at 437G and 540E, respectively. Quintuple mutations (at all the five codons) conferring total SP resistance had the highest prevalence of 85.8%. Quadruple mutations were observed at a frequency of 10.4%, and 24.5% had a mixed outcome of both wildtype and mutant genotypes in the genes of interest. Conclusion The data suggest a high prevalence of P. falciparum genetic variations conferring resistance to SP among pregnant women, which may explain reduced efficacy of IPTp treatment in Kenya. There is need for extensive SP resistance profiling in Kenya to inform IPTp drug choices for successful malaria prevention during pregnancy.

Background Measurement-based care (MBC) has emerged as an effective strategy for improving outcomes in patients with mood disorders. Suicide is a particularly devastating outcome of mood disorders. Using data from a new MBC program from the National Network of Depression Centers (NNDC), we examined whether capturing a patient-rated symptom measure, the patient health questionnaire (PHQ-9), along with a provider-rated global functioning measure, the clinical global impression scale (CGI-S), improves identification of patients at risk of suicide over using either measure alone. Methods A total of 126 adults with mood disorders from nine sites in the NNDC completed the PHQ-9 and CGI-S and had at least one subsequent visit where they completed the Columbia-suicide severity rating scale (C-SSRS). The PHQ-9 (≥10) and CGI-S (≥4) were dichotomized at commonly accepted severity thresholds. Associations of the PHQ-9 and CGI-S with suicidal ideation or behavior were examined using Firth's logistic regression to accommodate small samples while controlling for age, sex, race, and diagnosis. Results Patients who scored higher on only the PHQ-9 or CGI-S were not significantly more likely to experience subsequent suicidal ideation or behaviors. However, patients who scored higher on both the PHQ-9 and CGI-S were significantly more likely to experience suicidal ideation (OR = 4.70, p = 0.0005) and suicidal behaviors (OR = 25.38, p = 0.0003). Discussion Information from both patient and clinician-rated measures was better able to identify patients with mood disorders at risk for suicidal ideation and behaviors. Using both together may help reduce the risk of suicide by identifying those patients at greatest risk and allowing for more targeted interventions.

Despite therapeutic advances, patients with acute coronary syndrome (ACS) are at an increased long-term risk of recurrent cardiovascular events. This risk continues to rise as the number of associated comorbidities, often observed in patients presenting with ACS, increases. Such a level of clinical complexity can lead to gaps in care and subsequently worse outcomes. Guidelines recommend providing an evidence-based post-discharge plan to prevent readmission and recurrent ACS, including cardiac rehabilitation, medication, patient/caregiver education, and ongoing follow-up. A patient-centric multidisciplinary approach is critical for the effective management of the transition of care from acute care in the hospital setting to the outpatient care setting in patients with ACS. Ongoing communication between in-hospital and outpatient healthcare providers ensures that the transition is smooth. Primary care providers and pharmacists have a pivotal role to play in the effective management of transitions of care in patients with ACS. Guideline recommendations regarding the post-discharge care of patients with ACS and the role of the primary care provider and the pharmacist in the management of transitions of care will be reviewed.

Background Thrombotic events continue to be a major cause of morbidity and mortality worldwide. Tissue plasminogen activator (tPA) is used for the treatment of acute ischemic stroke and other thrombotic disorders. Use of tPA is limited by its narrow therapeutic time window, hemorrhagic complications, and insufficient delivery to the location of the thrombus. Magnetic nanoparticles (MNPs) have been proposed for targeting tPA delivery. It would be advantageous to develop an improved in vitro model of clot formation, to screen thrombolytic therapies that could be enhanced by addition of MNPs, and to test magnetic drug targeting at human-sized distances. Methods We utilized commercially available blood and endothelial cells to construct 1/8th inch (and larger) biomimetic vascular channels in acrylic trays. MNP clusters were moved at a distance by a rotating permanent magnet and moved along the channels by surface walking. The effect of different transport media on MNP velocity was studied using video photography. MNPs with and without tPA were analyzed to determine their velocities in the channels, and their fibrinolytic effect in wells and the trays. Results MNP clusters could be moved through fluids including blood, at human-sized distances, down straight or branched channels, using the rotating permanent magnet. The greatest MNP velocity was closest to the magnet: 0.76 ± 0.03 cm/sec. In serum, the average MNP velocity was 0.10 ± 0.02 cm/sec. MNPs were found to enhance tPA delivery, and cause fibrinolysis in both static and dynamic studies. Fibrinolysis was observed to occur in 85% of the dynamic MNP + tPA experiments. Conclusion MNPs hold great promise for use in augmenting delivery of tPA for the treatment of stroke and other thrombotic conditions. This model system facilitates side by side comparisons of MNP-facilitated drug delivery, at a human scale.

