Acute bronchiolitis: The economic impact of non-compliance with national guidelines.

INTRODUCTION: Acute bronchiolitis is a common reason for admission to the pediatric emergency department. Evidence has shown that most interventions do not change the natural course of the disease. MATERIAL AND METHODS: This study aimed to evaluate the economic impact of the non-compliance with the acute bronchiolitis Portuguese national guideline. A retrospective study of pediatric emergency episodes of a Portuguese hospital that had a diagnosis of acute bronchiolitis during 2019, was conducted. RESULTS: The sample included 344 emergency episodes. Non-compliance with the guideline occurred in 71.8% of the episodes, mostly due to unjustified treatment. Following guideline in the studied hospital for one year would have resulted in an estimated overall 76.6% cost reduction, with a reduction in mean direct costs per patient of 14.93 €, corresponding to a medium saving of 3.89 € for each patient and a reduction of 11.03 € for the Portuguese National Health Service. Analyzing the unjustified mean direct costs, of these 2.97 € were related to inpatient diagnostic tests and therapeutic and the remaining 11.96 € were related to outpatient therapy. Mean direct costs imputed to the patient for outpatient treatment represented only 3.31 €, therefore most of mean direct costs is paid by the National Health Service. CONCLUSIONS: Compliance with guideline would allow the reduction of total estimated costs by about 76.6%, representing a waste of resources, without compromising the quality of care provided. Most of the cost associated with non-compliance with the guideline is justified by outpatient therapy, 67% of which was paid by the National Health Service.

In Bacterial Membranes Lipid II Changes the Stability of Pores Formed by the Antimicrobial Peptide Nisin.

Resistance to available antibiotics poses a growing challenge to modern medicine, as this often disallows infections to be controlled. This problem can only be alleviated by the development of new drugs. Nisin, a natural lantibiotic with broad antimicrobial activity, has shown promise as a potential candidate for combating antibiotic-resistant bacteria. However, nisin is poorly soluble and barely stable at physiological pH, which despite attempts to address these issues through mutant design has restricted its use as an antibacterial drug. Therefore, gaining a deeper understanding of the antimicrobial effectiveness, which relies in part on its ability to form pores, is crucial for finding innovative ways to manage infections caused by resistant bacteria. Using large-scale molecular dynamics simulations, we find that the bacterial membrane-specific lipid II increases the stability of pores formed by nisin and that the interplay of nisin and lipid II reduces the overall integrity of bacterial membranes by changing the local thickness and viscosity.

Immune Control in Repeated Babesia microti Infection in a Patient With B-Cell Deficiency.

The immunology of human babesiosis is poorly investigated. We present a comprehensive investigation of a 75-year-old man with B-cell deficiency who experienced 3 episodes of babesiosis over a 6-year period. Slowly evolving clinical immunity was observed, as evidenced by milder clinical symptoms and lower peak parasite burden after each subsequent babesiosis episode. The patient exhibited several striking immunologic findings. First, the patient had exceptionally high Babesia microti-specific antibodies despite very few circulating B cells, which predominantly coexpressed CD27 (memory marker) and CD95 (death receptor). Second, we demonstrated the presence of long-lasting NK cells and expansion of T memory stem cells. Third, levels of the IP-10 cytokine directly correlated with parasite burden. These results raise fundamental questions on the priming, maintenance, and location of a B-cell population that produces high antibody levels in the face of severe B-cell deficiency. Our results should invoke interest among researchers to study the immunology and pathogenesis of human babesiosis.

More problems, more money: Identifying and predicting high-cost rescue after colorectal surgery.

