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Objectives: The aims of our study were to establish a reference interval for glycated albumin (GA) in gestational week 30, to investigate whether GA can replace or reduce the need for oral glucose tolerance test (OGTT) in pregnancy, and to reassess the usefulness of body mass-index (BMI), age and fasting glucose in detection of gestational diabetes (GDM). Design: and methods: We measured GA in 486 healthy pregnant women. Reference interval was calculated using the central 95 % of the results. ROC curves were created to assess the ability of GA, fasting glucose and BMI separately to detect GDM, and logistic regression analysis was used to estimate risk of developing GDM given the level of the same markers. Finally, multiple logistic regression analysis based on GA, fasting glucose and BMI was used to find a strategy of predicting a patient's risk of GDM. Results: The reference interval for GA at week 30 of gestation is 6.8–10.3 %. The analysis has a low AUC (0.53) with respect to detecting GDM. It increases slightly to 0.64 when corrected for BMI, as GA is inversely correlated to BMI. Combining GA with fasting glucose and BMI at gestational weeks 16–20 could raise the AUC to 0.80. Conclusion: GA cannot be recommended to replace OGTT for the diagnosis of GDM. Nor can it be used to identify women at risk of developing GDM. GA combined with fasting glucose and BMI in early pregnancy could be a useful model to estimate risk of GDM.

Introduction: Exposure to endocrine disruptors during early childhood poses significant health risks. This study examines the exposure levels of French 3.5-year-old children to various persistent and non-persistent pollutants and pesticides using hair analysis as part of the ELFE national birth cohort. Differences in sex and geographical location among the children were investigated as ppossible determinants of exposure. Methods: Exposure biomarkers from 32 chemical families were analyzed using LC-MS/MS and GC-MS/MS in 222 hair samples from children in the ELFE cohort. Of these, 46 mother–child pairs from the same cohort provided unique insight into prenatal and postnatal exposure. Regressions, correlations and discriminate analysis were used to assess relationships between exposure and possible confounding factors. Results and Discussion: Among the biomarkers tested in children’s hair samples, 69 had a detection frequency of ≥ 50 %, with 20 showing a 100 % detection rate. The most detected biomarkers belonged to the bisphenol, organochlorine and organophosphate families. Sex-specific differences were observed for 26 biomarkers, indicating the role of the child’s sex in exposure levels. Additionally, regional differences were noted, with Hexachlorobenzene varying significantly across the different French regions. Nicotine presented both the highest concentration (16 303 pg/mg) and highest median concentration (81 pg/mg) measured in the children’s hair. Statistically significant correlations between the levels of biomarkers found in the hair samples of the mothers and their respective children were observed for fipronil (correlation coefficient = 0.32, p = 0.03), fipronil sulfone (correlation coefficient = 0.34, p = 0.02) and azoxystrobin (correlation coefficient = 0.29, p = 0.05). Conclusions: The study highlights the elevated exposure levels of young children to various pollutants, highlighting the influence of sex and geography. Hair analysis emerges as a crucial tool for monitoring endocrine disruptors, offering insights into exposure risks and reinforcing the need for protective measures against these harmful substances.

While much of the studies within the Uses and Gratifications (U&G) tradition were set to predict facets of media use, the current study examines how use motivations, nature of platform use, and privacy-related perceptions predict users’ use continuance intentions for Facebook, Instagram, Twitter, and TikTok and their problematic use (i.e., addiction), simultaneously. The study uses a cross-sectional survey of undergraduate students at a large Midwestern University ( N = 685), where participants expressed their motivations to use each of the four platforms (depending on their active use of the platform), platform affinity and other usage factors, their intentions to continue using the platform, and their problematic use of the platform. Findings showed superiority of Instagram in terms of U&G. Regression models highlighted differences in the four platforms’ problematic use and continuance intentions. Findings are discussed within the framework of reconceptualizing U&G outcomes within the evolving social media environment.

Endometrial cancer (EC) is the most common gynecologic cancer in the United States. A majority of new cases are diagnosed as low-grade International Federation of Gynecology and Obstetrics (FIGO) Stage I, with a recurrence risk cited as less than 9 % in the first 2–3 years post-treatment. In this case series, we present three unique cases of patients with FIGO 2009 Stage I EC who all went on to present with pelvic colonic recurrences years after their initial treatment, two of the patients outside of the 5-year standard surveillance period. These presentations are described in the context of the available literature on EC colonic recurrence.A review of the literature suggests a previously cited association between endometriosis and unusual recurrence locations may not be as important of a risk factor as previously considered, as most of the cases in the series had no clinical or pathologic history of endometriosis. In addition, most of the included cases did not report a history of endometriosis and 60% of the cohort had received postoperative adjuvant radiation and still went on to experience locoregional recurrence. Further study on the associations between endometriosis, MMR status and EC recurrence, particularly for uncommon anatomic recurrence sites, are warranted to ensure appropriate and timely treatment.

Objective: This study sought to determine if patients with early stage cervical cancer who possessed intermediate-high risk factors (defined by Peters or Sedlis criteria) and had pathologically negative lymph nodes at the time of surgery had higher rates of low volume metastases (LVM) on retrospective ultrastaging. Methods: This IRB-approved retrospective cohort study collected data via chart review on early stage, surgically-treated node-negative cervical cancer patients who underwent postoperative adjuvant therapy, treated at a single institution from January 2011 through June 2021. Nodal blocks were retrospectively ultrastaged per standard protocol. Descriptive statistics were performed for analysis. Results: Over the 10-year study period, n = 20 patients met study inclusion criteria. Most patients were white with squamous cell histology, with a mean number of 25.15 (SD = 12) nodes examined on initial pathologic evaluation. 85 % (n = 17) patients were pathologic stage IB. 85 % of the cohort were recommended for adjuvant radiation, with the remaining 15 % for cisplatin-based chemoradiation. LVM in the form of micrometastasis was retrospectively identified in one patient (5 %) who had received whole pelvic radiation and recurred locally within the irradiated field. Conclusions: This small retrospective series of surgically managed cervical cancer with intermediate-high risk tumor factors identified only 1 patient with LVM, representing 5% of the total population. The biologic importance of ITC and LVM remains unclear in cervical cancer, however this investigation highlights the low incidence even when all nodes are evaluated in a higher risk cohort. The presence of LVM would not have changed management decisions based on this retrospective analysis.

Craniosynostosis (CS) or the premature fusion of one or more cranial sutures in utero, or during the first years of life, can present in isolation or as a multisystem clinical disorder with a particular impact on visual function. Among ophthalmic complications, optic neuropathy is a significant cause of irreversible vision loss in these patients. Children with CS are at higher risk of developing elevated intracranial pressure which can lead to papilledema and, ultimately, optic atrophy. In addition, sometimes associated obstructive sleep apnea, abnormalities in central nervous system venous development, and Chiari malformation may contribute to optic neuropathy. Ophthalmologists have an important role in managing a number of coexistent ophthalmologic complications such as strabismus, anisometropia, amblyopia, ptosis, and exposure keratopathy in addition to maintaining surveillance for early signs of optic neuropathy; they play a critical consultative role contributing to the decision for primary or repeat decompressive surgery. In this article, we aim to review the etiology, diagnostic approach, and management of optic neuropathies in patients with craniosynostosis.

