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Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate 5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important in initiation of allergic inflammation. Single nucleotide polymorphisms (SNPs) in TSLP are associated with asthma, yet studies have shown inconsistent associations between circulating TSLP and asthma. Studies that integrate the combined effects of TSLP genotype, TSLP mRNA, circulating TSLP levels, and asthma outcome are lacking. OBJECTIVE: To recruit a novel cohort based on asthma-relevant TSLP SNPs and determine their impact on TSLP mRNA expression and TSLP circulating protein levels, and their individual and combined effects on asthma. METHODS: We developed an algorithm to prioritize TSLP SNPs and recruited 51 carriers and non-carriers based on TSLP genotypes. We quantified TSLP mRNA in nasal epithelial cells and circulating TSLP levels in plasma. We determined associations of defined TSLP risk genotypes and/or TSLP mRNA and protein levels with asthma. RESULTS: TSLP mRNA expression, but not circulating TSLP, was significantly increased in asthmatics compared to non-asthmatics (P=0.007; OR=1.44). Notably, 90% of children with the defined TSLP risk genotypes and high nasal TSLP mRNA expression (top tertile) had asthma compared to 40% of subjects without risk genotypes and with low TSLP expression (bottom tertile) (P=0.024). No association between circulating TSLP and asthma was observed. CONCLUSION: Collectively, these data suggest childhood asthma is modified by the combined effects of TSLP genotype and TSLP expression in the nasal epithelium. The increased asthma risk likely manifests when genetic variation enables eQTL in the TSLP locus to elevate TSLP. It is important to consider both biomarkers when factoring asthma risk. CLINICAL IMPLICATIONS: TSLP genotype and nasal mRNA expression may be useful biomarkers to aid asthma prediction and/or identify individuals who would benefit from therapy targeting this pathway.

The first wave of the coronavirus disease 2019 (COVID‐19) pandemic had an enormous impact on health‐care services, including on care provision for children with atopic dermatitis (AD). We investigated the impact of COVID‐19 on the care for children with moderate to severe AD at our tertiary outpatient clinic and examined satisfaction with care. We reviewed outpatient records, comparing total number and types of consultations during the first COVID‐19 wave (March until July 2020) with the corresponding months of 2019 and 2018. In addition, we conducted a questionnaire‐based study investigating the impact of COVID‐19 on clinical and psychological symptoms, and satisfaction with care. A total number of 913 consultations (466 individual children) were conducted during the first COVID‐19 wave in 2020, while 698 (391 individual children) and 591 consultations (356 individual children) were conducted in 2019 and 2018. The proportion of remote consultations was higher (56.2%) compared to 14.0% in 2019 and 12.7% in 2018. Worsening of AD was reported by 9.7% of caretakers. Overall satisfaction with provided care was high (8.6; interquartile range [IQR] = 7.3–10.0). Caretakers receiving face‐to‐face consultation were significantly (p = 0.026) more satisfied (9.0; IQR = 8.0–10.0) than caretakers receiving remote consultation (7.9; IQR = 7.0–9.5). The COVID‐19 pandemic had an unprecedented impact on care provision for children with AD, particularly on the number of remote consultations. Overall satisfaction with care was high. The impact of COVID‐19 on disease severity remained limited. Remote consultations seem to be a useful tool that can be put into practice during the COVID‐19 pandemic.

The confounding effects of next-generation sequencing (NGS) noise on detection of low frequency circulating tumor DNA (ctDNA) without a priori knowledge of solid tumor mutations has limited the applications of circulating cell-free DNA (ccfDNA) in clinical oncology. Here, we use a 118 gene panel and leverage ccfDNA technical replicates to eliminate NGS-associated errors while also enhancing detection of ctDNA from pancreatic ductal adenocarcinomas (PDACs). Pre-operative ccfDNA and tumor DNA were acquired from 14 patients with PDAC (78.6% stage II-III). Post-operative ccfDNA was also collected from 11 of the patients within 100 days of surgery. ctDNA detection was restricted to variants corresponding to pathogenic mutations in PDAC present in both replicates. PDAC-associated pathogenic mutations were detected in pre-operative ccfDNA in four genes (KRAS, TP53, SMAD4, ALK) from five patients. Of the nine ctDNA variants detected (variant allele frequency: 0.08%-1.59%), five had a corresponding mutation in tumor DNA. Pre-operative detection of ctDNA was associated with shorter survival (312 vs. 826 days; χ 2 =5.4, P = 0.021). Guiding ctDNA detection in pre-operative ccfDNA based on mutations present in tumor DNA yielded a similar survival analysis. Detection of ctDNA in the post-operative ccfDNA with or without tumor-informed guidance was not associated with outcomes. Therefore, the detection of PDAC-derived ctDNA during a broad and untargeted survey of ccfDNA with NGS may be a valuable, non-invasive, prognostic biomarker to integrate into the clinical assessment and management of patients prior to surgery.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months.METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812.FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups.INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale.FUNDING: Fonds NutsOhra.

Background Routine maternal immunisation against influenza and pertussis are recommended by the WHO to protect mother and child, and new vaccines are under development. Introducing maternal vaccines into national programmes requires an understanding of vaccine delivery costs – particularly in low resource settings. Methods We searched Medline, Embase, Econlit, and Global Health for studies reporting costs of delivering vaccination during pregnancy but excluded studies that did not separate the vaccine purchase price. Extracted costs were inflated and converted to 2018 US dollars. Results Sixteen studies were included, of which two used primary data to estimate vaccine delivery costs. Costs per dose ranged from $0.55 to $0.64 in low-income countries, from $1.25 to $6.55 for middle-income countries, and from $5.76 to $39.87 in high-income countries. Conclusions More research is needed on the costs of delivering maternal immunisation during pregnancy, and of integrating vaccine delivery into existing programmes of antenatal care especially in low and middle-income countries.