Background: Successful rescue after elective surgery is associated with increased healthcare costs, but costs vary widely. Treating all rescue events the same may overlook targeted opportunities for improvement. The purpose of this study was to predict high-cost rescue after elective colorectal surgery. Methods: We identified adult patients in the National Inpatient Sample (2016-2021) who underwent elective colectomy or proctectomy. Rescued patients were defined as those who underwent additional major procedures. Three groups were stratified: 1) uneventful recovery; 2) Low-cost rescue; 3) High-cost rescue. Multivariable Poisson regression was used to identify preoperative clinical predictors of high-cost versus low-cost rescue. Results: We identified 448,590 elective surgeries, and rescued patients composed 4.8 %(21,635) of the total sample. The median increase in costs in rescued patients was $25,544(p < 0.001). Median total inpatient costs were $95,926 in the most expensive rescued versus $34,811 in the less expensive rescued versus $16,751 in the uneventfully discharged(p < 0.001). When comparing the secondary procedures between the less expensive and most expensive rescued groups, the most expensive had an increased proportion of reoperation (73.4 % versus 53.0 %,p < 0.001). When controlling for other factors and stratification by congestive heart failure due to an interaction effect, a reoperation was independently associated with high-cost rescue (RR with CHF = 3.29,95%CI:2.69-4.04; RR without CHF = 2.29,95%CI:1.97-2.67). Conclusions: High-cost rescue after colorectal surgery is associated with disproportionately greater healthcare utilization and reoperation. For cost-conscious care, preemptive strategies that reduce reoperation-related complications can be prioritized.

Critical elements of synthesis questions are incompletely reported: survey of systematic reviews of intervention effects.

OBJECTIVES: To examine the characteristics of population, intervention and outcome groups and the extent to which they were completely reported for each synthesis in a sample of systematic reviews (SRs) of interventions. STUDY DESIGN AND SETTING: We coded groups that were intended (or used) for comparisons in 100 randomly sampled SRs of public health and health systems interventions published in 2018 from the Health Evidence and Health Systems Evidence databases. RESULTS: Authors commonly used population, intervention and outcome groups to structure comparisons, but these groups were often incompletely reported. For example, of 41 SRs that identified and/or used intervention groups for comparisons, 29 (71%) identified the groups in their methods description before reporting of the results (e.g., in the Background or Methods), 12 (29%) defined the groups in enough detail to replicate decisions about which included studies were eligible for each synthesis, 6 (15%) provided a rationale, and 24 (59%) stated that the groups would be used for comparisons. Sixteen (39%) SRs used intervention groups in their synthesis without any mention in the methods. Reporting for population, outcome and methodological groups was similarly incomplete. CONCLUSION: Complete reporting of the groups used for synthesis would improve transparency and replicability of reviews, and help ensure that the synthesis is not driven by what is reported in the included studies. Although concerted effort is needed to improve reporting, this should lead to more focused and useful reviews for decision-makers.

ß-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner.

Inositol pyrophosphates (PP-InsPs) are energetic signaling molecules with important functions in mammals. As their biosynthesis depends on ATP concentration, PP-InsPs are tightly connected to cellular energy homeostasis. Consequently, an increasing number of studies involve PP-InsPs in metabolic disorders, such as type 2 diabetes, aspects of tumorigenesis, and hyperphosphatemia. Research conducted in yeast suggests that the PP-InsP pathway is activated in response to reactive oxygen species (ROS). However, the precise modulation of PP-InsPs during cellular ROS signaling is unknown. Here, we report how mammalian PP-InsP levels are changing during exposure to exogenous (H2O2) and endogenous ROS. Using capillary electrophoresis electrospray ionization mass spectrometry (CE-ESI-MS), we found that PP-InsP levels decrease upon exposure to oxidative stressors in HCT116 cells. Application of quinone drugs, particularly ß-lapachone (ß-lap), under normoxic and hypoxic conditions enabled us to produce ROS in cellulo and to show that ß-lap treatment caused PP-InsP changes that are oxygen-dependent. Experiments in MDA-MB-231 breast cancer cells deficient of NAD(P)H:quinone oxidoreductase-1 (NQO1) demonstrated that ß-lap requires NQO1 bioactivation to regulate the cellular metabolism of PP-InsPs. Critically, significant reductions in cellular ATP concentrations were not directly mirrored in reduced PP-InsP levels as shown in NQO1-deficient MDA-MB-231 cells treated with ß-lap. The data presented here unveil unique aspects of ß-lap pharmacology and its impact on PP-InsP levels. The identification of different quinone drugs as modulators of PP-InsP synthesis will allow the overall impact on cellular function of such drugs to be better appreciated.