Background: Heart failure (HF) is a debilitating and often fatal disease that affects millions of people worldwide. Diminished nitric oxide synthesis, signaling, and bioavailability are believed to contribute to poor skeletal muscle function and aerobic capacity. The aim of this clinical trial (iNIX-HF) is to determine the acute and longer-term effectiveness of inorganic nitrate supplementation on exercise performance in patients with HF with reduced ejection fraction (HFrEF). Methods: This clinical trial is a double-blind, placebo-controlled, randomized, parallel-arm design study in which patients with HFrEF (n = 75) are randomized to receive 10 mmol potassium nitrate (KNO3) or a placebo capsule daily for 6 wk. Primary outcome measures are muscle power determined by isokinetic dynamometry and peak aerobic capacity (VO2peak) determined during an incremental treadmill exercise test. Endpoints include the acute effects of a single dose of KNO3 and longer-term effects of 6 wk of KNO3. The study is adequately powered to detect expected increases in these outcomes at P 0.80. Discussion: The iNIX-HF phase II clinical trial will evaluate the effectiveness of inorganic nitrate supplements as a new treatment to ameliorate poor exercise capacity in HFrEF. This study also will provide critical preliminary data for a future ‘pivotal’, phase III, multi-center trial of the effectiveness of nitrate supplements not only for improving exercise performance, but also for improving symptoms and decreasing other major cardiovascular endpoints. The potential public health impact of identifying a new, relatively inexpensive, safe, and effective treatment that improves overall exercise performance in patients with HFrEF is significant.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC’s excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. Methods We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed. Results Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements. Conclusions Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

Background: Studies have demonstrated improved clinical outcomes with extended infusion (EI) piperacillin/tazobactam (TZP) compared to standard infusion (SI). However, there is less evidence on its benefits in noncritically-ill patients. Hospital-wide EI TZP was implemented at our site on February 21, 2012. Our objectives were to compare clinical, safety and economic outcomes between EI and SI TZP. Methods: A retrospective cohort study of all adult patients who received EI TZP (3.375 g IV q8h infused over 4 hours and SI TZP for ≥ 48 hours during 3 years pre-and postimplementation was conducted. The primary study outcome was 14-day mortality while secondary outcomes included length of hospital stay (LOS), nursing plus pharmacy cost, occurrence of Clostridioides difficile infection, readmission within 30 days and change in Pseudomonas aeruginosa minimum inhibitory concentration (MIC) distribution for TZP. The primary outcome and binary secondary outcomes were analyzed using a logistic regression model. LOS was examined using time to event analysis. Cost was examined using linear regression modelling. Results: Overall, 2034 patients received EI TZP and 1364 patients received SI TZP. EI TZP was associated with lower odds of mortality (OR 0.76, 95% CI 0.63–0.91), lower odds of C. difficile infection (OR 0.59, 95% CI 0.41–0.84) and 8% lower cost (estimate 0.92, 95% CI 0.87–0.98) compared to SI TZP. Conclusions: Hospital-wide implementation of EI TZP was associated with lower odds of 14-day mortality and incidence of C. difficile infection with cost savings at our institution.

Abstract Background To evaluate the effects of a shared decision making (SDM) intervention for older adults with multiple chronic conditions (MCCs). Methods A pragmatic trial evaluated the effects of the SDMMCC intervention, existing of SDM training for nine geriatricians in two hospitals and a preparatory tool for patients. A prospective pre-intervention post-intervention multi-center clinical study was conducted in which an usual care group of older patients with MCC and their informal caregivers was included before the implementation of the intervention and a new cohort of patients and informal caregivers after the implementation of the intervention. SDM was observed using the OPTIONMCC during video-recorded consultations. Patient- and caregivers reported outcomes regarding their role in SDM, involvement, perceived SDM and decisional conflict were measured. The differences between groups regarding the level of observed SDM (OPTIONMCC) were analyzed with a mixed model analysis. Dichotomous patient-reported outcomes were analyzed with a logistic mixed model. Results From two outpatient geriatric clinics 216 patients with MCCs participated. The mean age was 77.3 years, and 56.3% of patients were female. No significant difference was found in the overall level of SDM as measured with the OPTIONMCC or in patient-reported outcomes. However, at item level the items discussing ‘goals’, ‘options’, and ‘decision making’ significantly improved after the intervention. The items discussing ‘partnership’ and ‘evaluating the decision-making process’ showed a significant decrease. Fifty-two percent of the patients completed the preparatory tool, but the results were only discussed in 12% of the consultations. Conclusion This study provides scope for improvement of SDM in geriatrics. Engaging older adults with MCCs and informal caregivers in the decision making process should be an essential part of SDM training for geriatricians, beyond the SDM steps of explaining options, benefits and harms. More attention should be paid to the integration of preparatory work in the consultation.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Abstract Metabolic syndrome may contribute to the rising incidence of multiple gastrointestinal (GI) cancers in recent birth cohorts. However, other than hepatocellular carcinoma, the association between nonalcoholic fatty liver disease (NAFLD) and risk of non‐liver GI cancers is unexplored. We prospectively examined the associations of NAFLD risk with GI cancers among 319,290 participants in the UK Biobank (2006–2019). Baseline risk for NAFLD was estimated using the Dallas Steatosis Index, a validated prediction tool. Multivariable Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) according to NAFLD risk categories: low (

A challenge for central nervous system (CNS) tissue analysis in neuroscience research has been the difficulty to codetect and colocalize gene and protein expression in the same tissue. Given the importance of identifying gene expression relative to proteins of interest, for example, cell-type specific markers, we aimed to develop a protocol to optimize their codetection. RNAscope fluorescent in situ hybridization (FISH) combined with immunohistochemistry (IHC) in fixed (CNS) tissue sections allows for reliable quantification of gene transcripts of interest within IHC-labeled cells. This paper describes a new method for simultaneous visualization of FISH and IHC in thicker (14-μm), fixed tissue samples, using spinal cord sections. This method’s effectiveness is shown by the cell-type-specific quantification of two genes, namely the proinflammatory cytokine interleukin-1beta (IL-1b) and the inflammasome NLR family pyrin domain containing 3 (NLRP3). These genes are challenging to measure accurately using immunohistochemistry (IHC) due to the nonspecificity of available antibodies and the hard-to-distinguish, dot-like visualizations of the labeled proteins within the tissue. These measurements were carried out in spinal cord sections after unilateral chronic constriction injury of the sciatic nerve to induce neuroinflammation in the spinal cord. RNAscope is used to label transcripts of genes of interest and IHC is used to label cell-type specific antigens (IBA1 for microglia, NeuN for neurons). This combination allowed for labeled RNA transcripts to be quantified within cell-type specific boundaries using confocal microscopy and standard image analysis methods. This method makes it easy to answer empirical questions that are intractable with standard IHC or in situ hybridization alone. The method, which has been optimized for spinal cord tissue and to minimize tissue preparation time and costs, is described in detail from tissue collection to image analysis. Further, the relative expression changes in inflammatory genes NLRP3 and IL-1b in spinal cord microglia vs. neurons of somatotopically relevant laminae are described for the first time.