Background: Despite recommendations from the American Academy of Pediatrics (AAP) regarding infant safe sleep practices, 39% of sleep-related infant deaths (SRID) occur among African American (AA) families each year. Effective interventions that promote AA parents/caregivers’ safe sleep practices for infants could help reduce SRID. Objective: To identify appropriate safe sleep interventions that increased compliance of AAP recommendations to reduce the risk of SRID among AA mothers/caregivers, a literature review was conducted. Methods: PubMed, EBSCOhost, and Google Scholar search engines were utilized to identify evidence-based research studies, published in English from 2000-2019 in the U.S that demonstrated the effectiveness of safe sleep interventions for AA parents/caregivers based on the AAP recommendations. Findings: The literature review revealed that multiple-element interventions such as free cribs and related materials, and safe sleep education increased adherence to AAP recommendations as evidenced by the majority mothers using the crib and adopting safe sleep recommendations. Conclusion and Recommendations: Although multiple interventions including education are valuable, culturally appropriate research is needed to better understand what specific intervention(s) will work to increase adherence to the AAP safe sleep recommendations among the remaining 39% of AA parents/caregivers who contribute disproportionately to the SRID disparity. Behavioral and environmental barriers preventing the adoption of safe sleep interventions also need to be studied in this target group of AA parents/caregivers. It is recommended that findings from these highly targeted evidence-based culturally appropriate studies be used to focus on funding, prevention programming, and policies toward the causes of SRID to close the disparity gap.

Background Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. Methods An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. Results In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17–.28 and OR, 0.12; 95% CI, .08–.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. Conclusions Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P 10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.

Introduction Patients with chronic kidney disease (CKD)/end stage renal disease (ESRD) can experience several severe complications, including acute coronary syndrome (ACS). While troponin is the biomarker of choice for evaluation of ACS, interpretation of troponin in CKD/ESRD can be challenging. Objective This narrative review evaluates troponin elevation in patients with CKD/ESRD, pitfalls in the evaluation with troponin, and an approach to using troponin in these high-risk patients. Discussion Patients with CKD/ESRD are at greater risk for ACS and possess higher levels of circulating troponin. Relatedly, these patients often present atypically for ACS. Several pitfalls must be considered in the use of troponin when evaluating for ACS. While troponin elevation in patients with CKD/ESRD is often considered to be due to underlying renal disease, this elevation has several etiologies including uremic skeletal myopathy, microinfarctions, left ventricular hypertrophy (LVH), decreased clearance, and unrecognized congestive heart failure (CHF). Utilizing troponin assays in this patient population requires a nuanced approach, as the sensitivity and specificity for troponin testing in CKD varies. Concern for ACS with elevated troponin warrants treatment for ACS until proven otherwise, with consideration of atypical presentations along with other causes for patient symptoms that may result in troponin elevation. Conclusions Patients with CKD/ESRD presenting with symptoms concerning for ACS are challenging. The utilization of troponin assays is important in this population given their high risk of ACS but requires an educated and nuanced approach.

Background Male infants have a higher incidence of invasive group B Streptococcus disease (iGBS) compared with female infants; however, data on sex differences in mortality and long-term outcomes after iGBS are lacking. We assessed whether a child’s sex influences the effects of iGBS on mortality and risk of neurodevelopmental impairments (NDIs). Methods We used Danish and Dutch registry data to conduct a nationwide cohort study of infants with a history of iGBS. A comparison cohort, children without a history of iGBS, was randomly selected and matched on relevant factors. Effect modification by sex was assessed on additive and multiplicative scales. Results Our analyses included data from children with a history of iGBS in Denmark (period 1997 -2017; n = 1432) and the Netherlands (2000 -2017; n = 697) and from 21 172 children without iGBS. There was no clear evidence of between-sex heterogeneity in iGBS-associated mortality. Boys had a higher risk of NDI, with evidence for effect modification on additive scale at the age of 5 years for any NDI (relative excess risk due to interaction = 1.28; 95% confidence interval [CI], -0.53 to 3.09 in Denmark and 1.14; 95% CI, -5.13 to 7.41 in the Netherlands). A similar pattern was observed for moderate/severe NDI at age 5 years in Denmark and age 10 years in the Netherlands. Conclusion Boys are at higher risk of NDI ; our results suggest this is disproportionally increased in those who develop iGBS. Future studies should investigate mechanisms of this effect modification by sex.

