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Multiple antiviral and monoclonal antibody therapies are now available for mild-moderate COVID-19 in high-risk patients ≥12 years of age. However, data for the use of these agents in children is limited. We reviewed 94 pediatric patients for whom early therapy was requested since the emergence of the Omicron variant and describe patient characteristics, treatment logistics and associated short-term events.

Diabetes and hyperglycaemia are associated with increased morbidity and large healthcare and economic costs.1 Glucocorticoid-induced diabetes and hyperglycaemia are common. Glucocorticoids are used widely to treat people with inflammatory and autoimmune conditions,2 malignancies3 and in hospitalised patients with COVID-19.4 In the United Kingdom (UK), among hospitalised patients, the prevalence of glucocorticoid use is 10% in all patients5 and 25–40% in those with diabetes.6 This is associated with adverse metabolic outcomes including impaired glycaemic control7 and can manifest as a new-onset diabetes (glucocorticoid-induced diabetes) or worsening hyperglycaemia in people with diabetes (glucocorticoid-induced hyperglycaemia). The hypothesised mechanism for glucocorticoid-induced diabetes and hyperglycaemia is reduced insulin sensitivity and increased gluconeogenesis. Approximately 2% of all newly diagnosed diabetes cases in the United Kingdom are related to glucocorticoid use over a mean duration of 8.9 (±1.7) years.8 A meta-analysis by Liu et al.9 demonstrated that the incidence of glucocorticoid-induced diabetes and hyperglycaemia is 18.6% and 32.3%, respectively, over the period of 1–12 months. Patients from the included studies were adults in outpatient and inpatient settings treated with systemic glucocorticoids for a variety of indications including haematological malignancies, rheumatoid arthritis, pemphigus, pemphigoid, systemic lupus erythematosus, respiratory and neurological conditions.9\ud \ud

Isolation of bacterial small colony variants (SCVs) from clinical specimens is not uncommon and can fundamentally change the outcome of the associated infections. Bacterial SCVs often emerge with their normal colony phenotype (NCV) co-isolates in the same sample. The basis of SCV emergence in vivo is not well understood in Gram-negative bacteria. In this study, we interrogated the causal genetic lesions of SCV growth in three pairs of NCV and SCV co-isolates of Escherichia coli, Citrobacter freundii, and Enterobacter hormaechei. We confirmed SCV emergence was attributed to limited genomic mutations: 4 single nucleotide variants in the E. coli SCV, 5 in C. freundii, and 8 in E. hormaechei. In addition, a 10.2 kb chromosomal segment containing 11 genes was deleted in the E. hormaechei SCV isolate. Each SCV had at least one coding change in a gene associated with bacterial oxidative respiration and another involved in iron capture. Chemical and genetic rescue confirmed defects in heme biosynthesis for E. coli and C. freundii and lipoic acid biosynthesis in E. hormaachei were responsible for the SCV phenotype. Prototrophic growth in all 3 SCV Enterobacteriaceae species was unaffected under anaerobic culture conditions in vitro, illustrating how SCVs may persist in vivo.

Detection of Covid-19 through a Citywide Surveillance Platform The Seattle Flu study, initiated in 2018, mailed kits for home collection of midnasal swabs to people reporting respiratory symptoms. ...

Children are strikingly underrepresented in COVID-19 case counts. In the United States, children represent 22% of the population but only 1.7% of confirmed SARS-CoV-2 cases as of April 2, 2020. One possibility is that symptom-based viral testing is less likely to identify infected children, since they often experience milder disease than adults. Here, to better assess the frequency of pediatric SARS-CoV-2 infection, we serologically screen 1,775 residual samples from Seattle Children’s Hospital collected from 1,076 children seeking medical care during March and April of 2020. Only one child was seropositive in March, but seven were seropositive in April for a period seroprevalence of ≈1%. Most seropositive children (6/8) were not suspected of having had COVID-19. The sera of seropositive children have neutralizing activity, including one that neutralized at a dilution > 1:18,000. Therefore, an increasing number of children seeking medical care were infected by SARS-CoV-2 during the early Seattle outbreak despite few positive viral tests., COVID-19 disease is less common in children than adults, but the extent to which SARS-CoV-2 infections are missed through symptom-driven testing is not well understood. In this study, the authors show that approximately 1% of children seeking care for reasons other than COVID-19 at a Seattle hospital in March/April 2020 were seropositive for SARS-CoV-2.

