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In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during night-time display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by brain and muscle Arnt-like protein 1 (BMAL1) and peroxisome proliferator-activated receptor alpha (PPARα) and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1., Using a model of time-restricted feeding in mice, Levine et al. show that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.

As one of the promising next-generation probiotics (NGPs), Akkermansia muciniphila, a well-known mucin-degrading bacterium, has been proven to be closely related to the metabolic diseases of its human host. However, the role of A. muciniphila in the host’s intestinal health remains ambiguous. Here, we comprehensively summarize and discuss the characteristics, the distribution, and the colonization of A. muciniphila in the human gastrointestinal tract (GIT). We propose that the application of A. muciniphila as a biomarker for longevity, for diagnostics and prognostics of intestinal diseases, or for intestinal health should be cautiously considered. Precise dietary regulation can mediate the treatment of intestinal diseases by altering the abundance of A. muciniphila. Although the beneficial role of A. muciniphila and its component in intestinal inflammation has been discovered, in gnotobiotic mice with specific gut microbiota, certain genotype, and colorectal cancer, or in animal models infected with a specific pathogen, A. muciniphila may be related to the occurrence and development of intestinal diseases. Genomic analysis, emphasizing the strain-level phylogenetic differences of A. muciniphila, indicates that a clear description and discussion of each strain is critical before its practical application. Our review provides much needed insight for the precise application of A. muciniphila.

Dysregulated neutrophilic inflammation can be highly destructive in chronic inflammatory diseases due to prolonged neutrophil lifespan and continual release of histotoxic mediators in inflamed tissues. Therapeutic induction of neutrophil apoptosis, an immunologically silent form of cell death, may be beneficial in these diseases, provided that the apoptotic neutrophils are efficiently cleared from the tissue. Previous research in our group identified ErbB inhibitors as able to induce neutrophil apoptosis and reduce neutrophilic inflammation both in vitro and in vivo. Here, we extend that work using a clinical ErbB inhibitor, neratinib, which has the potential to be repurposed in inflammatory diseases. We show that neratinib reduces neutrophilic migration o an inflammatory site in zebrafish larvae. Neratinib upregulates efferocytosis and reduces the number of persisting neutrophil corpses in mouse models of acute, but not chronic, lung injury, suggesting that the drug may have therapeutic benefits in acute inflammatory settings. Phosphoproteomic analysis of human neutrophils shows that neratinib modifies the phosphorylation of proteins regulating apoptosis, migration, and efferocytosis. This work identifies a potential mechanism for neratinib in treating acute lung inflammation by upregulating the clearance of dead neutrophils and, through examination of the neutrophil phosphoproteome, provides important insights into the mechanisms by which this may be occurring.

In mammalian cells, DNA double-strand breaks (DSBs) are mainly repaired by nonhomologous end joining (NHEJ) pathway. Ku (a heterodimer formed by Ku70 and Ku80 proteins) and DNA ligase IV are the core NHEJ factors. Ku could also be involved in other cellular processes, including telomere length regulation, DNA replication, transcription, and translation control.

Patient-centred care is a key priority for governments, providers and stakeholders, yet little is known about the care preferences of patient groups. We completed a scoping review that yielded 193 articles for analysis. Five health states were used to account for the diversity of possible preferences based on health needs. Five broad themes were identified and expressed differently across the health states, including personalized care, navigation, choice, holistic care and care continuity. Patients' perspectives must be considered to meet the diverse needs of targeted patient groups, which can inform health system planning, quality improvement initiatives and targeting of investments.

BACKGROUND: New case-mix tools from the Canadian Institute for Health Information offer a novel way of exploring the prevalence of chronic disease and multimorbidity using diagnostic data. We took a comprehensive approach to determine whether the prevalence of chronic disease and multimorbidity has been rising in Ontario, Canada. METHODS: In this observational study, we applied case-mix methodology to a population-based cohort. We used 10 years of patient-level data (fiscal years 2008/09 to 2017/18) from multiple care settings to compute the rolling 5-year prevalence of 85 chronic diseases and multimorbidity (i.e., the co-occurrence of 2 or more diagnoses). Diseases were further classified based on type and severity. We report both crude and age- and sex-standardized trends. RESULTS: The number of patients with chronic disease increased by 11.0% over the 10-year study period to 9.8 million in 2017/18, and the number with multimorbidity increased 12.2% to 6.5 million. Overall increases from 2008/09 to 2017/18 in the crude prevalence of chronic conditions and multimorbidity were driven by population aging. After adjustments for age and sex, the prevalence of patients with ≥ 1 chronic conditions decreased from 70.2% to 69.1%, and the prevalence of multimorbidity decreased from 47.1% to 45.6%. This downward trend was concentrated in minor and moderate diseases, whereas the prevalence of many major chronic diseases rose, along with instances of extreme multimorbidity (≥ 8 conditions). Age- and sex-standardized resource intensity weights, which reflect relative expected costs associated with patient diagnostic profiles, increased 4.6%. INTERPRETATION: Evidence of an upward trend in the prevalence of chronic disease was mixed. However, the change in case mix toward more serious conditions, along with increasing patient resource intensity weights overall, may portend a future need for population health management and increased health system spending above that predicted by population aging.