Diet modifies the risk of colorectal cancer (CRC), and inconclusive evidence suggests that yogurt may protect against CRC. We analysed the data collected from two separate colonoscopy-based case–control studies. The Tennessee Colorectal Polyp Study (TCPS) and Johns Hopkins Biofilm Study included 5446 and 1061 participants, respectively, diagnosed with hyperplastic polyp (HP), sessile serrated polyp, adenomatous polyp (AP) or without any polyps. Multinomial logistic regression models were used to derive OR and 95 % CI to evaluate comparisons between cases and polyp-free controls and case–case comparisons between different polyp types. We evaluated the association between frequency of yogurt intake and probiotic use with the diagnosis of colorectal polyps. In the TCPS, daily yogurt intake v. no/rare intake was associated with decreased odds of HP (OR 0·54; 95 % CI 0·31, 0·95) and weekly yogurt intake was associated with decreased odds of AP among women (OR 0·73; 95 % CI 0·55, 0·98). In the Biofilm Study, both weekly yogurt intake and probiotic use were associated with a non-significant reduction in odds of overall AP (OR 0·75; 95 % CI 0·54, 1·04) and (OR 0·72; 95 % CI 0·49, 1·06) in comparison with no use, respectively. In summary, yogurt intake may be associated with decreased odds of HP and AP and probiotic use may be associated with decreased odds of AP. Further prospective studies are needed to verify these associations.

Treatment options for weight loss vary considerably with regard to risks and benefits, but the relative importance of treatment characteristics in patient decision-making is largely unknown, particularly amongst patients with severe obesity. Developing such services requires insight into the preferences of recipients for service attributes. The objective of this study was to quantify, using a discrete choice experiment, the preferences of treatment-seeking patients with severe obesity within the Irish population regarding different attributes of various obesity treatments. Within a cohort of patients with severe obesity attending a hospital-based weight management programme, patients’ attitudes to and perceptions of three distinct treatment modalities were compared to those regarding not having treatment. The treatments included a structured lifestyle modification programme, lifestyle modification alongside weight loss medication, and bariatric surgery. On average, patients with severe and complicated obesity who were attending a weight management programme were more enthusiastic about participating in a programme to help improve their diet and physical activity than they were about having surgery if the methods of treatment had equivalent results and costs. The findings provide insights into preferences that might assist the development of more appropriate treatments for severe obesity.

Objective Low energy meal replacement regimens can induce short-term weight loss in patients with severe obesity, but usually require specially formulated dietary supplements. We sought to determine the effects of a milk-based meal replacement program on anthropometric and metabolic characteristics in adults with severe obesity. Methods We conducted a retrospective cohort study of patients attending our hospital-based bariatric medicine service who completed a 24-week program consisting of eight weeks of milk-based meal replacement followed by weight stabilisation and maintenance phases. Patients were seen fortnightly by the bariatric physician, nurse and dietitian. We assessed changes in anthropometric and metabolic outcomes in completers at 0, 8, 16 and 24 weeks. Results Of 105 program completers available for follow-up, 53.3% were female. Mean age was 51.1±11.2 years. Body weight decreased from 144.0±27.6 kg at baseline to 121.1±25.0 kg at 24 weeks (P