Abstract Background Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer’s disease (AD). Although the increased risk of AD in APOE ε4-carriers is well-established, the protein levels have received limited attention. Methods We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 39), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 30), patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and α-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6. Results Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE ε2/ε3 versus APOE ε4/ε4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-β (Aβ42) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF Aβ42, lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF α-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed. Conclusions Our results demonstrate important associations between low plasma apoE levels, Aβ pathology, and progression from aMCI to a clinical ADD diagnosis.

Brain organoids replicate cellular organization found in the developing human brain. Here, the authors utilize microelectronics to map activity in brain organoids and assemble functional circuits that mirror complexity found in brain networks in vivo.

Background:. Apert syndrome is characterized by eyelid dysmorphology, V-pattern strabismus, extraocular muscle excyclorotation, and elevated intracranial pressure (ICP). We compare eyelid characteristics, severity of V-pattern strabismus, rectus muscle excyclorotation, and ICP control in Apert syndrome patients initially treated by endoscopic strip craniectomy (ESC) at about 4 months of age versus fronto-orbital advancement (FOA) performed about 1 year of age. Methods:. Twenty-five patients treated at Boston Children’s Hospital met inclusion criteria for this retrospective cohort study. Primary outcomes were magnitude of palpebral fissure downslanting at 1, 3, and 5 years of age, severity of V-pattern strabismus, rectus muscle excyclorotation, and interventions to control ICP. Results:. Before craniofacial repair and through 1 year of age, none of the studied parameters differed for FOA versus ESC treated patients. Palpebral fissure downslanting became statistically greater for those treated by FOA by 3 (P < 0.001) and 5 years of age (P = 0.001). Likewise, severity of palpebral fissure downslanting correlated with severity of V-pattern strabismus at 3 (P = 0.004) and 5 (P = 0.002) years of age. Palpebral fissure downslanting and rectus muscle excyclorotation were typically coexistent (P = 0.053). Secondary interventions to control ICP were required in four of 14 patients treated by ESC (primarily FOA) and in two of 11 patients initially treated by FOA (primarily third ventriculostomy) (P = 0.661). Conclusions:. Apert patients initially treated by ESC had less severe palpebral fissure downslanting and V-pattern strabismus, normalizing their appearance. Thirty percent initially treated by ESC required secondary FOA to control ICP.

South Africa has taken an iterative approach to marine ecosystem mapping over 18 years that has provided a valuable foundation for ecosystem assessment, planning and decision-making, supporting improved ecosystem-based management and protection. Iterative progress has been made in overcoming challenges faced by developing countries, especially in the inaccessible marine realm. Our aim is to report on the approach to produce and improve a national marine ecosystem map to guide other countries facing similar challenges, and to illustrate the impact of even the simplest ecosystem map. South Africa has produced four map versions, from a rudimentary map of 34 biozones informed by bathymetry data, to the latest version comprising 163 ecosystem types informed by 83 environmental and biodiversity datasets that aligns with the IUCN Global Ecosystem Typology. Data were unlocked through academic and industry collaborations; multi-disciplinary, multi-realm and multi-generational networks of practitioners; and targeted research to address key gaps. To advance toward a more transparent, reproducible and data-driven approach, limitations, barriers and opportunities for improvement were identified. Challenges included limited human and data infrastructure capacity to collate, curate and assimilate many data sources, covering a variety of ecosystem components, methods and scales. Five key lessons that are of relevance for others working to advance ecosystem classification and mapping, were distilled. These include (1) the benefits of iterative improvement; (2) the value of fostering relationships among a co-ordinated network of practitioners including early-career researchers; (3) strategically prioritizing and leveraging resources to build and curate key foundational biodiversity datasets and understand drivers of biodiversity pattern; (4) the need for developing, transferring and applying capacity and tools that enhance data quality, analytical workflows and outputs; and (5) the application of new technology and emerging statistical tools to improve the classification and prediction of biodiversity pattern. South Africa’s map of marine ecosystem types has been successfully applied in spatial biodiversity assessment, prioritization to support protected area expansion and marine spatial planning. These successes demonstrate the value of a co-ordinated network of practitioners who continually build an evidence base and iteratively improve ecosystem mapping while simultaneously growing ecological knowledge and informing changing priorities and policy.

Introduction: This study presents data from 2 population-based surveys of youth (reservation-area American Indian adolescents and U.S. adolescents) on self, family, and friend morbidity and changes in substance use and negative impacts during COVID-19. Methods: Data were obtained in spring 2021 from surveys of American Indian students living on or near reservations (8th grade, n=398; 10th grade, n=367; 12th grade, n=290) and national students from Monitoring the Future (8th grade, n=11,446; 10th grade, n=11,792; 12th grade, n=9,022). The main outcomes were COVID-19 testing, perceived morbidity/mortality, substance-use changes, and emotional changes during COVID-19. Results: The American Indian sample had a greater proportion of testing (e.g., American Indian 8th grade: 58.1% [95% CI=48.6, 68.8]; Monitoring the Future 8th grade: 43.6% [95% CI=39.8, 47.5]) and friend/family hospitalization (e.g., American Indian 8th grade: 36.2% [95% CI=26.2, 47.5]; Monitoring the Future 8th grade: 11.9% [95% CI=10.6, 13.3]). Across grades, greater proportions of the national sample reported increased anxiety, anger, boredom, loneliness, depression, worry, and trouble concentrating, whereas greater proportions of reservation-area American Indians reported decreased anxiety, loneliness, and depression. Conclusions: Findings indicate that reservation-area American Indian youth experienced unique health consequences 1 year into the COVID-19 pandemic compared with national students, illustrating the need for American Indian‒specific COVID-19 public health monitoring and response.

Abstract Aim To explore the experiences of Registered Nurses who administered medications to patients using the electronic medication administration record (eMAR) in Electronic Record for Intensive Care (eRIC) at one adult intensive care unit (ICU) in NSW, Australia. Design The study research design used a qualitative descriptive exploratory approach that took place in two stages. Methods Five participants attended one focus group followed by the observation of each participant as medications were administered to their assigned patient using the eMAR in eRIC. Results From the data, three themes and one subtheme were identified. Themes included forcing nurses to work outside legal boundaries; patient safety; with a subtheme titled experiencing computer fatigue; and taking time away from the patient. To practise safely, nurses were required to implement workaround practices when using the new eMAR in ICU. Nurses also were concerned that the eMAR in eRIC took time away from the patient at the bedside and ‘added more screen time’ to their day.