BACKGROUND: Prior research has consistently shown that the heaviest users account for a disproportionate share of health care costs. As such, predicting high-cost users may be a precondition for cost containment. We evaluated the ability of a new health risk predictive modelling tool, which was developed by the Canadian Institute for Health Information (CIHI), to identify future high-cost cases. METHODS: We ran the CIHI model using administrative health care data for Ontario (fiscal years 2014/15 and 2015/16) to predict the risk, for each individual in the study population, of being a high-cost user 1 year in the future. We also estimated actual costs for the prediction period. We evaluated model performance for selected percentiles of cost based on the discrimination and calibration of the model. RESULTS: A total of 11 684 427 individuals were included in the analysis. Overall, 10% of this population had annual costs exceeding $3050 per person in fiscal year 2016/17, accounting for 71.6% of total expenditures; 5% had costs above $6374 (58.2% of total expenditures); and 1% exceeded $22 995 (30.5% of total expenditures). Model performance increased with higher cost thresholds. The c-statistic was 0.78 (reasonable), 0.81 (strong) and 0.86 (very strong) at the 10%, 5% and 1% cost thresholds, respectively. INTERPRETATION: The CIHI Population Grouping Methodology was designed to predict the average user of health care services, yet performed adequately for predicting high-cost users. Although we recommend the development of a purpose-designed tool to improve model performance, the existing CIHI Population Grouping Methodology may be used — as is or in concert with additional information — for many applications requiring prediction of future high-cost users.

Purpose The purpose of the study was to assess the use of geofence technology to raise awareness of a dental clinic in rural North Carolina. Methods The catchment area of the dental clinic was defined by ZIP Codes. A geofence was identified, and cell phones within the perimeter were targeted for oral health message drops to occur over 3 months from April to June 2017. Surveys conducted twice, pre- and postintervention (message drop), evaluated change in community awareness of services available at the dental clinic. A cross-sectional analysis was used to measure the effect of the exposure to the geofence technology in survey respondents. Findings The survey included 200 participants (100 pre- and 100 postintervention). There were no significant differences in race or age for pre- and postintervention survey groups. The majority of respondents were American Indians (47.0% pre, 58.6% post) or black (28.8% pre, 25.5% post). There was a statistically significant improvement in awareness of the dental clinic (P = .045) from pre- to postintervention. A significant increase was also observed in the question related to dental visits by the respondent or family member of the respondent (from 6.5% to 15.0%, P = .04). A more modest improvement was found in questions related to the cost of dental care, type of insurance accepted, and services provided. Conclusion Geofencing has the potential to increase awareness of health care services and ultimately increase the number of patients receiving care.

Gene regulation by steroid hormones has been at the forefront in elucidating the intricacies of transcriptional regulation in eukaryotes ever since the discovery by Karlson and Clever that the insect steroid hormone ecdysone induces chromatin puffs in giant chromosomes. After the successful cloning of the hormone receptors toward the end of the past century, detailed mechanistic insight emerged in some model systems, in particular the MMTV provirus. With the arrival of next generation DNA sequencing and the omics techniques, we have gained even further insight into the global cellular response to steroid hormones that in the past decades also extended to the function of the 3D genome topology. More recently, advances in high resolution microcopy, single cell genomics and the new vision of liquid-liquid phase transitions in the context of nuclear space bring us closer than ever to unravelling the logic of gene regulation and its complex integration of global cellular signaling networks. Using the function of progesterone and its cellular receptor in breast cancer cells, we will briefly summarize the history and describe the present extent of our knowledge on how regulatory proteins deal with the chromatin structure to gain access to DNA sequences and interpret the genomic instructions that enable cells to respond selectively to external signals by reshaping their gene regulatory networks. First, the authors thank all the members of the Chromatin and Gene Expression Group, who had performed most of the experiments commented in this review and have made suggestions for the text. The authors also thank their collaborators, most of them cited as authors of the referenced papers. The authors thank the CRG for the continuous support of the group and for the availability of essential core facilities. The experimental work mentioned was supported by the core funding of the CRG, the European Research Council (Project ‘4D Genome’ 609989), the Ministerio de Economía y Competitividad (Project G62426937) and the Generalitat de Catalunya (Project AGAUR SGR 575). We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa as well as CERCA Programme / Generalitat de Catalunya.