Background Preterm birth and neonatal infections are both associated with mortality and long-term neurodevelopmental impairments (NDIs). We examined whether the effect of invasive group B Streptococcus disease (iGBS) on mortality and long-term NDI differs for preterm and term infants, and whether co-occurrence of iGBS and prematurity leads to worse outcome. Methods Nationwide cohort studies of children with a history of iGBS were conducted using Danish and Dutch medical databases. Comparison cohorts of children without iGBS were matched on birth year/month, sex, and gestational age. Effects of iGBS on all-cause mortality and NDI were analyzed using Cox proportional hazards and logistic regression. Effect modification by prematurity was evaluated on additive and multiplicative scales. Results We identified 487 preterm and 1642 term children with a history of iGBS and 21 172 matched comparators. Dutch preterm children exposed to iGBS had the highest mortality rate by 3 months of age (671/1000 [95% CI, 412–929/1000] person-years). Approximately 30% of this mortality rate could be due to the common effect of iGBS and prematurity. Preterm children with iGBS had the highest NDI risk (8.8% in Denmark, 9.0% in the Netherlands). Of this NDI risk 36% (Denmark) and 60% (the Netherlands) might be due to the combined effect of iGBS and prematurity. Conclusions Prematurity is associated with iGBS development. Our study shows that it also negatively impacts outcomes of children who survive iGBS. Preterm infants would benefit from additional approaches to prevent maternal GBS colonization, as this decreases risk of both preterm birth and iGBS.

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

BACKGROUND The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE We sought to define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (n = 601), we assessed longitudinal sensitization, food allergy (FA), allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), Scoring for Atopic Dermatitis (SCORAD), transepidermal water loss, skin filaggrin (FLG) expression, exposures, and genetic heritability to define AD progression endotypes in Black and White children. RESULTS White MPAACH children were more likely to be sensitized to aero and food allergens (P = .0001) and over 3 times more likely to develop FA and/or allergic rhinitis (AR) without asthma risk (P < .0001). In contrast, Black children were over 6 times more likely to proceed to high asthma risk without FA, sensitization, or AR (P < .0001). White children had higher lesional and nonlesional transepidermal water loss (both P < .001) as well as decreased nonlesional keratinocyte FLG expression (P = .02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier and less sensitization, FA, and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR, and sensitization. The observed racial differences are likely due in part to increased genetic heritability for asthma risk and harmful environmental exposures in Black children. Collectively, our findings provide a new paradigm for an atopic march that is inclusive of Black children.

The Old Javanese Rāmāyaṇa Kakawin, the earliest known Javanese literary work, is based on the sixth-century Sanskrit Bhaṭṭikāvya. It is an outcome of a careful and thorough project of translation and adaptation that took place at a formative moment in the cultural exchange between South and Southeast Asia. In this essay we explore what it was that the Javanese poets set out to capture when they rendered the Bhaṭṭikāvya into Old Javanese, what sort of knowledge and protocols informed their work, in what way the outcome was different from the original, and what the Old Javanese Rāmāyaṇa can teach us about Bhaṭṭi’s poem and the nascent poetics of kakawin literature. In particular, we show how Sanskrit figures of speech, or ornaments (alaṃkāra) were understood, commented upon, expanded, and reconfigured. A close look at these texts allows us insights into this remarkable moment of cultural exchange.

Context Synthetic lifting media, OriseTM gel and Eleview®, are increasingly utilized in gastrointestinal endoscopy, but neither comparative features nor pitfalls are well-established. Objective Media histopathology, morphologic mimics, and complications are described, along with helpful stains and endoscopist media preference. Design A 3-year retrospective search was performed. Pan-mucin, amyloid, and infectious disease stains were performed. Endoscopist lifting media preferences were surveyed. Results 123 cases (108 endoscopies, 15 subsequent surgeries) were identified. Orise gel was used in 86 (79.6%), Eleview in 20 (13.9%), and others in 7 (6.5%). Orise gel was histologically identified in 58.1% (n=50) of endoscopic specimens and all 15 resections. Eleview media was not detected histologically. Orise gel mimicked mucin in H&E-stained biopsies, concerning for adenocarcinoma misdiagnosis and/or upstaging, but did not stain for mucin. Acid fast bacterial staining highlights Orise gel for specific and definitive identification. In resections, Orise evolves into an amorphous eosinophilic material, often with exuberant giant-cell reaction and transmural bowel penetration. Polyp formation lead to polypectomy in one patient, and operative lesions concerning for adenocarcinoma resulted in frozen sections in two patients. Orise gel mimics mucin, malignant masses, amyloid, pulse granulomata, elastofibromas, and infectious granulomata. No significant endoscopist media preference was identified. Conclusions Recognition of Orise gel in tissues eliminates multiple pitfalls. Eleview was not detectable, yielded none of the pitfalls seen with Orise gel, and on our survey, has equivalent endoscopist acceptance. In this largest published series to date, Eleview is clearly preferable to Orise gel.

Purpose: The desirability of evaluating transition programs is widely acknowledged. This study aimed to explore the added value of transitional care investments for young adults with type 1 diabetes mellitus. Design and methods: Based on qualitative data, two groups of diabetes teams were created through cluster analysis: paying more (HI-ATT) versus less attention (LO-ATT) to transitional care. Retrospective controlled evaluation included chart reviews on healthcare use and clinical outcomes; and a survey on young adults' experiences, satisfaction with care, and self-management skills. Results: Data from 320 patients in fifteen diabetes teams were collected; 123 young adults (38.4%) completed a questionnaire. Self-reported outcomes showed that young adults treated by a HI-ATT team felt better prepared for transfer (p < .05). Self-management outcomes did not differ between groups. HI-ATT teams had more scheduled consultations in the year after transfer (p < .05); only 10.6% of all measurements had reached targeted HbA1c scores. Conclusions: Current transitional care investments in Dutch diabetes care did not lead to notable improvements in experiences and outcomes, except for preparation for transfer. The period after transfer, however, is just as important. Attention is required for parent involvement. Practice implications: Transitional care investments should extend beyond the transfer. By educating young adults about the importance of regular clinic attendance and introducing additional person-centered consultations in adult care, nurses may help ensure continuity of care. Nurses could also introduce support programs for parents to prepare for the transition and their change in role, taking into account their continuing partnership.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (&lt, 50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.