Abstract Background A randomized, placebo-controlled clinical trial (FDREST) of a novel formulation of caraway oil and L-menthol (COLM-SST) demonstrated symptom relief in patients with functional dyspepsia (FD). Two follow-up studies were conducted to evaluate patient satisfaction, self-regulated dosing, and long-term safety data: FDACT, Functional Dyspepsia Adherence and Compliance Trial, and FDSU36, Functional Dyspepsia Safety Update at 36 months. Methods A patient reported outcomes (PRO) questionnaire was designed and distributed online to assess real-world satisfaction and dosing frequency of open-label COLM-SST in patients with FD. A separate study analyzing voluntary safety surveillance data evaluated the frequency and severity of reported adverse events (AEs). Results A total of 600 FD patients were enrolled in the PRO study. Ninety five percent of respondents reported a major or moderate improvement in their FD symptoms and 91.7% indicated a major or moderate improvement in quality of life (QOL) using COLM-SST. Between 1 and 4 capsules were consumed daily by 91.2% of respondents, with 56.2% taking them before meals. Symptom relief was rapid, with 86.4% of respondents indicating relief within 2 h of taking COLM-SST. Few adverse events (AEs) were reported (0.0187%) by patients using COLM-SST. No serious AEs were identified. Conclusion COLM-SST is safe, well tolerated, and provides rapid relief of FD symptoms. These findings, demonstrated in the FDREST trial, were further supported by a large prospective PRO study evaluating self-regulated dosing frequency, symptom improvement, and QOL. COLM-SST was well-tolerated based on review of AE data at 36 months.

Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.

Disturbances to forested watersheds often result in increases of nutrients and light to nearby streams. Such changes are generally expected to produce a shift to a more autotrophic aquatic ecosystem, with measurable increases in algae, and associated implications for food webs and fisheries. Although this paradigm is widely established, results from our 10-year study (2007-2016) in 12 headwater streams and four sites downstream in the Trask River Watershed (Oregon, USA), did not concur. In 2012, one watershed was thinned, three were clearcut harvested with variable buffers and three with uniform riparian buffers. After harvest, light to the stream surface significantly increased at the three watersheds with variable buffers while dissolved inorganic nitrogen (DIN) significantly increased in all of the clearcut harvested streams. Despite the increase in DIN and light, algal standing stocks and chlorophyll a concentrations did not significantly increase. The common assumption of increased autotrophic responses in stream food webs following increases of nitrogen and light was not supported here. We postulate the co-limitation of nutrients, driven by low phosphorus concentrations, which unlike DIN did not increase post-harvest, and the characteristics of the algal community, which were dominated by low light adapted diatoms rather than green algae, contributed to our findings of no responses for standing stocks of epilithic algae or concentrations of chlorophyll a. The inclusion of multiple statistical analyses provided more certainty around our findings. This study documents responses to current forest practices and provides cautionary information for management and restoration activities aiming to increase fish abundance and standing stocks by opening riparian canopies and adding nutrients.

Summary: Background: Traditional approaches for surgical site infection (SSI) surveillance have deficiencies that delay detection of SSI outbreaks and other clinically important increases in SSI rates. We investigated whether use of optimised statistical process control (SPC) methods and feedback for SSI surveillance would decrease rates of SSI in a network of US community hospitals. Methods: We conducted a stepped wedge cluster randomised trial of patients who underwent any of 13 types of common surgical procedures across 29 community hospitals in the Southeastern United States. We divided the 13 procedures into six clusters; a cluster of procedures at a single hospital was the unit of randomisation and analysis. In total, 105 clusters were randomised to 12 groups of 8–10 clusters. All participating clusters began the trial in a 12-month baseline period of control or “traditional” SSI surveillance, including prospective analysis of SSI rates and consultative support for SSI outbreaks and investigations. Thereafter, a group of clusters transitioned from control to intervention surveillance every three months until all clusters received the intervention. Electronic randomisation by the study statistician determined the sequence by which clusters crossed over from control to intervention surveillance. The intervention was the addition of weekly application of optimised SPC methods and feedback to existing traditional SSI surveillance methods. Epidemiologists were blinded to hospital identity and randomisation status while adjudicating SPC signals of increased SSI rates, but blinding was not possible during SSI investigations. The primary outcome was the overall SSI prevalence rate (PR=SSIs/100 procedures), evaluated via generalised estimating equations with a Poisson regression model. Secondary outcomes compared traditional and optimised SPC signals that identified SSI rate increases, including the number of formal SSI investigations generated and deficiencies identified in best practices for SSI prevention. This trial was registered at ClinicalTrials.gov, NCT03075813. Findings: Between Mar 1, 2016, and Feb 29, 2020, 204,233 unique patients underwent 237,704 surgical procedures. 148,365 procedures received traditional SSI surveillance and feedback alone, and 89,339 procedures additionally received the intervention of optimised SPC surveillance. The primary outcome of SSI was assessed for all procedures performed within participating clusters. SSIs occurred after 1171 procedures assigned control surveillance (prevalence rate [PR] 0.79 per 100 procedures), compared to 781 procedures that received the intervention (PR 0·87 per 100 procedures; model-based PR ratio 1.10, 95% CI 0.94–1.30, p=0.25). Traditional surveillance generated 24 formal SSI investigations that identified 120 SSIs with deficiencies in two or more perioperative best practices for SSI prevention. In comparison, optimised SPC surveillance generated 74 formal investigations that identified 458 SSIs with multiple best practice deficiencies. Interpretation: The addition of optimised SPC methods and feedback to traditional methods for SSI surveillance led to greater detection of important SSI rate increases and best practice deficiencies but did not decrease SSI rates. Additional research is needed to determine how to best utilise SPC methods and feedback to improve adherence to SSI quality measures and prevent SSIs. Funding: Agency for Healthcare Research and Quality.

Objective: At an academic institution in rural Virginia, we noticed a trend of increased re-admissions for postoperative pelvic abscesses. The primary study objective was to determine if intraoperative use of hemostatic agents (HA) was associated with postoperative abscess formation in patients undergoing hysterectomy. Methods: Retrospective chart review identified women who underwent hysterectomy by a Gynecologic Oncologist for any indication at a single institution from January 1, 2019 through December 31, 2019. Patient and surgical characteristics were abstracted and comparisons were made among those who received any HA and those that did not. The relationship between intraoperative HA use and postoperative pelvic abscess formation was determined using multivariate logistic regression. Secondary outcomes evaluated included the presence of other major post-operative adverse events. Results: 428 hysterectomies were identified with a postoperative pelvic abscess rate of 3.7 %. Abscesses were identified in 4 (2.2 %) of cases without vs 12 (4.9 %) of cases with HA use with a logistic regression model demonstrating no significant difference in the groups (OR = 2.10, p = 0.22). Data showed an increase in presentation to the Emergency Department (ED) (OR = 3.43, p = 0.002 adjusted) and higher odds of readmission within 30 days of surgery (OR = 3.19, p = 0.03) with HA use. Conclusions: No association was found between HA use and abscess formation; however, data showed HA use was associated with increased odds of presentation to the ED and readmission to the hospital within 30 days of surgery. Given the potential negative impact on patient outcomes, use of these products at time of hysterectomy should be made with careful consideration.