Studies have estimated that a large backlog of procedures was generated by emergency measures implemented in Ontario, Canada, at the onset of the COVID-19 pandemic, when nonessential and scheduled procedures were postponed. Understanding the impact of the COVID-19 pandemic on the time needed to perform a procedure may help to determine the resources needed to tackle the substantial backlog caused by the deferral of cases. The purpose of this study was to examine the duration of operating room (OR) procedures before and after the onset of the COVID-19 pandemic to inform planning around changes in required resources.A population-based, retrospective cohort study was conducted using Ontario Health Insurance Plan claims data and other administrative health care data from Apr. 1, 2019, to Sept. 30, 2020. Statistical analysis was conducted using multivariate regression, with procedure duration as the outcome variable.Results showed that the average duration of nonelective procedures increased by 34 minutes during the COVID-19 period and by 19 minutes after the resumption of scheduled procedures. Controlling for physician, patient and hospital characteristics, and the procedure code submitted, procedure duration increased by 12 minutes in the nonelective COVID-19 period and by 5 minutes when scheduled procedures resumed, compared with the pre-COVID-19 period.Procedures may take longer in the COVID-19 period. This will affect wait times, which had already increased because of the deferral of procedures at the beginning of the pandemic, and will have an impact on Ontario's ability to provide patients with timely care.

ObjectivesTo estimate the impact of the SARS-CoV-2 (COVID-19) pandemic on levels of burnout among physicians in Ontario, Canada, and to understand physician perceptions of the contributors and solutions to burnout.DesignRepeated cross-sectional survey.SettingActive and retired physicians, residents and medical students in Canada’s largest province were invited to participate in an online survey via an email newsletter.ParticipantsIn the first survey wave (March 2020), 1400 members responded (representing 76.3% of those who could be confirmed to have received the survey and 3.1% of total membership). In the second wave (March 2021), 2638 responded (75.9% of confirmed survey recipients and 5.8% of membership).Key outcome measureLevel of burnout was assessed using a validated, single-item, self-defined burnout measure where options ranged from 1 (no symptoms of burnout) to 5 (completely burned out).ResultsThe overall rate of high levels of burnout (self-reported levels 4–5) increased from 28.0% in 2020 (99% CI: 24.3% to 31.7%) to 34.7% in 2021 (99% CI: 31.8% to 37.7%), a 1-year increase of 6.8 percentage points (pConclusionsDuring the first 12 months of the COVID-19 pandemic in Ontario, prevalence of high levels of burnout had significantly increased. The contributors and solutions ranked highest by physicians were system-level or organisational in nature.

Advances in high-throughput sequencing (HTS) are revolutionizing monitoring in marine environments by enabling rapid, accurate and holistic detection of species within complex biological samples. Research institutions worldwide increasingly employ HTS methods for biodiversity assessments. However, variance in laboratory procedures, analytical workflows and bioinformatic pipelines impede the transferability and comparability of results across research groups. An international experiment was conducted to assess the consistency of metabarcoding results derived from identical samples and primer sets using varying laboratory procedures. Homogenized biofouling samples collected from four coastal locations (Australia, Canada, New Zealand and the USA) were distributed to 12 independent laboratories. Participants were asked to follow one of two HTS library preparation workflows. While DNA extraction, primers and bioinformatic analyses were purposefully standardized to allow comparison, many other technical variables were allowed to vary among laboratories (e.g., amplification protocols, type of instrument used, etc.). Despite substantial variation observed in raw results, the primary signal in the data was consistent, with the samples grouping strongly by geographic origin for all datasets. Simple post-hoc data clean-up by removing low quality samples gave the best improvement in sample classification for nuclear 18S rRNA gene data, with an overall 92.81% correct group attribution. For mitochondrial COI gene data, the best classification result (95.58%) was achieved after correction for contamination errors. The identified critical methodological factors that introduced the greatest variability (preservation buffer, sample defrosting, template concentration, DNA polymerase, PCR enhancer) should be of great assistance in standardizing future comparative biodiversity studies using metabarcoding.