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Purpose: In patients with >1 non–small cell lung carcinoma (NSCLC), the distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is a common diagnostic dilemma with critical staging implications. Here, we compared the performance of comprehensive next-generation sequencing (NGS) with standard histopathologic approaches for distinguishing NSCLC clonal relationships in clinical practice. Experimental Design: We queried 4,119 NSCLCs analyzed by 341–468 gene MSK-IMPACT NGS assay for patients with >1 surgically resected tumor profiled by NGS. Tumor relatedness predicted by prospective histopathologic assessment was contrasted with comparative genomic profiling by subsequent NGS. Results: Sixty patients with NGS performed on >1 NSCLCs were identified, yielding 76 tumor pairs. NGS classified tumor pairs into 51 definite SPLCs (median, 14; up to 72 unique somatic mutations per pair), and 25 IPMs (24 definite, one high probability; median, 5; up to 16 shared somatic mutations per pair). Prospective histologic prediction was discordant with NGS in 17 cases (22%), particularly in the prediction of IPMs (44% discordant). Retrospective review highlighted several histologic challenges, including morphologic progression in some IPMs. We subsampled MSK-IMPACT data to model the performance of less comprehensive assays, and identified several clinicopathologic differences between NGS-defined tumor pairs, including increased risk of subsequent recurrence for IPMs. Conclusions: Comprehensive NGS allows unambiguous delineation of clonal relationship among NSCLCs. In comparison, standard histopathologic approach is adequate in most cases, but has notable limitations in the recognition of IPMs. Our results support the adoption of broad panel NGS to supplement histology for robust discrimination of NSCLC clonal relationships in clinical practice.

Introduction The prevalence of cardiovascular disease in sub-Saharan Africa is substantial and growing. Much remains to be learned about the relative burden of acute coronary syndrome (ACS), heart failure, and stroke on emergency departments and hospital admissions. Methods A retrospective chart review of admissions from September 2017 through March 2018 was conducted at the emergency department of a tertiary care center in northern Tanzania. Stroke admission volume was compared to previously published data from the same hospital and adjusted for population growth. Results Of 2418 adult admissions, heart failure and stroke were the two most common admission diagnoses, accounting for 294 (12.2%) and 204 (8.4%) admissions, respectively. ACS was uncommon, accounting for 9 (0.3%) admissions. Of patients admitted for heart failure, uncontrolled hypertension was the most commonly identified etiology of heart failure, cited in 124 (42.2%) cases. Ischemic heart disease was cited as the etiology in only 1 (0.3%) case. Adjusting for population growth, the annual volume of stroke admissions increased 70-fold in 43 years, from 2.9 admissions per 100,000 population in 1974 to 202.2 admissions per 100,000 in 2017. Conclusions The burden of heart failure and stroke on hospital admissions in Tanzania is substantial, and the volume of stroke admissions is rising precipitously. ACS is a rare diagnosis, and the distribution of cardiovascular disease phenotypes in Tanzania differs from what has been observed outside of Africa. Further research is needed to ascertain the reasons for these differences., Highlights • In northern Tanzania, acute coronary syndrome is a rare admission diagnosis • Heart failure and stroke are the most common admission diagnoses • The burden of stroke admissions in this community is rising rapidly

Significance Recently, investigators have shown that only a few driver gene mutational events appear to be needed for cancer to occur. However, the reason that some mutational events precede others in the same cancer and the explanation for tissue-specific differences in this timing, remain mysterious. We here combine mathematical modeling with epidemiologic studies and sequencing data to address these questions. We suggest that the first driver event in cancers generally occurred at early ages and provide estimates for the fitness of different types of drivers during tumor evolution, showing how they vary with the tissue of origin., Cancer is driven by the sequential accumulation of genetic and epigenetic changes in oncogenes and tumor suppressor genes. The timing of these events is not well understood. Moreover, it is currently unknown why the same driver gene change appears as an early event in some cancer types and as a later event, or not at all, in others. These questions have become even more topical with the recent progress brought by genome-wide sequencing studies of cancer. Focusing on mutational events, we provide a mathematical model of the full process of tumor evolution that includes different types of fitness advantages for driver genes and carrying-capacity considerations. The model is able to recapitulate a substantial proportion of the observed cancer incidence in several cancer types (colorectal, pancreatic, and leukemia) and inherited conditions (Lynch and familial adenomatous polyposis), by changing only 2 tissue-specific parameters: the number of stem cells in a tissue and its cell division frequency. The model sheds light on the evolutionary dynamics of cancer by suggesting a generalized early onset of tumorigenesis followed by slow mutational waves, in contrast to previous conclusions. Formulas and estimates are provided for the fitness increases induced by driver mutations, often much larger than previously described, and highly tissue dependent. Our results suggest a mechanistic explanation for why the selective fitness advantage introduced by specific driver genes is tissue dependent.