As freshwater environments become increasingly threatened, the need for efficient and effective protection grows more urgent. Yet quantitative evidence of management effectiveness within freshwater protected areas is limited, inhibiting our ability to infer the practicality and efficacy of practices. Herein, we employ linear mixed-effects models and time series models to evaluate the connection between catchment-scale management actions and surface water quality within a freshwater protected area, over the past three decades. Within the study area, all croplands were restored to traditional grasslands resulting in a landscape dominated by meadows and forests. The extent of land use change and time frame needed for water quality improvements were investigated and management effectiveness appraised. Results indicate that the complete grassing of croplands was approximately three times more effective at reducing concentrations of nitrate than electrical conductivity and calcium. Significant improvements in water quality occurred within nine years of management implementation, with mean annual nitrate concentrations decreasing from 5.5 to 1.9 mg/L following the grassing of all croplands covering 3.1% of the study area, whereas gradual improvements continued over the next 20 years, ultimately resulting in nitrate concentrations below 1.0 mg/L. The results of this study provide valuable insights on how land use conversions in small headwater catchments can influence stream water quality and helps to establish expectations for outcomes when planning conservation strategies.

Up to 92% of patients suffering from multiple sclerosis (MS) experience pain, most without adequate treatment, and many report pain long before motor symptoms associated with MS diagnosis. In the most commonly studied rodent model of MS, experimental autoimmune encephalomyelitis (EAE), motor impairments/disabilities caused by EAE can interfere with pain testing. In this study, we characterize a novel low-dose myelin-oligodendrocyte-glycoprotein (MOG)-induced Sprague-Dawley (SD) model of EAE-related pain in male rats, optimized to minimize motor impairments/disabilities. Adult male SD rats were treated with increasing doses of intradermal myelin-oligodendrocyte-glycoprotein (MOG1−125) (0, 4, 8, and 16 μg) in incomplete Freund's adjuvant (IFA) vehicle to induce mild EAE. Von Frey testing and motor assessments were conducted prior to EAE induction and then weekly thereafter to assess EAE-induced pain and motor impairment. Results from these studies demonstrated that doses of 8 and 16 μg MOG1−125 were sufficient to produce stable mechanical allodynia for up to 1 month in the absence of hindpaw motor impairments/disabilities. In the follow-up studies, these doses of MOG1−125, were administered to create allodynia in the absence of confounded motor impairments. Then, 2 weeks later, rats began daily subcutaneous injections of the Toll-like receptor 2 and 4 (TLR2–TLR4) antagonist (+)-naltrexone [(+)-NTX] or saline for an additional 13 days. We found that (+)-NTX also reverses EAE-induced mechanical allodynia in the MOG-induced SD rat model of EAE, supporting parallels between models, but now allowing a protracted timecourse to be examined completely free of motor confounds. Exploring further mechanisms, we demonstrated that both spinal NOD-like receptor protein 3 (NLRP3) and interleukin-17 (IL-17) are necessary for EAE-induced pain, as intrathecal injections of NLRP3 antagonist MCC950 and IL-17 neutralizing antibody both acutely reversed EAE-induced pain. Finally, we show that spinal glial immunoreactivity induced by EAE is reversed by (+)-NTX, and that spinal demyelination correlates with the severity of motor impairments/disabilities. These findings characterize an optimized MOG-induced SD rat model of EAE for the study of pain with minimal motor impairments/disabilities. Finally, these studies support the role of TLR2–TLR4 antagonists as a potential treatment for MS-related pain and other pain and inflammatory-related disorders.

Introduction Given that exercise training reduces the risk of developing Alzheimer’s disease (AD), induces changes in the blood composition and has widespread systemic benefits, it is reasonable to hypothesise that exercised plasma (ExPlas) may have rejuvenative properties. The main objective is to test safety and tolerability of transfusing ExPlas from young, healthy, fit adults to patients with mild cognitive impairment (MCI) or early AD. The study is a pilot for a future efficacy study. The key secondary objectives are examining the effect of plasma transfusions on cognitive function, fitness level, vascular risk profile, assessment of cerebral blood flow and hippocampal volume, quality of life, functional connectivity assessed by resting state functional MRI and biomarkers in blood and cerebrospinal fluid.Methods and analysis ExPlas is a double-blinded, randomised controlled clinical single-centre trial. Patients up to 75 years of age with diagnosis early symptomatic phase AD will be recruited from two Norwegian hospitals. ExPlas is plasma drawn by plasmapheresis once a month for 4 months, from a total of 30 fit male donors (aged 18–40, BMI≤27 kg/m2 and maximal oxygen uptake>55 mL/kg/min). All units will be virus inactivated by the Intercept method in accordance with procedures at St. Olavs University Hospital. Comparison with isotonic saline allows differentiation from a non-blood product. The main study consists of 6 rounds of examinations in addition to 12 plasma transfusions divided over three 4-week periods during study year-1. It is also planned to conduct follow-up examinations 2 and 5 years after baselineEthics and dissemination Written informed consent will be obtained from all participants and participation is voluntary. All participants have a next of kin who will follow them throughout the study to represent the patient’s interest. The study is approved by the Regional Committee for Medical and Health Research Ethics (REK 2018/702) and the Norwegian Medicines Agency (EudraCT No. 2018-000148-24). The study will be published in an open access journal and results will be presented at numerous national and international meetings as well as on social media platforms.Trial registration number EudraCT No. 2018-000148-24. ClinicalTrials.gov, NCT05068830

Research objective: Long-term reversible contraceptive method (LTRC) is the most effective form of contraception but women prefer lesser effective method. In this study we explored whether women of reproductive age will accept or reject LTRC as their contraceptive innovation, and how their perceptions on the innovation's attributes influence their decision in choosing LTRC. Design, participants, interventions, and outcomes: The research design used was a qualitative descriptive study with high-risk reproductive women who were over 35 years old (16 people) spread over 4 health centers (puskesmas) as participants. Data collection was done by using focus group discussion. The results were analyzed using thematic content analysis. Result: Data analysis revealed that there were 2 subgroups of participants based on their tendency to use LTRC: positive (n 6) and negative (n 10). Most of the participants were aware of the advantages of long-term reversible contraceptive methods. They get information from health workers, the media and other people's experiences. They think that both IUD and implants have a high complexity / difficulty, especially the IUD. The characteristics of innovation in the form of relative advantage, compatibility, complexity, trialability and ease of observation greatly influence the decision to choose a long-term reversible contraceptive method. Most of the participants refused to try using the LTRC because it was too risky to try and too complicated to use. Conclusion: Most women are still hesitant to choose LTRC as a contraceptive, especially intrauterine contraceptives. They need more information about the advantages of LTRC

Abstract We developed a method to non-invasively detect synaptic relationships among neurons from in vitro networks. Our method uses microelectrode arrays on which neurons are cultured and from which propagation of extracellular action potentials (eAPs) in single axons are recorded at multiple electrodes. Detecting eAP propagation bypasses ambiguity introduced by spike sorting. Our methods identify short latency spiking relationships between neurons with properties expected of synaptically coupled neurons, namely they were recapitulated by direct stimulation and were sensitive to changing the number of active synaptic sites. Our methods enabled us to assemble a functional subset of neuronal connectivity in our cultures.