Supplemental Digital Content is available in the text., Objective: Until recently, the options for summarizing Canadian patient complexity were limited to health risk predictive modeling tools developed outside of Canada. This study aims to validate a new model created by the Canadian Institute for Health Information (CIHI) for Canada’s health care environment. Research Design: This was a cohort study. Subjects: The rolling population eligible for coverage under Ontario’s Universal Provincial Health Insurance Program in the fiscal years (FYs) 2006/2007–2016/2017 (12–13 million annually) comprised the subjects. Measures: To evaluate model performance, we compared predicted cost risk at the individual level, on the basis of diagnosis history, with estimates of actual patient-level cost using “out-of-the-box” cost weights created by running the CIHI software “as is.” We next considered whether performance could be improved by recalibrating the model weights, censoring outliers, or adding prior cost. Results: We were able to closely match model performance reported by CIHI for their 2010–2012 development sample (concurrent R2=48.0%; prospective R2=8.9%) and show that performance improved over time (concurrent R2=51.9%; prospective R2=9.7% in 2014–2016). Recalibrating the model did not substantively affect prospective period performance, even with the addition of prior cost and censoring of cost outliers. However, censoring substantively improved concurrent period explanatory power (from R2=53.6% to 66.7%). Conclusions: We validated the CIHI model for 2 periods, FYs 2010/2011–2012/2013 and FYs 2014/2015—2016/2017. Out-of-the-box model performance for Ontario was as good as that reported by CIHI for the development sample based on 3-province data (British Columbia, Alberta, and Ontario). We found that performance was robust to variations in model specification, data sources, and time.

In breast cancer cells, some topologically associating domains (TADs) behave as hormonal gene regulation units, within which gene transcription is coordinately regulated in response to steroid hormones. Here we further describe that responsive TADs contain 20- to 100-kb-long clusters of intermingled estrogen receptor (ESR1) and progesterone receptor (PGR) binding sites, hereafter called hormone-control regions (HCRs). In T47D cells, we identified more than 200 HCRs, which are frequently bound by unliganded ESR1 and PGR. These HCRs establish steady long-distance inter-TAD interactions between them and organize characteristic looping structures with promoters in their TADs even in the absence of hormones in ESR1-PGR cells. This organization is dependent on the expression of the receptors and is further dynamically modulated in response to steroid hormones. HCRs function as platforms that integrate different signals, resulting in some cases in opposite transcriptional responses to estrogens or progestins. Altogether, these results suggest that steroid hormone receptors act not only as hormone-regulated sequence-specific transcription factors but also as local and global genome organizers., Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013–2017’ and Plan Nacional (SAF2016-75006-P), as well as support of the CERCA Programme/ Generalitat de Catalunya

Background Electronic medical record (EMR) systems have the potential to facilitate appropriate laboratory testing. We examined three common medical tests in primary care—hemoglobin A1c (HbA1c), lipid, and thyroid stimulating hormone (TSH)— to assess whether adoption of a laboratory EMR system in Ontario had an impact on the rate of inappropriate testing among primary care physicians. Methods We used FY2016–17 population-level laboratory data to estimate the association between adoption of a laboratory EMR system and the rate of inappropriate testing. Inappropriate testing was assessed based on recommendations for screening, monitoring, and follow-up that take into account risk factors related to patient age and certain clinical conditions. To overcome the problem of potential endogeneity of physician choice to use the EMR, the EMR penetration rate in the physician’s geographical area of practice was used as an instrumental variable in an ordinary least squares (OLS) regression. We then simulated the change in the rate of inappropriate testing, by physician payment model, as the EMR penetration rate increased from the baseline percentage. Results The simulation models showed that an increase in the rate of EMR penetration from a baseline average was associated with a statistically significant decrease in inappropriate hbA1c and lipid testing, but a statistically insignificant increase in inappropriate TSH testing. The impact of EMR penetration also varied by payment model. Conclusions This study demonstrated a positive association between availability of an EMR system and appropriate service utilization. Varying impacts of the EMR system availability by primary care payment model may be reflective of different incentives or attributes inherent in payment models. Policies to encourage physicians to increase their use of laboratory EMR systems could improve the quality and continuity of patient care.