Background The non-motor symptoms of Parkinson's disease (PD), pain, depression, anxiety and sleep disturbances are highly prevalent in persons with PD and have a profound impact on their quality of life (QOL). Catastrophizing is a negative coping style known to influence individuals' ability to cope with their medical symptoms and contributes to negative health-related outcomes, yet, it has not been studied in persons with PD. Objective The objectives of this study were to measure catastrophizing in PD and explore its role as a mediator of the relationship between non-motor symptoms and QOL. Methods One-hundred and three individuals diagnosed with PD completed questionnaires regarding pain catastrophizing, QOL and non-motor symptoms: pain, depression, anxiety and sleep disturbances. Results More than half of the sample exhibited high levels of pain, anxiety and sleep disturbances. Catastrophizing was significantly correlated with QOL and with all of the non-motor symptoms. Catastrophizing mediated the relationship between all of non-motor symptoms and QOL as well as the relationship between age and QOL. Conclusions Negative psychologic coping, specifically catastrophizing, has an important role in determining how destructive non-motor symptoms can be on the QOL of persons with PD. This is the first study to measure catastrophizing in this population and demonstrate its negative impact on QOL. Our findings emphasize the need to identify persons at risk for poor QOL and referrer them to appropriate psychological care. Evidence based interventions that target catastrophizing should be tested for their efficacy in persons with PD.

The construction of gearbox housings is severely restricted by all the currently used machining processes. 3D metal printing opens up new possibilities in this area. However, a clear additional benefit compared to the standard cast housing must be given, in order to make additive manufacturing viable. The objective of the present project was to research both the potential and restrictions of additive manufacturing technologies regarding the design of gearbox housings. As a result of this investigation, a topology optimized lightweight gearbox housing with integrated oil channels and scraper was obtained. The topology optimization process of the new gearbox was carried out in two work steps. The first consisted of the determination and design of the primary load-bearing structure of the housing. Therefore, an iterative design process was needed in order to develop the final support structure, because the topology optimization only provides a design draft of the framework structure. Concerning the iteration, an FEM analysis was performed to check and improve the draft after each loop. During the evaluation, safety and weight were compared with the previous version. During the second step of the topology optimization, the structure of all the oil channels was developed, creating a morphological box. Finally, the new gearbox housing was generated by combining the topology optimization with the concepts from the morphological box. Selective Laser Melting (SLM) was chosen for manufacturing because it allows the printing of components of the desired dimension with the required accuracy. The developed gearbox prototype was printed using the aluminum alloy AlSi10Mg (A360). Due to the flexibility of the SLM technology, it was possible to fulfill all specific design criteria while also showing the typical topology-optimized structure too. Afterwards, the housing was machined to achieve precise dimensions and tolerances. Finally, the gearbox was assembled, and both its mechanical integrity and the functionality of the integrated oil systems were fully checked with short-term tests.

The term dance encompasses a broad range of different styles; much of the orthopaedic literature has focused on ballet dancers. Injury is common in dancers at all levels, and many serious dancers sustain multiple injuries as they progress through their career. Foot and ankle injuries are among the most common injuries experienced by dancers. These injuries include those that are specific to dancers because of the unique physical maneuvers required to effectively perform, but they can also include common injuries that may require relatively different treatment because of the physical demands of the dancer. Os trigonum syndrome and flexor hallucis longus tenosynovitis generally fall into the former category as they are injuries that are more prevalent in dancers due to the extreme plantarflexion involved in dancing, especially ballet, and the relative demand placed on the toe flexors, most notably the flexor hallucis longus. On the other hand, anterior ankle impingement occurs both in dancers and in the general public. In many cases, a team approach to treatment with knowledgeable physical therapists can obviate the need for surgical treatment. If surgical treatment proves necessary, good results can be achieved with sound surgical technique and a well thought-out rehabilitation program.

Lethal organ donation is a hypothetical procedure in which vital organs are removed from living donors, resulting in their death. An important objection to lethal organ donation is that it would infringe the prohibition on doctors intentionally causing the death of patients. I present a series of arguments intended to undermine this objection. In a case of lethal organ donation, the donor’s death is merely foreseen, and not intended.

Unintended pregnancy and sexually transmitted infections (STIs) pose a huge public health problem in the United States. Efforts towards reducing unintended pregnancies have previously focused on women, but the role of men in family planning and preventing unwanted pregnancy is becoming clearer. The primary objective of the study was to fully examine the utilization of family planning services by men in the US, and to determine whether factors such as race, health insurance type and number of sexual partners influenced their utilization and receipt of family planning services and STI-related health services. Data were from the 2006–2010 National Survey on Family Growth (NSFG) study conducted in the US. The study sample comprised 7686 men aged 14–44 who ever had sex with women, and who had had at least one sexual partner in the 12 months before the survey. The receipt of family planning and STI-related health services by this group of men was estimated. The results showed that non-Hispanic Black men were more likely to receive family planning and STI-related services than Hispanic and non-Hispanic White males. Given that non-Hispanic Black men are disproportionately affected by STIs and are a high-risk group, the finding that this group received more family planning and STI services is a positive step towards reducing the disproportionately high prevalence of STIs in men in this under-privileged population.