Diverticulitis in Older Adults: Is Cognitive Impairment Associated With Outcomes?

INTRODUCTION: Older age is associated with increased prevalence of both diverticulitis and cognitive impairment. The association between cognitive impairment and outcomes among older adults presenting to the emergency department (ED) for diverticulitis is unknown. METHODS: Adults aged ≥65 y presenting to an ED with a primary diagnosis of colonic diverticulitis were identified using the Nationwide Emergency Department Sample (2016-2019) and stratified by cognitive impairment status in this retrospective cohort study. Multivariable Poisson regression models adjusted for patient age, sex, Elixhauser Comorbidity Index, primary payer status, and presence of complicated diverticulitis quantified relative risk of a) inpatient admission, b) operative intervention, and c) in-hospital mortality comparing patients with or without a diagnosis code suggestive of cognitive impairment. RESULTS: Among 683,444 older adults with an ED encounter for diverticulitis from 2016 to 2019, there were 468,226 patients with isolated colonic diverticulitis and 26,388 (5.6%) with comorbid cognitive impairment. After adjustment, the risk of inpatient admission for those with cognitive impairment was 18% higher than for those without cognitive impairment (adjusted relative risks [aRR]: 1.18, 95% confidence interval [CI]: 1.17-1.20). Those with cognitive impairment were 34% more likely to undergo colectomy than those without cognitive impairment (aRR: 1.34, 95% CI: 1.24-1.44). Older adults with cognitive impairment had a 32% greater mortality than those without cognitive impairment (aRR: 1.32, 95% CI: 1.05-1.67). CONCLUSIONS: Among older adults presenting for ED care with a primary diagnosis of colonic diverticulitis, individuals with cognitive impairment had higher rates of hospitalization, operative intervention, and in-hospital mortality than those without cognitive impairment.

Animal performance and meat quality characteristics from feedlot-finished steers fed increasing levels of wet distillers grain.

One hundred forty-four steers were group-housed in 24 pens that were randomly assigned to one of four dietary treatments defined by the proportion of wet distiller grain plus solubles (WDGS; 0, 15, 30, or 45%) and fed for 84 d pre-slaughter. Animal performance was evaluated using the pen as the experimental unit. Whereas for carcass and meat quality characteristics, meat oxidative stability, and the consumer sensory quality of longissimus thoracis muscle one animal from each pen was randomly selected and used as the experimental unit. No differences (P > 0.05) were observed for subcutaneous fat thickness, rib eye area, marbling score or pH, color parameters, proximate composition, sarcomere length, Warner Bratzler shear force, and cooking loss. Feeding WDGS linearly increased total PUFA (P = 0.05), C18:2 n-6 (P = 0.004) proportions, and n-6/n-3 ratio (P < 0.01) but reduced C16:1 to C18:0 ratio (P < 0.01). Lipid oxidation was greater in beef from steers fed 30% and 45% WDGS (P = 0.05). Dietary WDGS linearly improved (P < 0.05) flavor and overall linking score in the consumer sensory panel.

Effect estimates can be accurately calculated with data digitally extracted from interrupted time series graphs.

Interrupted time series (ITS) studies are frequently used to examine the impact of population-level interventions or exposures. Systematic reviews with meta-analyses including ITS designs may inform public health and policy decision-making. Re-analysis of ITS may be required for inclusion in meta-analysis. While publications of ITS rarely provide raw data for re-analysis, graphs are often included, from which time series data can be digitally extracted. However, the accuracy of effect estimates calculated from data digitally extracted from ITS graphs is currently unknown. Forty-three ITS with available datasets and time series graphs were included. Time series data from each graph was extracted by four researchers using digital data extraction software. Data extraction errors were analysed. Segmented linear regression models were fitted to the extracted and provided datasets, from which estimates of immediate level and slope change (and associated statistics) were calculated and compared across the datasets. Although there were some data extraction errors of time points, primarily due to complications in the original graphs, they did not translate into important differences in estimates of interruption effects (and associated statistics). Using digital data extraction to obtain data from ITS graphs should be considered in reviews including ITS. Including these studies in meta-analyses, even with slight inaccuracy, is likely to outweigh the loss of information from non-inclusion.