Abstract Background Approximate Bayesian Computation (ABC) has become a key tool for calibrating the parameters of discrete stochastic biochemical models. For higher dimensional models and data, its performance is strongly dependent on having a representative set of summary statistics. While regression-based methods have been demonstrated to allow for the automatic construction of effective summary statistics, their reliance on first simulating a large training set creates a significant overhead when applying these methods to discrete stochastic models for which simulation is relatively expensive. In this τ work, we present a method to reduce this computational burden by leveraging approximate simulators of these systems, such as ordinary differential equations and τ-Leaping approximations. Results We have developed an algorithm to accelerate the construction of regression-based summary statistics for Approximate Bayesian Computation by selectively using the faster approximate algorithms for simulations. By posing the problem as one of ratio estimation, we use state-of-the-art methods in machine learning to show that, in many cases, our algorithm can significantly reduce the number of simulations from the full resolution model at a minimal cost to accuracy and little additional tuning from the user. We demonstrate the usefulness and robustness of our method with four different experiments. Conclusions We provide a novel algorithm for accelerating the construction of summary statistics for stochastic biochemical systems. Compared to the standard practice of exclusively training from exact simulator samples, our method is able to dramatically reduce the number of required calls to the stochastic simulator at a minimal loss in accuracy. This can immediately be implemented to increase the overall speed of the ABC workflow for estimating parameters in complex systems.

Objective: Microsatellite instability (MSI) due to defective DNA mismatch repair has emerged as an actionable biomarker in advanced endometrial cancer (aEC). Currently, there are no treatment patterns and outcomes data in non-MSI-high (non-MSI-H) or mismatch repair proficient (pMMR) aEC patients following prior systemic therapy (FPST). Our goal was to describe real-world data in this population in the US in 2019 and prior years. Methods: Endometrial Cancer Health Outcomes (ECHO) is a retrospective patient chart review study conducted in the US. Patients with non-MSI-H/pMMR aEC and progression between 06/01/2016–06/30/2019 FPST were eligible. Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS), and overall survival (OS), separately by treatment category. Results: A total of 165 eligible patients initiated second-line therapy with chemotherapy ± bevacizumab (n = 140) or hormonal therapy (n = 25). Median age was 66.0 years at aEC diagnosis, 70.2% were Stage IIIB-IV, 40.0% had ECOG ≥ 2 at second-line therapy initiation. Median rwPFS was 5.0 months (95% CI: 4.0–6.0) for patients receiving chemotherapy ± bevacizumab and 5.5 months (95% CI: 3.0–29.0) for those receiving hormonal therapy. Median OS was 10.0 months (95% CI: 8.0–13.0) and 9.0 months (95% CI: 6.0-NA) in these groups, respectively. Conclusions: Non-MSI-H/pMMR patients who initiated second-line therapy with chemotherapy ± bevacizumab or hormonal therapy had poor clinical outcomes with a median survival less than 1 year and rwPFS less than 6 months. This was the first study to define the clinical unmet need in patients with non-MSI-H/pMMR aEC with conventional therapy.

Despite advances over the past few decades, heart failure with reduced ejection fraction (HFrEF) remains not only a mortal but a disabling disease. Indeed, the New York Heart Association classification of HFrEF severity is based on how much exercise a patient can perform. Moreover, exercise capacity—both aerobic exercise performance and muscle power—are intimately linked with survival in patients with HFrEF. This review will highlight the pathologic changes in skeletal muscle in HFrEF that are related to impaired exercise performance. Next, it will discuss the key role that impaired nitric oxide (NO) bioavailability plays in HFrEF skeletal muscle pathology. Lastly, it will discuss intriguing new data suggesting that the inorganic nitrate ‘enterosalivary pathway’ may be leveraged to increase NO bioavailability via ingestion of inorganic nitrate. This ingestion of inorganic nitrate has several advantages over organic nitrate (e.g., nitroglycerin) and the endogenous nitric oxide synthase pathway. Moreover, inorganic nitrate has been shown to improve exercise performance: both muscle power and aerobic capacity, in some recent small but well-controlled, cross-over studies in patients with HFrEF. Given the critical importance of better exercise performance for the amelioration of disability as well as its links with improved outcomes in patients with HFrEF, further studies of inorganic nitrate as a potential novel treatment is critical.

Scientific diasporas from developing countries represent an opportunity to strengthen international collaborations. These collaborations build upon the desire of members of the diasporas to establish scientific, academic, technological, and cultural exchange networks with the communities in their country of origin. While Mexico has a significant number of scientists residing abroad, particularly in North America, and most of them are committed to aid in the country's development, institutional coordination has not harnessed its benefits. In this work, we present an analysis of initiatives carried out by Mexican scientists, members of the diaspora, studying or working in the United States of America and Canada. The study is based on a set of interviews with members of this diaspora. We asked scientists about the conditions that enabled or obstructed their initiatives back in Mexico, and we discussed the role of these factors for capacity building. We also provide general recommendations to enhance contributions to the advancement of science in the country.

Despite the increasing number of tools and indicators to measure biodiversity status and trends, many developing countries struggle to initiate and advance coastal and marine assessments needed to monitor and track national and international progress in biodiversity targets. We identified five key challenges that hinder progress in this context, based on a national marine assessment workshop held in South Africa, and developed recommendations and tangible actions to address these challenges drawing from multiple national assessments, regional initiatives, and global collaborations over the last 15 years. Challenges include a poor understanding of methods, limited capacity and funding for assessments, a lack of systematic approaches to biodiversity assessment and indicator development, and scattered efforts that often fail to link science to policy. Key actions could enable the development of a coordinated framework to feed into policy and decision-making at multiple scales. We provide South African examples to highlight a developing country’s progress toward marine biodiversity assessment and provide a roadmap to integrated monitoring, assessment, and reporting based on positive outcomes. Recommendations to address challenges include building collective understanding of assessment tools and methods, prioritizing pressures urgently needing mitigation measures, using relevant indicators to support reporting at multiple scales, applying coordinated approaches to identify gaps and opportunities, codeveloping coordinated approaches with direct policy links, and leveraging resources and technical capacity for iterative improvement. This roadmap can guide developing and developed countries and support global best practices to collaboratively advance marine and coastal ecosystem monitoring and assessment at multiple scales for meeting many objectives.