We report an envenomation to a professional herpetologist by a South American rattlesnake (Crotalus durissus terrificus) that resulted in respiratory failure, and therapeutic improvement following antivenom administration. A 56-year-old male was bitten on the left wrist by a Crotalus durissus terrificus (C. d. terrificus) while attempting to tube the snake for maintaining safe control while performing venom extraction. The patient was intubated due to rapidly ensuing respiratory failure and administration of Antivipmyn-TRI® was initiated while being transported via ambulance. The patient was admitted to the hospital unconscious and unresponsive. Mechanical ventilation was required until 5 h after completion of antivenom administration. No significant adverse effects were observed with antivenom administration. The patient was discharged approximately 55 h following envenomation. This is the first reported case in the United States of a patient following a C. d. terrificus envenomation with consequent respiratory failure, and in which Antivipmyn-TRI® was successfully administered.

BACKGROUND: The Association of American Medical Colleges instituted a standardized video interview (SVI) for all applicants to emergency medicine (EM). It is unclear how the SVI affects a faculty reviewer's decision on likelihood to invite an applicant (LTI) for an interview. OBJECTIVES: The objective was to determine whether the SVI affects the LTI. METHODS: Nine Accreditation Council of Graduate Medication Education (ACGME)‐accredited EM residency programs participated in this prospective, observational study. LTI was defined on a 5‐point Likert scale as follows: 1 = definitely not invite, 2 = likely not invite, 3 = might invite, 4 = probably invite, 5 = definitely invite. LTI was recorded at three instances during each review: 1) after typical screening (blinded to the SVI), 2) after unblinding to the SVI score, and 3) after viewing the SVI video. RESULTS: Seventeen reviewers at nine ACGME‐accredited residency programs participated. We reviewed 2,219 applications representing 1,424 unique applicants. After unblinding the SVI score, LTI did not change in 2,065 (93.1%), increased in 85 (3.8%) and decreased in 69 (3.1%; p = 0.22). In subgroup analyses, the effect of the SVI on LTI was unchanged by United States Medical Licensing Examination score. However, when examining subgroups of SVI scores, the percentage of applicants in whom the SVI score changed the LTI was significantly different in those that scored in the lower and upper subgroups (p

Environmental exposures interplay with human host factors to promote the development and progression of allergic diseases. The worldwide prevalence of allergic disease is rising as a result of complex gene-environment interactions that shape the immune system and host response. Research shows an association between the rise of allergic diseases and increasingly modern Westernized lifestyles, which are characterized by increased urbanization, time spent indoors, and antibiotic usage. These environmental changes result in increased exposure to air and traffic pollution, fungi, infectious agents, tobacco smoke, and other early-life and lifelong risk factors for the development and exacerbation of asthma and allergic diseases. It is increasingly recognized that the timing, load, and route of allergen exposure affect allergic disease phenotypes and development. Still, our ability to prevent allergic diseases is hindered by gaps in understanding of the underlying mechanisms and interaction of environmental, viral, and allergen exposures with immune pathways that impact disease development. This Review highlights epidemiologic and mechanistic evidence linking environmental exposures to the development and exacerbation of allergic airway responses.

There are no outcomes measures that focus on the unique functional requirements of dancers.To evaluate test-retest reliability, internal consistency, construct validity, sensitivity, and responsiveness of the Dance Functional Outcome Survey (DFOS) in professional and preprofessional adult dancers.This prospective cohort study examined test-retest reliability of the DFOS in 198 healthy and injured dancers over 2 weeks, using intraclass correlation coefficients (ICCThe DFOS demonstrated high test-retest reliability (ICC≥0.93). Single-factor loading in exploratory factor analysis supported unidimensionality of the scale, with high internal consistency (α = .96). The DFOS total score and activities-of-daily-living (ADL) and dance technique subscores had strong construct validity compared with scores on the SF-36 physical component summary (r≥0.77). This study found excellent sensitivity, with high AUC values (AUC≥0.91). There were significant differences across time for DFOS scores (P.001), demonstrating responsiveness to change. There were no floor or ceiling effects.The DFOS demonstrates acceptable psychometric performance as an outcome and screening measure for dancers. The DFOS is a useful tool to monitor both healthy state and functional limitation following lower extremity or low back injury in adult ballet and modern dancers. J Orthop Sports Phys Ther 2019;49(2):64-79. Epub 27 Jul 2018. doi: 10.2519/jospt.2019.8247.