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Background: Lifestyle modification is the cornerstone of management for patients with severe and complicated obesity, but the effects of structured lifestyle programmes on quality of life, anxiety and depression scores and cardiovascular risk factors are not well-described. We sought to describe changes in self-reported quality of life and mental health-related outcomes as well as cardiovascular risk factors in patients completing a 10-week multidisciplinary lifestyle-modification programme. Methods: We conducted a prospective cohort study of all patients referred from our bariatric service who completed the programme between 2013 and 2019. In addition to weight, body mass index (BMI), blood pressure, HbA1c, lipid profile and functional capacity, we quantified health-related quality of life using the Dartmouth COOP Questionnaire and the European Quality of Life Questionnaire Visual Analogue Scale (EQVAS) and mental health using the Hospital Anxiety and Depression Scale (HADS). Results: Of 1122 patients who started the programme, 877 (78.2%) completed it and were included in per protocol analyses. Mean age was 47.3 ± 11.9 years, 66.9% were female, 34.8% were in full- or part-time employment and 69.4% were entitled to state-provided medical care. BMI decreased from 47.0 ± 7.8 to 46.2 ± 7.8 kg m−2 and weight decreased from 131.6 ± 25.5 to 129.5 ± 25.4 kg (both p < 0.001). There were significant reductions in anxiety and depression scores and improvements in all Dartmouth COOP domains. The EQVAS score increased from 52 ± 22 to 63 ± 19 (p < 0.001). Small but statistically significant reductions in LDL cholesterol, systolic blood pressure and HBA1c were also observed. Conclusions: Adults with severe and complicated obesity completing a specialised bariatric lifestyle-modification programme showed significant improvements in self-reported mental health and quality of life, in addition to reductions in cardiovascular risk factors.

Background Metastatic triple negative breast cancer (mTNBC) is an inherently diverse disease and while molecular classification of mTNBC has assisted in treatment decisions, if based on only an initial biopsy, it does not take into account the evolution of metastatic cancer. Characterization of emerging metastases is needed to reveal both new resistance or sensitivity to available therapeutics. The goal of “Intensive Trial of OMics in Cancer (ITOMIC) - Intensive Longitudinal Monitoring in Subjects With Triple-Negative Breast Cancer” (NCT01957514) - was to determine the feasibility of longitudinal collection of patient biopsies that would be subjected to molecular analysis to provide actionable, relevant and timely information to guide treatment decisions.Methods Multiple biopsies were collected longitudinally, including pre- and post-treatment, from 29 mTNBC patients enrolled in the ITOMIC study and subjected to multi-dimensional molecular profiling including WES, WGS, cancer gene panel sequencing, RNA-seq, and proteomics and/or IHC for tumor biomarkers. This information was used to guide iterative, patient- and tumor- individualized treatment recommendations made by a multi-institutional ITOMIC Tumor Board (ITB) and conveyed to each subject’s oncologist.Results Longitudinal biopsy collection was found to be safe. Molecular profiling revealed that 2 of an original 31 enrolled subjects likely had lung cancer rather than mTNBC, supporting the merit of repeated tissue analysis. While the other 29 subjects had all been given a diagnosis of mTNBC before entering the trial, estrogen receptor, progesterone receptor, and/or HER2 were found to be over-expressed in at least one sample for 12 subjects; appearance of receptor positivity suggests targeted therapy may be effective. Tumor evolution in response to the first on-study treatment for most subjects (cisplatin) was revealed by copy number alterations, changes in single nucleotide variants, and insertions/deletions in pre-/post-treatment biopsies. Over the course of the study, the ITB convened 54 times and 39 of 182 recommended treatments were evaluated and accessed through either an existing clinical trial, a single patient IND, approved off label or label indication. While not all ITB treatment recommendations were followed, 24 subjects did receive at least one ITB-recommended drug, frequently as part of a clinical trial. Currently, for 27 subjects (2 withdrew) median survival is ~31 months. There are 4 surviving patients in treatment with a remarkable median survival of >51 months.Conclusion Collection and molecular analysis of multiple biopsies during the course of patient’s disease, shown here to be safe and feasible, provides information vital to appropriate treatment choice and reveals new targets for and resistance to therapy in metastatic TNBC. Citation Format: Kimberly A Burton, Eric Q Konnick, Sibel Blau, Michael O Dorschner, Julie Gralow, Rahul Parulkar, Elisabeth Mahen, Patricia Spilman, Stephanie Parker, Francis M Senecal, Colin Pritchard, Christopher Szeto, Jing Zhu, Vijayakrishna K Gadi, Stephen C Benz, Shahrooz Rabizadeh, Patrick Soon-Shiong, Carl Anthony Blau. Multidimensional molecular profiling of repeated metastatic TNBC biopsies in the intensive trial of omics safely guides treatment decisions [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-13.