A series of unfortunate events The history of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread around the planet has been far from clear. Several narratives have been propagated by social media and, in some cases, national policies were forged in response. Now that many thousands of virus sequences are available, two studies analyzed some of the key early events in the spread of SARS-CoV-2. Bedford et al. found that the virus arrived in Washington state in late January or early February. The viral genome from the first case detected had mutations similar to those found in Chinese samples and rapidly spread and dominated subsequent undetected community transmission. The other viruses detected had origins in Europe. Worobey et al. found that early introductions into Germany and the west coast of the United States were extinguished by vigorous public health efforts, but these successes were largely unrecognized. Unfortunately, several major travel events occurred in February, including repatriations from China, with lax public health follow-up. Serial, independent introductions triggered the major outbreaks in the United States and Europe that still hold us in the grip of control measures. Science, this issue p. 571, p. 564, The first case of SARS-CoV-2 in Washington state occurred at the end of January and, by going undetected, sparked community transmission., After its emergence in Wuhan, China, in late November or early December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus rapidly spread globally. Genome sequencing of SARS-CoV-2 allows the reconstruction of its transmission history, although this is contingent on sampling. We analyzed 453 SARS-CoV-2 genomes collected between 20 February and 15 March 2020 from infected patients in Washington state in the United States. We find that most SARS-CoV-2 infections sampled during this time derive from a single introduction in late January or early February 2020, which subsequently spread locally before active community surveillance was implemented.

Fecal microbiota transplantation (FMT) is a safe and effective therapy for adults with recurrent Clostridium difficile colitis, but data regarding FMT in children are limited and focus on colonoscopic administration of FMT. We present 10 consecutive children who received FMT via nasogastric tube for treatment of recurrent C difficile infection. Median age was 5.4 years, and 30% were receiving simultaneous immunosuppression. Median follow-up was 44 days, and 90% of patients resolved their C difficile infection; one patient relapsed 2 months later after receiving antibiotics. FMT via nasogastric tube appears safe, well tolerated, and effective in treating pediatric recurrent C difficile colitis.

The objective of this study is to describe the epidemiology of intestinal carriage with extended-spectrum-cephalosporin-resistant Enterobacteriaceae in children with index infections with these organisms. Patients with resistant Escherichia coli or Klebsiella bacteria isolated from the urine or a normally sterile site between January 2006 and December 2010 were included in this study. Available infection and stool isolates underwent phenotypic and molecular characterization. Clinical data relevant to the infections were collected and analyzed. Overall, 105 patients were identified with 106 extended-spectrum-cephalosporin-resistant E. coli ( n = 92) or Klebsiella ( n = 14) strains isolated from urine or a sterile site. Among the 27 patients who also had stool screening for resistant Enterobacteriaceae , 17 (63%) had intestinal carriage lasting a median of 199 days (range, 62 to 1,576). There were no significant differences in demographic, clinical, and microbiological variables between those with and those without intestinal carriage. Eighteen (17%) patients had 37 subsequent resistant Enterobacteriaceae infections identified: 31 urine and 6 blood. In a multivariable analysis, antibiotic intake in the 91 days prior to subsequent urine culture was significantly associated with subsequent urinary tract infection with a resistant organism (hazard ratio, 14.3; 95% confidence interval [CI], 1.6 to 130.6). Intestinal carriage and reinfection were most commonly due to bacterial strains of the same sequence type and with the same resistance determinants as the index extended-spectrum-cephalosporin-resistant Enterobacteriaceae , but carriage and reinfection with different resistant Enterobacteriaceae strains also occurred.