Extubação paliativa em uma unidade de terapia intensiva cardiológica ­ um relato de caso / Palliative extubation in a cardiac intensive care unit ­ a case report

INTRODUÇÃO: A extubação paliativa é descrita como a retirada do tubo traqueal e da ventilação mecânica, quando todas as possibilidades de desmame ventilatório falharam ou o prognóstico do paciente é desfavorável. É um procedimento que evita prolongar a vida de maneira artificial e deve ser acordado juntamente com os familiares e a equipe. OBJETIVO: Relatar um caso de extubação paliativa numa unidade de terapia intensiva cardiológica. MÉTODO: Relato de caso RESULTADOS: Paciente do sexo feminino, portadora de Miocardiopatia Dilatada deu entrada no pronto-socorro em Insuficiência Cardíaca perfil C. Após a realização das medidas farmacológicas e o uso de ventilação não invasiva, não houve resposta satisfatória, evoluindo para intubação orotraqueal. A extubação ocorreu após 6 dias, porém em 24 horas houve falha de extubação, seguida de parada cardiorrespiratória (PCR) de 15 minutos. Foram realizadas todas as medidas pós PCR e mesmo a compensação clínica, não houve resposta neurológica favorável para progredir com uma nova extubação, desse modo, a equipe definiu os Cuidados Paliativos. O filho da paciente trouxe o relato de que ela não gostaria de viver de forma artificial e mesmo estando apreensivo com a possibilidade de óbito iminente após a extubação, visto que a mãe não tinha resposta favorável, ele não gostaria que mantivéssemos as medidas invasivas. Após uma conferência familiar com consenso entre a equipe e os familiares optou-se por realizar a extubação paliativa, para tal houve a suspensão de medicamentos não essenciais e foi otimizado as medicações para prevenir o estridor laríngeo. Para a extubação, foi realizado aspiração de alívio e o teste de respiração espontânea com resposta satisfatória e após 19 dias de intubação a paciente foi extubada, o procedimento ocorreu de maneira tranquila, não houve necessidade de aspiração ou suplementação com oxigênio, a paciente permaneceu com um Glasgow 6, eupneica em ar ambiente com uma fisionomia confortável, sem sinais de desconforto respiratório ou de dor. O atendimento fisioterapêutico foi mantido visando manter o conforto, a paciente teve o acompanhamento dos familiares com visita estendida e veio a falecer após 4 dias da extubação. CONCLUSÃO: A extubação paliativa ocorreu com o suporte da equipe e dos familiares, livre de dor ou desconforto e a paciente veio a falecer 4 dias após o procedimento. Esse relato de caso reforça a importância do alinhamento de condutas, da presença da família e a possibilidade de sobrevida após uma extubação paliativa.

Arterial Diameter and Percentage of Monocytes are Sex-Dependent Predictors of Early Arteriovenous Fistula Maturation.

BACKGROUND: Arteriovenous fistulae mature less frequently in women than in men, leading to inferior patency and decreased fistula utilization in women. We hypothesized that both anatomic and physiologic sex differences explain reduced maturation. METHODS: The electronic medical records of patients who had a primary arteriovenous fistula created from 2016 to 2021 at a single center were reviewed; sample size was determined using a power calculation. Postoperative ultrasound and laboratory tests were obtained at least 4 weeks after fistula creation. Primary unassisted fistula maturation was determined up to 4 years postprocedure. RESULTS: A total of 28 women and 28 men with a brachial-cephalic fistula were analyzed. The inflow brachial artery diameter was smaller in women than in men, both preoperatively (4.2 ± 0.9 vs. 4.9 ± 1.0 mm, P = 0.008) and postoperatively (4.8 ± 0.8 vs. 5.3 ± 0.9 mm, P = 0.039). Despite similar preoperative brachial artery peak systolic velocity, women had significantly lower postoperative arterial velocity (P = 0.027). Fistula flow was reduced in women, particularly in the midhumerus (747.0 ± 570.4 vs. 1,117.1 ± 471.3 cc/min, P = 0.003). Percentages of neutrophils and lymphocytes were similar among women and men 6 weeks after fistula creation. However, women had reduced monocytes (8.5 ± 2.0 vs. 10.0 ± 2.6%, P = 0.0168). Among 28 men, 24 of 28 (85.7%) achieved unassisted maturation, whereas only 15 of 28 (53.6%) women had fistulae that matured without intervention. Secondary analysis using logistic regression suggested that postoperative arterial diameter was associated with maturation in men, while postoperative monocyte percentage was associated with maturation in women. CONCLUSIONS: Sex differences during arteriovenous fistula maturation are present in arterial diameter and velocity, suggesting that both anatomic and physiologic differences in arterial inflow contribute to sex differences in fistula maturation. In men, postoperative arterial diameter is correlated with maturation, whereas in women, the significantly lower proportion of circulating monocytes suggests a role for the immune response in fistula maturation.