Erythropoietin (EPO) is the primary regulator of bone marrow erythropoiesis. Mouse models have provided evidence that EPO also promotes bone remodeling and that EPO‐stimulated erythropoiesis is accompanied by bone loss independent of increased red blood cell production. EPO has been used clinically for three decades to treat anemia in end‐stage renal disease, and notably, although the incidence of hip fractures decreased in the United States generally after 1990, it rose among hemodialysis patients coincident with the introduction and subsequent dose escalation of EPO treatment. Given this clinical paradox and findings from studies in mice that elevated EPO affects bone health, we examined EPO treatment as a risk factor for fractures in hemodialysis patients. Relationships between EPO treatment and hip fractures were analyzed using United States Renal Data System (USRDS) datasets from 1997 to 2013 and Consolidated Renal Operations in a Web‐enabled Network (CROWNWeb) datasets for 2013. Fracture risks for patients treated with

Background In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC. Patients and methods Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. Results Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel]. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. Conclusion Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. ClinicalTrials.gov NCT03125902.

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.

Aims To compare changes in gait kinematics and walking speed 24 months after conventional (C-MLS) and minimally invasive (MI-MLS) multilevel surgery for children with diplegic cerebral palsy (CP). Methods A retrospective analysis of 19 children following C-MLS, with mean age at surgery of 12 years five months (seven years ten months to 15 years 11 months), and 36 children following MI-MLS, with mean age at surgery of ten years seven months (seven years one month to 14 years ten months), was performed. The Gait Profile Score (GPS) and walking speed were collected preoperatively and six, 12 and 24 months postoperatively. Type and frequency of procedures as part of MLS, surgical adverse events, and subsequent surgery were recorded. Results In both groups, GPS improved from the preoperative gait analysis to the six-month assessment with maintenance at 12 and 24 months postoperatively. While reduced at six months in both groups, walking speed returned to preoperative speed by 12 months. The overall pattern of change in GPS and walking speed was similar over time following C-MLS and MI-MLS. There was a median of ten procedures per child as part of both C-MLS (interquartile range (IQR) 8.0 to 11.0) and MI-MLS (IQR 7.8 to 11.0). Surgical adverse events occurred in seven (37%) and 13 (36%) children, with four (21%) and 13 (36%) patients requiring subsequent surgery following C-MLS and MI-MLS, respectively. Conclusion This study indicates similar improvements in gait kinematics and walking speed 24 months after C-MLS and MI-MLS for children with diplegic CP. Cite this article: Bone Joint J 2021;103-B(1):192–197.

Small heat shock proteins (sHsps) are a family of ubiquitous intracellular molecular chaperones; some sHsp family members are upregulated under stress conditions and play a vital role in protein homeostasis (proteostasis). It is commonly accepted that these chaperones work by trapping misfolded proteins to prevent their aggregation; however, fundamental questions regarding the molecular mechanism by which sHsps interact with misfolded proteins remain unanswered. The dynamic and polydisperse nature of sHsp oligomers has made studying them challenging using traditional biochemical approaches. Therefore, we have utilized a single-molecule fluorescence-based approach to observe the chaperone action of human alphaB-crystallin (αBc, HSPB5). Using this approach we have, for the first time, determined the stoichiometries of complexes formed between αBc and a model client protein, chloride intracellular channel 1. By examining the dispersity and stoichiometries of these complexes over time, and in response to different concentrations of αBc, we have uncovered unique and important insights into a two-step mechanism by which αBc interacts with misfolded client proteins to prevent their aggregation.

Persons with mental illness have poorer oral health and are less likely to receive oral health care than those in the general population. A comprehensive understanding of barriers to and facilitators of accessing oral health care from a multidisciplinary perspective is lacking. The authors of this qualitative study sought to explore barriers and facilitators in addressing the oral health needs of individuals with mental illness from the perspectives of patients, psychiatrists, and dentists.A thematic content analysis approach was used to triangulate the perspectives of the three groups. Face-to-face semistructured interviews were conducted in 2018-2019 with patients with mental illness (N=20), psychiatrists (N=20), and dentists (N=25) at an academic medical campus in rural eastern North Carolina. Participants were recruited until thematic saturation for each group was reached.Reported barriers to oral health care were categorized under emerging themes: access to dental care, fear of dental care, characteristics of mental illness, lack of oral health screening by psychiatrists, lack of education and training, stigma of mental illness, and lack of communication. Facilitators of oral health care were linked to the reported need for education and training, financial support, dentists' chairside manner, community support, and interprofessional communication.The findings highlight health system gaps between oral health and mental health. The barriers and facilitators identified can help inform the development of interventions to improve oral health of patients with mental illness. Interventions should include interdisciplinary education and training, improved communication, and strategies to reduce financial barriers and anxiety in dental practice.