Objective Type 2 diabetes is associated with increased fracture risk, further elevated by treatments such as thiazolidinediones and sodium-glucose co-transporter-2 inhibitors. As data regarding dipeptidyl peptidase-4 inhibitors are mixed, we examined fracture incidence in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Research Design and Methods We used data from 14,671 TECOS patients randomized double-blind to sitagliptin (n=7332) or placebo (n=7339). Cumulative fracture incidence rates were calculated and their association with study treatment assignment examined using multivariable Cox proportional hazards regression. Results Baseline mean (SD) age was 65.5 (8.0) years, diabetes duration 11.6 (8.1) years, HbA1c 7.2% (0.5%) (55.2 mmol/mol [5.5]), with 29.3% of participants women and 32.1% non-White. During 43,222 person-years’ follow-up, 375 (2.6%; 8.7 per 1000 person-years) had a fracture; 146 were major osteoporotic fractures (hip [n=34], upper extremity [n=81], and clinical spine [n=31]). Adjusted analyses showed fracture risk increased independently with older age (p Conclusion Fractures were common among TECOS patients with diabetes, but not related to sitagliptin therapy. Insulin and metformin treatment were associated with increased and decreased fracture risks, respectively.

Metformin is a safe, well-tolerated, inexpensive treatment that can be given in addition to current standard-of-care therapies for prostate cancer. Its use might mitigate the deleterious side effects of castration and exert an additional anticancer effect. It will be incorporated in the STAMPEDE trial platform in summer 2016. This will test its true utility as a repurposed treatment for men with high-risk locally advanced or metastatic prostate cancer at first presentation.

Multidrug-resistant (MDR) Enterobacteriaceae infections are associated with increased morbidity. We describe a 20-year-old hematopoietic cell transplantation recipient with recurrent MDR Klebsiella pneumoniae infection, prolonged intestinal colonization, and subsequent intestinal decontamination. Further study should evaluate stool surveillance, molecular typing, and fecal microbiota transplantation for patients with intestinal MDR Enterobacteriaceae carriage.

OBJECTIVE To identify risk factors for diabetic lower-extremity peripheral sensory neuropathy prospectively in a cohort of U.S. veterans with diabetes. RESEARCH DESIGN AND METHODS General medicine clinic outpatients with diabetes were followed prospectively for the development of insensitivity to the 5.07 monofilament on the foot. RESULTS Of 775 subjects, 388 (50%) had neuropathy at baseline. Of the 387 subjects without neuropathy at baseline, 288 were followed up, and of these, 58 (20%) developed neuropathy. Multivariate logistic regression modeling of prevalent neuropathy controlling for sex and race revealed independent and significant associations with age, duration of diabetes, glycohemoglobin level, height, history of lower-extremity ulceration, callus, and edema; an independent and inverse correlation was noted with ankle-arm index. Risk factors for incident neuropathy in multivariate logistic regression included age, baseline glycohemoglobin level, height, history of ulcer, and CAGE screening instrument alcohol score; current smoking and albumin level were inversely associated with risk. CONCLUSIONS Poorer glycemic control increases the risk of neuropathy and is amenable to intervention. Height and age directly increase risk of neuropathy and may help identify patients at risk. A proportion of neuropathy in diabetic veterans is probably due to or worsened by alcohol ingestion. Neuropathy was less common in current smokers than subjects not currently smoking.

What you need to know New evidence and developments regarding the management of blood glucose levels, antiplatelet therapy, and erectile dysfunction prompted this update of the 2009 guidance. There were safety concerns surrounding some blood glucose lowering medicines, new evidence on new dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, new indications and combinations for licensed drugs, and the potential impact of drugs coming off patent on health and economic issues. New evidence and safety issues relating to the off label use of antiplatelet therapy (aspirin and clopidogrel) in the primary prevention of cardiovascular disease were also considered. Type 2 diabetes affects 6% of the UK population1 and is commonly associated with obesity, physical inactivity, raised blood pressure, and disturbed blood lipid levels. It causes long term microvascular and macrovascular complications, plus reduced quality of life and life expectancy. The management of diabetes is complex and needs to address the prevention of cardiovascular disease and microvascular disease and the detection and management of early vascular complications. This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE),2 recently updated due to the availability of new evidence and developments. The article also summarises a selection of recommendations which still stand. #### What’s new in this guidance