BACKGROUND: Group B Streptococcus (GBS) disease is a leading cause of neonatal death, but its long-term effects have not been studied after early childhood. The aim of this study was to assess long-term mortality, neurodevelopmental impairments (NDIs), and economic outcomes after infant invasive GBS (iGBS) disease up to adolescence in Denmark and the Netherlands.METHODS: For this cohort study, children with iGBS disease were identified in Denmark and the Netherlands using national medical and administrative databases and culture results that confirmed their diagnoses. Exposed children were defined as having a history of iGBS disease (sepsis, meningitis, or pneumonia) by the age of 89 days. For each exposed child, ten unexposed children were randomly selected and matched by sex, year and month of birth, and gestational age. Mortality data were analysed with the use of Cox proportional hazards models. NDI data up to adolescence were captured from discharge diagnoses in the National Patient Registry (Denmark) and special educational support records (the Netherlands). Health care use and household income were also compared between the exposed and unexposed cohorts.FINDINGS: 2258 children-1561 in Denmark (born from Jan 1, 1997 to Dec 31, 2017) and 697 in the Netherlands (born from Jan 1, 2000 to Dec 31, 2017)-were identified to have iGBS disease and followed up for a median of 14 years (IQR 7-18) in Denmark and 9 years (6-11) in the Netherlands. 366 children had meningitis, 1763 had sepsis, and 129 had pneumonia (in Denmark only). These children were matched with 22 462 children with no history of iGBS disease. iGBS meningitis was associated with an increased mortality at age 5 years (adjusted hazard ratio 4·08 [95% CI 1·78-9·35] for Denmark and 6·73 [3·76-12·06] for the Netherlands). Any iGBS disease was associated with an increased risk of NDI at 10 years of age, both in Denmark (risk ratio 1·77 [95% CI 1·44-2·18]) and the Netherlands (2·28 [1·64-3·17]). A history of iGBS disease was associated with more frequent outpatient clinic visits (incidence rate ratio 1·93 [95% CI 1·79-2·09], pINTERPRETATION: iGBS disease, especially meningitis, was associated with increased mortality and a higher risk of NDIs in later childhood. This previously unquantified burden underlines the case for a maternal GBS vaccine, and the need to track and provide care for affected survivors of iGBS disease.FUNDING: The Bill & Melinda Gates Foundation.TRANSLATIONS: For the Dutch and Danish translations of the abstract see Supplementary Materials section.

Background: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, R t, for the two incidence estimates. Findings: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the R t of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, R t fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation: The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding: Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society.

Background:Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 10% to 20% of children and between 2% and 15% of the adults in Western Europe. Since 2000 therapeutic clothing or functional textiles based on silver or chitosan as antibacterial agents were introduced for AD. These agents aim to reduce skin colonization with Staphylococcus (S.) aureus. Increased colonization with S. aureus is correlated with increased AD severity. The antimicrobial effects of silver and chitosan have been demonstrated before. At this point there is insufficient evidence for the effectiveness of antibacterial therapeutic clothing in patients with AD.Methods: This is a pragmatic randomized controlled double-blind multi-center trial comparing the effectiveness of antibacterial therapeutic clothing based on silver or chitosan as compared with non-antibacterial therapeutic clothing in patients with moderate to severe AD. A total of 165 participants, aged 0 to 80, diagnosed with moderate to severe AD are included. The study is performed in the Erasmus MC University Medical Center, University Medical Center Groningen, University Medical Center Utrecht, Amsterdam University Medical Centers and St. Antonius Hospital Nieuwegein. Patients will be randomized 1:1:1 into one of the three intervention groups: Group A will receive therapeutic clothing without antimicrobial agents, group B will receive microbial growth reducing therapeutic clothing based on chitosan, and group C will receive antimicrobial clothing based on silver. All therapeutic clothing is to be worn at night during the 12-month intervention period. Usual care is continued. The primary objective is to assess the effectiveness of antibacterial clothing (silver and chitosan group) as compared to non-antibacterial clothing assessed with the Eczema Area and Severity Index at 12 months compared to baseline. Secondary outcomes include between-group differences in physician and patient-reported outcome measures, topical therapy use, S. aureus skin colonization, and safety. Data will be collected at baseline, after 1 month, 3 months, 6 months an at 12 months. A cost-effectiveness analysis will be performed.Discussion:This trial will provide data on the effectiveness, cost-effectiveness, and safety of antibacterial therapeutic clothing for patients with AD. Trial registration Clinicaltrials.gov, NCT04297215. Registered on 5 March 2020

Summary Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7–9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1·4 (95% CI 0·6–3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13–24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products.

Background:After Alzheimer’s disease, Parkinson’ disease (PD) is the second most common age-related neurodegenerative disorder globally. Approximately 1 million individuals in the United States (US) have PD; every year 60,000 more Americans are diagnosed. PD is a movement disorder caused by dopamine insufficiency in the substantia nigra. The disease process is complicated by falls, constipation, dysphagia, insomnia, anxiety, depression, and behavioral/cognitive disorders. Upon diagnosis, evidence-based symptom management should include individualized nonpharmacologic and pharmacologic interventions along with lifestyle changes that will promote positive outcomes.More than 50% of persons diagnosed with PD develop psychotic symptoms. Parkinson’s disease psychosis (PDP) is a non-motor symptom and consists primarily of hallucinations and delusions. PDP is caused by neurotransmitter changes in the brain, some related to long-term use of parkinsonian medications. In many cases, PDP symptoms are mis-diagnosed as a chronic co-morbid condition, such as mild cognitive impairment or dementia.Symptoms run from benign to aggressive. Undiagnosed and untreated symptoms can accelerate. Delirium caused by medications or infections may contribute to psychosis. Rapid Eye Movement Sleep (REMS) Disorder associated with PD results in daytime sleepiness and acting out dreams. All symptoms profoundly impact formal and informal care partners. When underlying causes are identified by expert clinicians, symptoms may be reversible. There are many evidence-based paths to follow such as managing polypharmacy, appropriate prescribing patterns, and the effective use of nonpharmacologic interventions.Conclusion:During this symposium the complexities of the disease are addressed including the toll PDP can have on the person living with PD, their care partner(s) and the interdisciplinary health care team. It is imperative clinicians can simultaneously manage the overlapping motor symptoms and PDP to prevent physical and mental disabilities and improve quality of life. After attending this session, clinicians will be able to provide quality care to individuals living with PDP and their care partners.