Laparoscopic gastric plication (LGP) is a relative new bariatric procedure with a high revision rate, mostly to sleeve gastrectomy. There are few reported cases of conversion to Roux-en-Y gastric bypass (RYGB). The purpose of this video was to show the feasibility and safety, as well as the main technical aspects, of a laparoscopic conversion of gastric plication to RYGB.A 40-year-old morbidly obese woman with a previous LGP, consulted for insufficient weight loss, weight regain, and gastroesophageal reflux disease (GERD) symptoms, and was converted to RYGB.Surgical technique included lysis of adhesions between the stomach and the greater omentum, take down of the plication, partial gastrectomy of the devascularized fundus and body and conversion to RYGB. At 30 months, she has achieved a total weight loss (TWL) of 42.43% with no GERD symptoms recurrence.Conversion to RYGB is a safe and effective option to treat weight recidivism and GERD after LGP.

PURPOSE: To assess rural-urban differences in dental service use and procedures and to explore the interaction effects of individual and county-level factors on having dental service use and procedures. METHODS: Data were from the 2016 Medical Expenditure Panel Survey (MEPS). We assessed rural-urban differences in three outcome variables: number of dental visits (1, 2, or 3+ visits), preventive care procedures (Yes/No), treatment procedures (Yes/No). The study sample included 8,334 adults ≥ 18 years of age who reported at least one dental visit in the past year. Sampling weights embedded in MEPS were incorporated into all the analyses. FINDINGS: A significant interaction between residential location and race/ethnicity (p=0.030) suggested limited access to dental visits for minority groups especially for blacks in the more rural areas. Adults from a more rural area were less likely to have received a preventive procedure (AOR=0.55, 95% CI: 0.35-0.87) than those from an urban area. Adults of racial/ethnic minority groups, with lower SES, and without dental insurance were less likely to have received a preventive procedure (all p

Applications of behavioral economics targeted at optimizing laboratory utilization among physicians have been implemented in Ontario through different types of nonfinancial interventions. Strict policy interventions restrict Ontario Health Insurance Plan (OHIP) payment for tests to patients with specific conditions or limit ordering to particular physician specialties, while soft policy interventions involve modifications to the laboratory requisition form. This study evaluates the effectiveness of these interventions in terms of changing physician ordering behavior for eight tests that were subject to a strict or soft policy intervention during the study period. We use a Bayesian structural time series model applied to Ontario laboratory claims data for FY2006 through FY2017. Results show a 16–75% reduction in laboratory services with a strict policy intervention and an 8–36% reduction in laboratory services with a soft policy intervention. Although the overall magnitude of change was smaller for soft policy interventions, interventions designed with soft or strict policy mechanisms addressing laboratory utilization management are effective at influencing physicians’ test ordering behavior.

Ceftazidime‐avibactam is a novel β‐lactam/β‐lactamase inhibitor combination for the treatment of serious infections caused by resistant gram‐negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra‐abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator‐associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well‐described by two‐compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady‐state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure‐microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime‐avibactam dosage regimens (2000‐500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).

Study question Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? Summary answer AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. What is known already Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. Study design, size, duration A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. Participants/materials, setting, methods Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. Main results and the role of chance Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). Limitations, reasons for caution Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. Wider implications of the findings Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. Study funding/competing interest(s) Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. Trial registration number Clinical Trials.gov number: NCT01044862.

Background The authors assessed the trends of annual dental visits in dentate adults with diabetes or prediabetes or no diabetes, and assessed whether the racial and ethnic disparities in dental visits changed from 2004 through 2014. Methods Data for this analysis came from the Behavioral Risk Factor Surveillance System, a US health survey that looks at behavioral risk factors that was developed by the Centers for Disease Control and Prevention in cooperation with state health departments. Respondents indicated whether they had a dental visit in the past 12 months. Weighted proportions were calculated for annual dental visits in adults by diabetes status, and trends were assessed by racial and ethnic groups. Results From 2004 through 2014, the proportion of annual dental visits declined from 66.1% to 61.4% (trend P = .02) in the diabetes group, 71.9% to 66.5% (trend P = .01) in the no diabetes group, and 66.0% to 64.9% (trend P = .33) in the prediabetes group. Age, income, and health insurance were moderators of the association between diabetes status and dental visits. Overall, the racial and ethnic disparity in dental visits did not change significantly during the period. Conclusions Dental visits and services were less frequent in people with diabetes and prediabetes. Racial and ethnic disparities in use of dental services persisted during the observed period. Practical Implications All patients, especially those with diabetes, are encouraged to visit a dentist at least annually. It is important for health care providers, such as primary care physicians and dental care and public health professionals, to make concerted efforts to promote oral health care in diabetes management. Improving access to dental services is vital to achieving this goal.