Resistance to extended-spectrum β-lactams is increasing worldwide among Escherichia coli and has been linked to a small number of emergent clones (e.g. ST38, ST131 and ST405) recovered from extraintestinal infections in community and hospital settings. There are, however, limited data about the relative contributions of bacterial strains, plasmids and β-lactamase genes to extended-spectrum β-lactam resistance in paediatric infections. We performed an extensive molecular analysis of phylogenetic, virulence and antibiotic resistance-related properties of 49 previously reported serial E. coli isolates recovered during 1999–2007 at Seattle Children's Hospital (Seattle, WA). Class C enzyme CMY-2 and class A enzyme CTX-M-15 were the most prominent extended-spectrum β-lactam resistance enzymes in the collection, first appearing in this patient population in 2001 and 2003, respectively, and then steadily increasing in frequency over the remainder of the study period. Among 19 CMY-2-positive isolates, 16 distinct STs were detected ( D =98.25%, 95% CI 96–100.25%), indicating that CMY spread is non-clonal at the host strain level. In contrast, among ten CTX-M-15-positive isolates, three STs were detected ( D =37.78%, 95% CI 2.36–73.20%), of which eight represented the worldwide-disseminated ST131 lineage, consistent with clonal spread of CTX-M-15-associated resistance. fimH TR subtyping of ten ST131 isolates (including two CTX-M-negative isolates) revealed that, within ST131, carriage of allele fimH TR 30 correlated with CTX-M-15 positivity, whilst carriage of non- fimH TR 30 alleles correlated with carriage of non-CTX-M enzymes. Thus, spread of CMY-2 is non-clonal at the ST level, but clonal spread of CTX-M-15 may be associated with a specific fimH TR -defined sublineage of ST131.

randomized controlled trials to help determine if intensive blood glucose control has benefit in reducing the risk of congestive heart failure (CHF). The study revealed that there was no significant reduction in risk of CHF among individuals randomized to intensive versus standard blood glucose control groups. The authors rightly point out the presence of important heterogeneity among the trials with regard to the use of thiazolidinediones (TZDs). As expected, among the 4 trials that had a high rate of TZD use (ie, PROactive, ACCORD, VADT, and RECORD), the risk of CHF was elevated in individuals randomized to intensive blood glucose control. On the other hand, among the remaining 3 trials (ie, UKPDS, ADVANCE, and VA-CSDM), the risk ratio was close to null with a wide CI, highlighting the limitedness of the available data (risk ratio 0.96, 95% CI 0.81-1.13). We believe that combining these 2 groups of trials that are fundamentally different with respect to CHF outcomes can give the reader a false sense of adequate power because, in actuality, the 4 trials that used TZDs (agents known to cause heart failure) to lower blood glucose levels are confounded by the intervention itself and, hence, are not appropriate to answer the question whether intensive blood glucose control can reduce the risk of CHF. Therefore, although Castagno et al discussed the various aspects of the observed null finding, it would have been useful to point out that the most relevant data on the topic come from only 2 trials (ie, UKPDS and ADVANCE, not counting the pilot trial with a total of 9 events of interest) and are not sufficiently powered to

OBJECTIVE To examine the association of seal oil and salmon consumption with impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) among Alaska Natives. RESEARCH DESIGN AND METHODS Screening was performed on 666 Yup'ik Eskimos and Athabaskan Indians ≥40 years old in 15 villages. Self-administered questionnaires were used to obtain partial food frequency data. A case was defined as IGT or NIDDM, either newly discovered or known. Newly discovered cases (11 patients with NIDDM and 17 with IGT) were determined by random blood glucose testing followed by a 2-h 75-g oral glucose tolerance test (OGTT) for those with values ≥ 6.72 mmol/l or for subjects with unconfirmed histories of glucose intolerance. Known cases included 26 patients with NIDDM and 1 with IGT. Control subjects had random blood glucoses RESULTS Compared with less-than-daily consumption, both daily seal oil (odds ratio [OR] 0.2, 95% confidence interval [CI] 0.1–0.8) and daily salmon consumption (OR 0.5, CI 0.2–1.1) were associated with a lower prevalence of glucose intolerance, controlling for age, ethnicity, body mass index, and sex. The effects were similar when limited to newly discovered cases: OR 0.3, CI 0.1–1.3 for seal oil and OR 0.4, CI 0.1–1.3 for salmon. Consumption of seal oil at least five times per week was required to reduce risk. CONCLUSIONS Consumption of seal oil and salmon, high in ω-3 fatty acids, appears to lower the risk of glucose intolerance and is a potentially modifiable risk factor for NIDDM in Alaska Natives.