Effectiveness of social prescribing for chronic disease prevention in adults: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Social prescribing (SP) enables healthcare professionals to link patients with non-medical interventions available in the community to address underlying socioeconomic and behavioural determinants. We synthesised the evidence to understand the effectiveness of SP for chronic disease prevention. METHODS: A systematic literature search was conducted using five databases and two registries. Eligible studies included randomised controlled trials of SP among community-dwelling adults recruited from primary care or community setting, investigating any chronic disease risk factors defined by the WHO (behavioural factors: smoking, physical inactivity, unhealthy diet and excessive alcohol consumption; metabolic factors: raised blood pressure, overweight/obesity, hyperlipidaemia and hyperglycaemia). Random effect meta-analyses were performed at two time points: completion of intervention and follow-up after trial. RESULTS: We identified nine reports from eight trials totalling 4621 participants. All studies evaluated SP exercise interventions which were highly heterogeneous regarding the content, duration, frequency and length of follow-up. Majority of studies had some concerns for risk of bias. Meta-analysis revealed that SP likely increased physical activity (completion: mean difference (MD) 21 min/week, 95% CI 3 to 39, I2=0%; follow-up ≤12 months: MD 19 min/week, 95% CI 8 to 29, I2=0%). However, SP may not improve markers of adiposity, blood pressure, glucose and serum lipid. There were no eligible studies that primarily target unhealthy diet, smoking and excessive alcohol drinking behaviours. CONCLUSIONS: SP exercise interventions probably increased physical activity slightly; however, no benefits were observed for metabolic factors. Determining whether SP is effective in modifying the determinants of chronic diseases and promotes sustainable healthy behaviours is limited by the current evidence of quantification and uncertainty, warranting further rigorous studies. PROSPERO REGISTRATION NUMBER: CRD42022346687.

Palliative Care in a Pandemic: A Multicenter Cohort of Critically Ill Patients with Coronavirus Disease 2019.

Background: Trends in mortality, palliative care, and end-of-life care among critically ill patients with coronavirus disease 2019 (COVID-19) remain underreported. We hypothesized that use of palliative care and end-of-life care would increase over time, because improved understanding of the disease course and prognosis would potentially lead to more frequent use of these services. Patients and Methods: Adult patients with severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) during pandemic wave one (W1: March 2020 to September 2020) or wave two (W2: October 2020 to June 2021) admitted to an intensive care unit (ICU) in one of six northeastern U.S. hospitals were identified and clinical characteristics obtained. Vaccination data were unavailable. Outcomes of interest included mortality, palliative care consultation, and any end-of-life care (including hospice and comfort care). Results: There were 1,904 critically ill patients with COVID-19: 817 (42.9%) in W1 and 1,087 (57.1%) in W2. Patients received mechanical ventilation more often during W1 than W2 (52.9% vs. 46.3%; p = 0.004), with no difference in ICU or hospital length of stay between waves. Mortality between W1 and W2 was similar (31.2% vs. 30.9%; p = 0.888). There was no difference in use of palliative care or any end-of-life care between waves. Patients who died during W2 versus W1 were more likely to have received both mechanical ventilation (77.1% vs. 67.1%; p = 0.007) and palliative care services (52.1% vs. 41.2%; p = 0.009). However, logistic regression adjusted for demographics, baseline comorbid disease, and clinical characteristics showed no difference in mortality (odds ratio [OR], 1.15; 95% confidence interval [CI], 0.89-1.48), palliative care (OR, 1.08; 95% CI, 0.84-1.40), or any end-of-life care (OR, 1.05; 95% CI, 0.82-1.34) in W2 versus W1. Conclusions: Mortality among critically ill patients with COVID-19 has remained constant across two pandemic waves with no change in use of palliative or end-of-life care.