Prostaglandins are formed by enzymatic and non-enzymatic mechanisms. They have been detected in human ovarian follicular fluid (HFF), a medium rich in growth factors and nutrients important for oocyte growth and fertility. However, the comprehensive identification of HFF prostaglandins has not been addressed. Here we use hybrid triple quadrupole time-of-flight and triple quadrupole mass spectrometers to comprehensively analyze prostaglandins in HFF. We identified PGE1, PGE2, PGF2α, and other prostaglandins synthesized via prostaglandin-endoperoxide synthase (i.e. Cox) cascades. We also identified specific PGF2α isomers (F2-isoprostanes) and PGF3α analogs whose structures are inconsistent with Cox-dependent formation. A prospective cohort pilot study of infertility patient subtypes revealed two potential associations. F2-isoprostanes are decreased in the diminished ovarian reserve subtype and elevated PGF2α may be associated with decreased live birth. Other than PGF2α, only body mass index > 25 kg/m2 correlated with poor in vitro fertilization outcome. Our studies suggest that HFF contains prostaglandins formed from at least two mechanisms, which may correlate with distinct clinical parameters.

Key Points Question Do male and female physicians in Ontario, Canada, receive equal payments for equal work? Findings In this cross-sectional study including 31 481 physicians (nearly all physicians in Ontario), women earned 32.8% less than men annually and 22.5% less daily. After controlling for observable factors associated with earnings, such as practice characteristics, geography (degree of rurality), and specialty, the daily pay gap remained significant, at 13.5%. Meaning This cross-sectional study describes a complex set of factors associated with payment disparities affecting female physicians, considering both daily and annual payment gaps and the variations by specialty, rurality, and practice settings., This cross-sectional study examines differences in pay by gender among physicians in Ontario, Canada., Importance Men and women should earn equal pay for equal work. An examination of the magnitude of pay disparities could inform strategies for remediation. Objective To examine gender-based differences in pay within a large, comprehensive physician population practicing within a variety of payment systems. Design, Setting, and Participants This cross-sectional study used data from the Ontario Health Insurance Plan (OHIP) in the 2017 to 2018 fiscal year to estimate differences in gross payments between men and women physicians in Ontario, Canada. Pay gaps were calculated annually and daily. Regression analyses were used to control for observable practice characteristics that could account for individual differences in daily pay. In Canada’s largest province, Ontario, medical services are predominantly provided by self-employed physicians who bill the province’s single payer, OHIP. All physicians who submitted claims to OHIP were included. Data were analyzed from January 2020 to July 2021. Exposures Physician gender, obtained from the OHIP Corporate Provider Database. Gender is recorded as male or female. Main Outcomes and Measures Gross clinical payments were tabulated for individual physicians on a daily and annual basis in conjunction with each physician’s practice characteristics, setting, and specialty. Results A total of 31 481 physicians were included in the study sample (12 604 [40.0%] women; 18 877 [60.0%] men; mean [SD] time since graduation, 23.3 [13.6] years), representing 99% of active physicians in Ontario. The unadjusted differences in clinical payments between male and female physicians were 32.8% (95% CI, 30.8%-34.6%) annually and 22.5% (95% CI, 21.2%-23.8%) daily. After accounting for practice characteristics, region, and specialty, the overall daily payment gap was 13.5% (95% CI, 12.3%-14.8%). The pay gap persisted with differing magnitudes when examined by specialty (ranging from 6.6% to 37.6%), practice setting (8.3% to 17.2%), payment model (13.4% to 22.8% for family medicine; 8.0% to 11.6% for other specialties), and rurality (8.0% to 16.5%). Conclusions and Relevance This cross-sectional study examined differences in magnitude of annual and daily payment gaps and between unadjusted and adjusted gaps. Comparing the gaps for different specialties, geography, and payment systems illustrated the complexity of the issue by showing that the pay gap varied for physicians in different practice settings. As such, multiple directed interventions will be necessary to ensure that all physicians are paid equally for equal work, regardless of gender.