OBJECTIVES The objectives of this article are to list the most commonly prescribed Oral Nutritional Supplements in the UK and Ireland and their sugar content; and to raise awareness among the dental profession regarding their uses and potential dental risks involved. BACKGROUND Many older patients benefit from Oral Nutritional Supplements. Prescribers may not consider dental implications of these. Patients may not think to disclose these medications to their dentist. MATERIALS AND METHODS A list of commonly prescribed Oral Nutritional Supplements in the UK and Ireland was compiled. Nutritional information was obtained from the manufacturers' website and arranged in order of decreasing sugar content. Potential dental implications are discussed and recommendations made for dental practitioners. RESULTS Pre-formed Oral Nutritional Supplements can contain between 6.6 and 27.2 g of sugar per serving. Powdered Oral Nutritional Supplements, which are to be mixed with 200 ml whole milk, contain between 16.4 and 35.0 g sugar per serving. The "shot"-type Oral Nutritional Supplements contain less sugar, ranging from 0.0 to 4.0 g per serving. CONCLUSIONS The sugar content of frequently prescribed Oral Nutritional Supplements can be high. While they are beneficial in assisting the patient to maintain a healthy BMI, they may increase the risk of dental caries. Dental professionals should enquire specifically about Oral Nutritional Supplements during history taking, particularly in groups who are likely to be prescribed such supplements. Consideration should also be given to increasing caries-preventive measures for patients who take these supplements.

Objective To characterize the clinical presentation, advanced imaging features, and outcome of orbital disease in a referral population of dogs and cats that underwent computed tomography (CT) or magnetic resonance imaging (MRI). Animals studied Client-owned animals. Procedures Animals referred for orbital disease undergoing ophthalmic examination and either head MRI or CT were included. Demographic and imaging features were compared between animals diagnosed with inflammatory disease and neoplastic disease using Mann-Whitney U and Fischer's exact tests. Results Ninety-seven animals (81 dogs and 16 cats) were included. Eighty-four and 13 patients underwent CT and MRI scanning, respectively. Inflammatory orbital disease was more frequently detected than neoplasia in dogs (59% vs. 41%) and cats (62% vs. 39%). Orbital cellulitis was the most common diagnosis in dogs (36/81, 44.4%) and cats (8/16, 80%). A foreign body was suspected in 36.1% of dogs with orbital cellulitis but only 3 were retrieved during orbitotomy. Multi-drug resistant bacteria were identified in 3 samples and influenced treatment plans. The most common neoplasms were sarcoma (10/30) and carcinoma (7/30) in dogs and lymphoma in cats (3/6). Imaging findings of osteolysis (p = 0.0002) and intracranial extension (p = 0.0001) were significantly associated with neoplasia in dogs. In contrast, osteolysis extension was present in cats with both inflammatory (7/10) and neoplastic (6/6) orbital disease. Conclusions Inflammatory disease, particularly orbital cellulitis, was more common than neoplasia in dogs and cats with orbital disease in our population. We recommend including bacterial culture and susceptibility as part of the diagnostic work up when orbital cellulitis is suspected.