As efforts to improve surveillance and decrease injury rates in pre-professional dancer's progress, it is important to identify injury patterns and contexts. The aim of this study was to examine sex, training-based injury characteristics, and external causal mechanisms of injury among pre-professional modern dancers. Using a prospective cohort study design, 180 dancers (females = 140, males = 40, age 18.15 ± 0.68 years) were screened at freshman enrollment and followed for the 4 years of their college training. Injury, defined as medical attention injury (MAI) or time-loss injury (TLI), was classified by diagnosis, tissue category, body region, and incident event (action and dance environment). Negative binomial log-linear analyses evaluated injury rates by sex and training year. Multinomial regression compared injury characteristics and incident events, p < 0.05. Sex characteristics differed in height, mass, years of dance training, and previous injury (p ≤ 0.037). Total, traumatic, and overuse injuries per 1,000 hours decreased across training years for both injury definitions, p < 0.001, with no sex differences. In year 1, dancers were more likely to sustain muscle, tendon, and bone injuries (p ≤ 0.008) and to injure leg, ankle, foot, and hip, thigh, and knee regions (p ≤ 0.001). Jumping and running was the most commonly cited action mechanism in MAI and TLI in both sexes. Females were more likely to report alignment in MAI and TLI and jumping and running in TLI. Males were 1.4 times more likely to sustain muscle or tendon MAI (p = 0.006), while reporting partnering in MAI. Ballet class and rehearsals accounted for the majority of attributed dance environment mechanisms in MAI and TLI. Injury rates in pre-professional modern dancers decreased with training. Understanding sex, training, and external causal mechanisms will allow teachers to tailor programs to reduce injuries during training.

Handheld dynamometry (HHD) using external fixation has demonstrated high inter- and intra-rater reliability. Handheld dynamometry offers an objective way to quantify strength; however, setting up external stabilization devices for HHD can be time consuming. This study examined the reliability of HHD for lower extremity strength in dancers using body weight stabilization. Twenty-six pre-professional dancers (age: 20.64 ± 2.21 years) were recruited and assessed by three testers: an experienced physical therapist (ePT), a novice physical therapist (nPT), and a student physical therapist (SPT). To avoid testing fatigue, dancers were divided into two testing groups and were evaluated on separate weekends. Testers used HHD to test isometric force production of six muscle groups in the first cohort and seven dif- ferent muscle groups in the second cohort. Testing positions were standardized and utilized a "make" test protocol. Intra- class correlation coefficients (ICC), 95% confidence interval, and standard error of measurement were calculated for each position. Inter-rater reliability was > 0.75 for all ICC measures except knee extension and ankle eversion. Intra-rater reliability was > 0.75 for all ICC measures except the ePT (tester A) day 2 for hip extension, internal rotation seated, knee extension, and ankle dorsiflexion; nPT (tester B) day 1 knee flexion; and SPT (tester C) for day 1 knee extension and ankle eversion and days 1 and 2 for ankle dorsiflexion and inversion. It is concluded that HHD can reliably measure force production of hip, knee, and ankle muscle groups without use of external fixation devices.

Background Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood. Patients and Methods We examined associations between Fn abundance and clinicopathologic characteristics among 105 treatment-naive CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in preoperative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption, and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models. Results Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n = 22) were 3-fold more likely to be diagnosed with rectal versus colon cancer (odds ratio [OR] = 3.01; 95% confidence interval [CI], 1.06-8.57; P = .04) after adjustment for patient sex, age, BMI, and study site. Patients with high Fn abundance also had a 5-fold increased risk of being diagnosed with rectal cancer versus right-sided colon cancer (OR = 5.32; 95% CI, 1.23-22.98; P = .03). There was no statistically significant association between Fn abundance and overall survival. Conclusion Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naive CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.

Background: Biobanks can accelerate research by providing researchers with samples and data. However, hospital-based recruitment as a source for controls may create bias as who comes to the hospital may be different from the broader population.Methods: In an effort to broadly improve the quality of research studies and reduce costs and challenges associated with recruitment and sample collection, a group of diverse researchers at Cincinnati Children's Hospital Medical Center led an institution-supported initiative to create a population representative pediatric “Greater Cincinnati Childhood Cohort (GCC).” Participants completed a detailed survey, underwent a brief physician-led physical exam, and provided blood, urine, and hair samples. DNA underwent high-throughput genotyping.Results: In total, 1,020 children ages 3–18 years living in the 7 county Greater Cincinnati Metropolitan region were recruited. Racial composition of the cohort was 84% non-Hispanic white, 15% non-Hispanic black, and 2% other race or Hispanic. Participants exhibited marked demographic and disease burden differences by race. Overall, the cohort was broadly used resulting in publications, grants and patents; yet, it did not meet the needs of all potential researchers.Conclusions: Learning from both the strengths and weaknesses, we propose leveraging a community-based participatory research framework for future broad use biobanking efforts.

Megatrends such as population growth, resource scarcity, and climate change drive and shape today’s businesses and society. For this reason, to achieve long-term business success, business leaders must keep a close eye on social and environmental dimensions in addition to the prerequisite of attaining adequate profits. This is especially true during times of major technological transformations. A fascinating breakthrough technology pushing such a transformation is artificial intelligence (AI). AI has great potential to make devices intelligent in the Internet of Things (IoT)—referred to as AIoT. In this chapter, we evaluate how a sustainable AIoT supports the three interrelated dimensions of profit, people, and planet.