Abstract Background Family meal participation is associated with healthier eating among children and adolescents. Less is known about family meal participation among infants and toddlers. The objective of the present study was to explore whether family meal participation at 12 months of age is associated with dietary intake and whether a potential relationship differs according to maternal education or child sex. Methods Follow-up data from children born to mothers participating in the Norwegian Fit for Delivery (NFFD) trial during pregnancy were used to assess the frequency of intake of 11 dietary items according to frequency of participating in the respective family meals. Dietary differences according to seldom (0–3 times/week) or often (4–7 times/week) participating in each respective meal category were assessed in linear regression models. Potential dose-response associations with frequency of participation in all family meal categories combined were also estimated. Models were adjusted for maternal randomization status, education, and child sex. Results The sample comprised 408 children. A total of 74, 53 and 74% had breakfast, lunch, and dinner with family ≥4 times/week, respectively, while 39% had supper and 27% between-meal snacks with family ≥4 times/week. Having family dinner ≥4 times/week was associated with more frequent intake of vegetables, homemade infant cereal, milk, and water, and less frequent intake of commercial infant foods while the other family meal categories were associated with fewer dietary outcomes. For each additional meal category eaten with family ≥4 times/week, frequency of vegetable intake (β = 0.45), water (β = 0.17), and milk (β = 0.09) per day increased, while commercial infant cereal was eaten less frequently (β = − 0.18). The inverse association between family meals and commercial infant cereal was only evident in children born to mothers in the intervention group. Several associations with diet were stronger and only significant among boys. Conclusions Being fed in the context of family meals at 12 months of age was associated with a more favorable diet. Including the infant in family meals has potential in the promotion of early nutritional health.

OBJECTIVES/GOALS: This study aimed to determine the prevalence of cardiovascular risk factors in a group of victims of CSA in Puerto Rico and determine the impact of both the offender and the number of victimizations on the presentation of cardiovascular risk factors. METHODS/STUDY POPULATION: A study design of a retrospective chart review at a clinical forensic service in Puerto Rico. The demographic variables were age, sex, and health plan; the CV risk factors were family health history, level of physical activity, blood pressure, BMI, and lipid profile. Sexual violence experience variables were sexual assault, sexual molestation, the relationship with the offender, and the number of victimizations. Medical records were used to identify cardiovascular risk factors and variables associated with child sexual abuse victimization. Central tendency and frequencies were used to describe the risk factors and victimization. The Mann–Whitney and Fisher exact tests were used to determine the differences between the type of victimization and the risk factors for cardiovascular health. RESULTS/ANTICIPATED RESULTS: Most of the victims were female (81%), with an average age of 10 (SD 3.8). According to the 31 reviewed charts, 55% were victims of sexual assault, the offender was a family member (84%), and the assault had occurred more than once (81%). The study also found that systolic blood pressure, diastolic blood pressure, total cholesterol, and body mass index (BMI) were at unhealthy levels (based on age and sex); when the victim reported sexual assault, the offender was a family member, and more than one assault occurred. Systolic blood pressure, diastolic blood pressure, and fasting blood sugar were statistically significant among victims who reported being either sexually assaulted or sexually molested when the offender was a family member, and the victimization occurred more than once. DISCUSSION/SIGNIFICANCE: This study indicated a higher prevalence of CVD risk factors in children victims of sexual assault. The blood pressure, lipid profiles, and BMIs were much higher than the standards. Early childhood screening is crucial in alerting health professionals to a child’s exposure to trauma.

While early empiric antibiotic therapy is beneficial for patients presenting with sepsis, the presentation of sepsis from Clostridioides difficile (formerly Clostridium difficile) infection (CDI) has not been well studied in large cohorts. We sought to determine whether the combination of extreme leukocytosis and diarrhea was strongly predictive of CDI in a cohort of 8659 patients admitted to the intensive care unit. We found that CDI was present in 15.0% (95% CI, 12.1–18.3%) of patients with extreme leukocytosis and diarrhea and that mortality for those with CDI, diarrhea, and extreme leukocytosis was 33.8% (95% CI, 23.2–44.3%). These data support consideration of empiric treatment for CDI in unstable critically ill patients with extreme leukocytosis and diarrhea, along with treatment of other possible sources of sepsis as appropriate. Empiric treatment for CDI can usually be discontinued promptly, along with narrowing of other broad-spectrum antimicrobial coverage, if a sensitive C. difficile test is negative.

A 37-year-old presented at 31 2/7 weeks with premature rupture of membranes. She was managed conservatively until she developed chorioamnionitis at 32 5/7 weeks. Her labor was induced and she reached 8 cm when a compound presentation was diagnosed. Because the fetal heart rate showed a category II tracing and no further descent, she underwent a low transverse c-section. At delivery the right arm and both feet had prolapsed against the fetal head with was severe edema and ecchymosis of the right arm necessitating an emergency fasciotomy due to compartment syndrome. The edema in the feet was conservatively managed and resolved spontaneously. The newborn had mild RDS, hyperbilirubinemia and feeding issues but was discharged on day 24 with complete recovery of function in the affected extremities.

Identifying key sites of marine biodiversity value and implementing the required practical spatial management measures is critical for safeguarding marine biodiversity and maintaining essential ecological processes, especially in the face of accelerating global change and expanding ocean economies. Delineating Ecologically or Biologically Significant Marine Areas (EBSAs) has been catalytic in progressing toward this aim. However, the Benguela Current Large Marine Ecosystem (BCLME; comprising three developing countries: Angola, Namibia, and South Africa) is one of few places where practical action to secure biodiversity in EBSAs has followed their description. We aim to document the process of moving from biodiversity priority areas to implemented conservation actions, and distil broadly applicable emerging lessons. EBSAs in the BCLME were reviewed using a systematic conservation planning approach, supplemented with expert input. In this data- and knowledge-driven process, the boundaries and descriptions of existing EBSAs were refined, and gaps filled with new EBSAs. The status of 29 EBSAs was assessed by determining the ecological condition, ecosystem threat status, and ecosystem protection level of constituent ecosystem types. Also, current human uses and their respective impacts were systematically reviewed per EBSA. Management recommendations were proposed by dividing EBSAs into zones with associated multi-sector sea-use guidelines. Throughout the process, facilitated by a regional cooperation project, there was stakeholder engagement, and national, regional, and international review. BCLME States are currently implementing enhanced EBSA management in their respective marine spatial planning and marine protected area processes, noting that there are different but valid outcomes for securing marine biodiversity in each country. Further, the regional approach allowed for cross-border alignment of priorities and management between countries, as well as pooled expertise, technical support, and capacity development. Although full implementation is still underway, the lessons to date highlight some key factors required for a successful process that could guide similar initiatives elsewhere.