INTRODUCTION AND OBJECTIVE:Diabetic bladder dysfunction (DBD) is a progressive deterioration of urinary function and it has been proposed that inflammation underlies this common complication. Bladd...

Background Rigorous incidence data for acute myocardial infarction (AMI) in sub‐Saharan Africa are lacking. Consequently, modeling studies based on limited data have suggested that the burden of AMI and AMI‐associated mortality in sub‐Saharan Africa is lower than in other world regions. Methods and Results We estimated the incidence of AMI in northern Tanzania in 2019 by integrating data from a prospective surveillance study (681 participants) and a community survey of healthcare‐seeking behavior (718 participants). In the surveillance study, adults presenting to an emergency department with chest pain or shortness of breath were screened for AMI with ECG and troponin testing. AMI was defined by the Fourth Universal Definition of AMI criteria. Mortality was assessed 30 days following enrollment via in‐person or telephone interviews. In the cluster‐based community survey, adults in northern Tanzania were asked where they would present for chest pain or shortness of breath. Multipliers were applied to account for AMI cases that would have been missed by our surveillance methods. The estimated annual incidence of AMI was 172 (207 among men and 139 among women) cases per 100 000 people. The age‐standardized annual incidence was 211 (263 among men and 170 among women) per 100 000 people. The estimated annual incidence of AMI‐associated mortality was 87 deaths per 100 000 people, and the age‐standardized annual incidence was 102 deaths per 100 000 people. Conclusions The incidence of AMI and AMI‐associated mortality in northern Tanzania is much higher than previously estimated and similar to that observed in high‐income countries.

Supplemental Digital Content is available in the text., IMPORTANCE: Even with its proclivity for older age, coronavirus disease 2019 has been shown to affect all age groups. However, there remains a lack of research focused primarily on the young adult population. OBJECTIVES: To describe the epidemiology and outcomes of coronavirus disease 2019 and identify the risk factors associated with critical illness and mortality in hospitalized young adults. DESIGN, SETTINGS, AND PARTICIPANTS: A retrospective cohort study of the Society of Critical Care Medicine’s Viral Infection and Respiratory Illness Universal Study registry. Patients 18–40 years old, hospitalized from coronavirus disease 2019 from March 2020 to April 2021, were included in the analysis. MAIN OUTCOMES AND MEASURES: Critical illness was defined as a composite of mortality and 21 predefined interventions and complications. Multivariable logistic regression was used to assess associations with critical illness and mortality. RESULTS: Data from 4,005 patients (152 centers, 19 countries, 18.6% non-U.S. patients) were analyzed. The median age was 32 years (interquartile range, 27–37 yr); 51% were female, 29.4% Hispanic, and 42.9% had obesity. Most patients (63.2%) had comorbidities, the most common being hypertension (14.5%) and diabetes (13.7%). Hospital and ICU mortality were 3.2% (129/4,005) and 8.3% (109/1,313), respectively. Critical illness occurred in 25% (n = 996), and 34.3% (n = 1,376) were admitted to the ICU. Older age (p = 0.03), male sex (adjusted odds ratio, 1.83 [95% CI, 1.2–2.6]), and obesity (adjusted odds ratio, 1.6 [95% CI, 1.1–2.4]) were associated with hospital mortality. In addition to the above factors, the presence of any comorbidity was associated with critical illness from coronavirus disease 2019. Multiple sensitivity analyses, including analysis with U.S. patients only and patients admitted to high-volume sites, showed similar risk factors. CONCLUSIONS: Among hospitalized young adults, obese males with comorbidities are at higher risk of developing critical illness or dying from coronavirus disease 2019.