Primaquine (PQ) is an antimalarial drug with the potential to reduce malaria transmission due to its capacity to clear mature Plasmodium falciparum gametocytes in the human host. However, the large-scale roll-out of PQ has to be counterbalanced by the additional risk of drug-induced hemolysis in individuals suffering from Glucose-6-phospate dehydrogenase (G6PD) deficiency, a genetic condition determined by polymorphisms on the X-linked G6PD gene. Most studies on G6PD deficiency and PQ-associated hemolysis focused on the G6PD A- variant, a combination of the two single nucleotide changes G202A (rs1050828) and A376G (rs1050829), although other polymorphisms may play a role. In this study, we tested the association of 20 G6PD single nucleotide polymorphisms (SNPs) with hemolysis measured seven days after low single dose of PQ given at the dose of 0.1 mg/kg to 0.75 mg/kg in 957 individuals from 6 previously published clinical trials investigating the safety and efficacy of this drug spanning five African countries. After adjusting for inter-study effects, age, gender, baseline hemoglobin level, PQ dose, and parasitemia at screening, our analysis showed putative association signals from the common G6PD mutation, A376G [−log10(p-value) = 2.44] and two less-known SNPs, rs2230037 [−log10(p-value] = 2.60), and rs28470352 [−log10(p-value) = 2.15]; A376G and rs2230037 were in very strong linkage disequilibrium with each other (R2 = 0.978). However, when the effects of these SNPs were included in the same regression model, the subsequent associations were in the borderline of statistical significance. In conclusion, whilst a role for the A- variant is well established, we did not observe an important additional role for other G6PD polymorphisms in determining post-treatment hemolysis in individuals treated with low single-dose PQ.

Platform companies like Airbnb, Amazon, or Google dominate our economy, and many more are on the rise to disrupt entire industries. In fact, eight of the ten most valuable companies worldwide follow a platform business model. Their success depends heavily on developing and sustaining network effects. This makes it almost inevitable for managers to analyze their own opportunities and risks in the platform economy. For traditional and product-focused companies, the Internet of Things has created new opportunities for platform business. In this article, we explain how the underlying platform mechanics work and bring together the perspectives of IoT, platform, and ecosystem. Using three successful but distinct IoT platform examples, we illustrate that platforms are not only for digital players and highlight key success factors for any practitioner looking to develop and manage an (IoT) platform.

Recent technological advances make it possible to connect almost any product, machine or device to the Internet. Specifically for manufacturing companies, this transition towards the Internet of things (IoT) opens up completely new business opportunities. However, most companies still struggle to monetize the IoT. Recent findings suggest that more than half of all IoT projects fail. In this article, we want to show how manufacturing companies can successfully leverage the IoT. More specifically, we elaborate on IoT platforms and their potential to create tangible business results, using the Bosch IoT Suite as an example. To illustrate this, we present six horizontal IoT use cases that have proven to be very successful across industry domains at Bosch and its customers.

­­Editorial: Natural Sciences is debuting“There’s a way to do it better – find it.” –Thomas A. EdisonWelcome to Wiley’s new flagship journal, Natural Sciences. Our aim is to meet the challenge of publishing top-tier papers in an open-science environment and thereby contribute to innovating the ways scientists communicate with one another and with society at large. We encourage you to partake in this transformative endeavor.Natural Sciences is an inter- and multidisciplinary journal that publishes outstanding research from the global community spanning biology, chemistry, and physics and their interfaces, as well as seminal works from related fields such as engineering and biomedical research. The journal’s aspiration is to promote the sharing and hybridization of disciplinary perspectives and thereby to foster crossing of the traditional boundaries that have previously separated disciplines. The journal will feature Research Articles of all lengths and formats, Commentaries, and Reviews, as well as Editorials, Highlights, Book Reviews, and News items.In contrast to many other high-ranking “elite” journals, Natural Sciences is run by practicing academic scientists who will treat submitted papers just like they wish their own papers would be treated – fairly, quickly, and without bias. That’s why our tagline readsA Journal of, by, and for scientists .By embracing open science, Natural Sciences will promote the global scientific community’s shared goal of enriching society with freely accessible prime scientific research. With open-science in general and open-access publishing in particular, the cost of scientific publishing will be carried by funding agencies or research institutions, and not the reader. Subscription-model-based academic publishing will be relegated to the sidelines, and scientific publications made freely accessible and re-usable for all.Moreover, Natural Sciences supports the cultural changes in the research community that call for increased transparency and openness in communicating and sharing the results of scientific research. Open science encompasses not only open-access publishing but also open peer review and sharing of primary scientific data. These, along with reviewer recognition, are key innovations effecting such a transformation and will be espoused by Natural Sciences .In developing the concept of Natural Sciences , we worked closely with Wiley to ensure efficient editorial practices. Wiley’s international network of experienced professionals steeped in scientific publishing are there for us 24/7. Together, we are committed to open-science publishing that is timely and rigorous – and to embracing open-science innovations in the process.The ideas and values that led us to envision Natural Sciences are summarized in our Manifesto [link to https://onlinelibrary.wiley.com/page/journal/26986248/homepage/manifesto].Natural Sciences is now open for submissions [link to https://mc.manuscriptcentral.com/naturalsciences]. The Article Processing Charge (APC) will be waived during the first two years.Looking forward to your submissions,Bretislav Friedrich, Executive EditorMarianne Bronner, Chief Biology EditorVivian Yam, Chief Chemistry EditorGerard Meijer, Chief Physics Editor [link all the names to https://onlinelibrary.wiley.com/page/journal/26986248/homepage/editorial-board]