Synthesis methods other than meta-analysis were commonly used but seldom specified: survey of systematic reviews.

OBJECTIVES: To examine the specification and use of summary and statistical synthesis methods, focusing on synthesis methods other than meta-analysis. STUDY DESIGN AND SETTING: We coded the specification and use of summary and synthesis methods in 100 randomly sampled systematic reviews (SRs) of public health and health systems interventions published in 2018 from the Health Evidence and Health Systems Evidence databases. RESULTS: Sixty of the 100 SRs used other synthesis methods for some (27/100) or all syntheses (33/100). Of these, 54/60 used vote counting: three based on direction of effect, 36 on statistical significance, and 15 were unclear. Eight SRs summarized effect estimates (for example, using medians). Seventeen SRs used the term 'narrative synthesis' (or equivalent) without describing methods; in practice 15 of these used vote counting. 58/100 SRs used meta-analysis. In SRs providing a rationale for not proceeding with meta-analysis, the most common reason was due to diversity in study characteristics (33/39). CONCLUSION: Statistical synthesis methods other than meta-analysis are commonly used, but few SRs describe the methods. Improved description of methods is required to allow users to appropriately interpret findings, critique methods used and verify the results. Greater awareness of the serious limitations of vote counting based on statistical significance is required.

Transcriptional reprogramming restores UBE3A brain-wide and rescues behavioral phenotypes in an Angelman syndrome mouse model.

Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. The UBE3A gene is paternally imprinted in brain neurons. Clinical features of AS are primarily due to the loss of maternally expressed UBE3A in the brain. A healthy copy of paternal UBE3A is present in the brain but is silenced by a long non-coding antisense transcript (UBE3A-ATS). Here, we demonstrate that an artificial transcription factor (ATF-S1K) can silence Ube3a-ATS in an adult mouse model of Angelman syndrome (AS) and restore endogenous physiological expression of paternal Ube3a. A single injection of adeno-associated virus (AAV) expressing ATF-S1K (AAV-S1K) into the tail vein enabled whole-brain transduction and restored UBE3A protein in neurons to ∼25% of wild-type protein. The ATF-S1K treatment was highly specific to the target site with no detectable inflammatory response 5 weeks after AAV-S1K administration. AAV-S1K treatment of AS mice showed behavioral rescue in exploratory locomotion, a task involving gross and fine motor abilities, similar to low ambulation and velocity in AS patients. The specificity and tolerability of a single injection of AAV-S1K therapy for AS demonstrate the use of ATFs as a promising translational approach for AS.

Thermodynamic determination of RNA duplex stability in magnesium solutions.

The prediction of RNA secondary structure and thermodynamics from sequence relies on free energy minimization and nearest neighbor parameters. Currently, algorithms used to make these predictions are based on parameters from optical melting studies performed in 1 M NaCl. However, many physiological and biochemical buffers containing RNA include much lower concentrations of monovalent cations and the presence of divalent cations. In order to improve these algorithms, thermodynamic data was previously collected for RNA duplexes in solutions containing 71, 121, 221, and 621 mM Na+. From this data, correction factors for free energy (ΔG°37) and melting temperature (Tm) were derived. Despite these newly derived correction factors for sodium, the stabilizing effects of magnesium have been ignored. Here, the same RNA duplexes were melted in solutions containing 0.5, 1.5, 3.0, and 10.0 mM Mg2+ in the absence of monovalent cations. Correction factors for Tm and ΔG°37 were derived to scale the current parameters to a range of magnesium concentrations. The Tm correction factor predicts the melting temperature within 1.2°C, and the ΔG°37 correction factor predicts the free energy within 0.30 kcalmol. These newly derived magnesium correction factors can be incorporated into algorithms that predict RNA secondary structure and stability from sequence.