Biology is suffused with rhythmic behaviour, and interacting biological oscillators often synchronize their rhythms with one another. Colonies of some ant species are able to synchronize their activity to fall into coherent bursts, but models of this phenomenon have neglected the potential effects of intrinsic noise and interspecific differences in individual-level behaviour. We investigated the individual and collective activity patterns of two Leptothorax ant species. We show that in one species (Leptothorax sp. W), ants converge onto rhythmic cycles of synchronized collective activity with a period of about 20 min. A second species (Leptothorax crassipilis) exhibits more complex collective dynamics, where dominant collective cycle periods range from 16 min to 2.8 h. Recordings that last 35 h reveal that, in both species, the same colony can exhibit multiple oscillation frequencies. We observe that workers of both species can be stimulated by nest-mates to become active after a refractory resting period, but the durations of refractory periods differ between the species and can be highly variable. We model the emergence of synchronized rhythms using an agent-based model informed by our empirical data. This simple model successfully generates synchronized group oscillations despite the addition of noise to ants' refractory periods. We also find that adding noise reduces the likelihood that the model will spontaneously switch between distinct collective cycle frequencies.

Cardiac dysfunction in T2D is associated with excessive FA uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect improvement in cardiac function in humans with T2D. Thus, our objective was to test the hypothesis that lowering lipid delivery to the heart would result in evidence of decreased “lipotoxicity,” improved cardiac function, and salutary effects on plasma biomarkers of cardiovascular risk. Thus, we performed a double-blind randomized placebo-controlled parallel design study of the effects of 12 weeks of fenofibrate-induced lipid lowering on cardiac function, inflammation, and oxidation biomarkers, and on the ratio of two plasma ceramides, Cer d18:1 (4E) (1OH, 3OH)/24:0 and Cer d18:1 (4E) (1OH, 3OH)/16:0 (i.e., “C24:0/C16:0”), which is associated with decreased risk of cardiac dysfunction and heart failure. Fenofibrate lowered plasma TG and cholesterol but did not improve heart systolic or diastolic function. Fenofibrate treatment lowered the plasma C24:0/C16:0 ceramide ratio and minimally altered oxidative stress markers but did not alter measures of inflammation. Overall, plasma TG lowering correlated with improvement of cardiac relaxation (diastolic function) as measured by tissue Doppler-derived parameter e′. Moreover, lowering the plasma C24:0/C16:0 ceramide ratio was correlated with worse diastolic function. These findings indicate that fenofibrate treatment per se is not sufficient to effect changes in cardiac function; however, decreases in plasma TG may be linked to improved diastolic function. In contrast, decreases in plasma C24:0/C16:0 are linked with worsening cardiac function.

Ojcow birch (Betula oycoviensis Besser) is a rare Central European tree taxon, micro-populations of which are found in only several localities. With a view to maintaining the B. oycoviensis gene pool, this study tested the species’ potential for micropropagation, grafting, and propagation by cuttings. Plant material for vegetative propagation was collected from ten genotypes in the Czech Republic. In vitro culture was established from axillary buds surfaces sterilized with 0.1% HgCl2 and cultivated on woody plant (WP) medium supplemented with 1 mg l-1 6-benzylaminopurine (BAP). Two genotypes of the species were successfully multiplied by in vitro propagation using WP medium supplemented with 0-2 mg l-1 BAP. The BAP concentration of 1 mg l-1 proved to be optimal, yielding 2.5 new shoots per explant in genotype 516 and 3.5 shoots per explant in genotype 545. The shoots were rooted on half-strength Murashige and Skoog (MS) medium supplemented with various concentrations of α-naphthylacetic acid (NAA) and indole-3-butyric acid (IBA). The highest rooting percentages (72.5% and 77.5% for genotypes 516 and 545, respectively) were achieved on the medium with the combination of both auxins at concentrations of 0.3 mg l-1. The rooted plants were transferred ex vitro in substrate composed of sand, peat, and perlite (1:1:1) and acclimated in the greenhouse. After 4 weeks, more than 90% of plants survived. Grafting was carried out in spring using Betula pendula as rootstock. The efficiency of this technique ranged from 0% to 50% across genotypes, and 4 out of 10 genotypes were successfully propagated by grafting. The cuttings were treated with commercial root stimulators Stimulax I and Stimulator AS-1, planted in a mixture of peat and sand (1:1) in the greenhouse, and watered regularly. This technique resulted in 0% rooting, however, and no cutting survived until the end of the vegetation period. The results of this study show that protocols for in vitro propagation and grafting can be employed for effective mass propagation of B. oycoviensis, although these processes show genotype-dependent responses.

Abstract Background We determined the association between ratios of plasma ceramide species of differing fatty‐acyl chain lengths and incident dementia and Alzheimer’s disease (AD) dementia in a large, community‐based sample. Methods We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia‐free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long‐chain (C24:0, C22:0) to long‐chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. Results During a median 6.5 year follow‐up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox‐proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56–0.96) and AD dementia (HR 0.73, 95% CI 0.53–1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57–0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53–1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross‐sectionally associated with lower white matter hyperintensity burden on MRI (−0.05 ± 0.02, P = 0.02; −0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. Conclusions Higher plasma ratios of very long‐chain to long‐chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community‐based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

Objective: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations. Methods: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment. Results: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2.83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (p=9.94E-09). Conclusion: SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.

Abstract Objective: To describe the evolution of respiratory antibiotic prescribing during the coronavirus disease 2019 (COVID-19) pandemic across 3 large hospitals that maintained antimicrobial stewardship services throughout the pandemic. Design: Retrospective interrupted time-series analysis. Setting: A multicenter study was conducted including medical and intensive care units (ICUs) from 3 hospitals within a Canadian epicenter for COVID-19. Methods: Interrupted time-series analysis was used to analyze rates of respiratory antibiotic utilization measured in days of therapy per 1,000 patient days (DOT/1,000 PD) in medical units and ICUs. Each of the first 3 waves of the pandemic were compared to the baseline. Results: Within the medical units, use of respiratory antibiotics increased during the first wave of the pandemic (rate ratio [RR], 1.76; 95% CI, 1.38–2.25) but returned to the baseline in waves 2 and 3 despite more COVID-19 admissions. In ICU, the use of respiratory antibiotics increased in wave 1 (RR, 1.30; 95% CI, 1.16–1.46) and wave 2 of the pandemic (RR, 1.21; 95% CI, 1.11–1.33) and returned to the baseline in the third wave, which had the most COVID-19 admissions. Conclusions: After an initial surge in respiratory antibiotic prescribing, we observed the normalization of prescribing trends at 3 large hospitals throughout the COVID-19 pandemic. This trend may have been due to the timely generation of new research and guidelines developed with frontline clinicians, allowing for the active application of new research to clinical practice.

Study objective: To evaluate whether an Intensive Cardiac Rehabilitation (ICR) program improves depression and cardiac self-efficacy among patients with a qualifying cardiac diagnosis. Design: Prospective, longitudinal cohort design. Setting: Single-center, tertiary referral, outpatient cardiac rehabilitation center. Participants: Patients with a qualifying diagnosis for ICR. Interventions: Outpatient ICR. Main outcome measure(s): Mental health, as assessed using the Patient Health Questionnaire-9 (PHQ-9) and cardiac self-efficacy using the Cardiac Self-Efficacy (CSE) scale. Results: Of the 268 patients included (median age 69 y, 73% men), 70% had no depressive symptoms at baseline (PHQ-9 score