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.

Clinical assessment of a patient, monitoring the progress of a condition, and/or titration of a therapy is dependent on the metrological characteristics of diagnostic equipment. While metrological performance of instruments is commonly assessed in research, it is not so often done in clinical practice. Physical rehabilitation applications may benefit individuals with mental health concerns and are associated with an accurate analysis of balance and gait. There is a paucity of published data regarding the metrological characteristics of commonly used clinical instruments used in posturographic measurements. We desired to assess the accuracy, trueness, precision and resolution of four posturography systems that we use clinically in practice: a Bertec BP-5050, a Vestibular Technologies CAPS® Professional and a Vestibular Technologies CAPS® Lite threecomponent balance platforms, and a NeuroCom® Balance Manager SMART EquiTest®. Metrological performance by posturography instruments was recommended in 2013 by the International Standardization Committee for Clinical Stabilometry of the International Society for Posture and Gait Research (ISPGR). Clinical and research findings may be erroneous, or at the least misleading, if the instruments used to make clinical decisions are associated with significant error. We suggest that there is a strong need for posturographic instrumentation with appropriate metrological characteristics used in clinical applications. The ISPRG recommendations appear to be reasonable and appropriate, and our results show they are obtainable. Physical measurements and functional testing used to correlate and design mental health and physical based rehabilitation strategies are often dependent upon the accuracy and metrological integrity of diagnostic instruments used in posturography.

INTRODUCTION: The objectives of this study were to describe trends of children being given dental checkup advice by primary care providers (PCPs) and having dental visits and to assess factors associated with being given dental checkup advice and having a dental visit. METHODS: Data were from the annual, cross-sectional Medical Expenditure Panel Survey (MEPS) from 2001 to 2016. The sample included 126,773 children ages 2–17 years. We used predictive margins to estimate the probability of being given dental checkup advice and having a dental visit. We examined time trends of the proportion of children being given dental checkup advice from PCPs, as well as trends in the proportion of children having a dental visit from 2001 to 2016. Multiple logistic regression was used to assess the association between being given dental checkup advice and having a dental visit. RESULTS: Overall, the proportion of children being given dental checkup advice increased from 31.4% in 2001 to 51.8% in 2016 (Trend P < 0.001). No significant increasing trend was found for having a dental visit among those being given dental checkup advice (Trend P > 0.05). Children being given dental checkup advice were more likely to have a dental visit (AOR = 1.54, P < 0.001). CONCLUSIONS: Although there was an increase in the proportion of children being given advice to have dental checkups by PCPs from 2001 to 2016, there was no significant increase in having a dental visit among children being given the advice. More research is needed to better understand how dental care advice from a PCP can effectively motivate and facilitate dental care for children.

Summary Objectives Predictive resting metabolic rate (RMR) equations in Australian populations are at least 10 years old, focused on males and do not commonly use overweight and obese weight categorisation. The aim of this study was to measure RMR via indirect calorimetry in overweight and obese Australian adults to develop population specific predictive equations and compare with other well-known international equations (Mifflin–St. Jeor, Owen and WHO/FAO/UNU). Methods Retrospective data from 278 participants (154 males, 124 females: 37% overweight, 63% obese) who had attended a weight management clinic were used to develop predictive RMR equations. These were then validated against another sample (from the same clinic) of 297 participants (150 males, 147 females: 47% overweight, 53% obese), and their accuracy compared with known standard equations. Results For the prediction sample, weight, BMI, resting VO 2 and measured RMR were significantly greater in the obese than overweight. Using the validation sample, the predictive equations met a ±10% of measured RMR criterion 42% (females), 41% (total sample) and 40% (males) of the time. Prediction accuracy was not improved by using specific overweight and obese weight category equations, or by applying the known standard equations from the literature. Conclusions In our sample of overweight and obese adults, RMR prediction to within ±10% of the measured value was only accurate ∼40% of the time, regardless of gender and weight classification. In clinical weight management settings direct measures of RMR should be made wherever possible.

Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, r 2 = 0.86, P < 0.0001, log 10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.)

Background Rapid arterial occlusion evaluation (RACE) scale is a valid prehospital tool used to predict large vessel occlusion of major cerebral arteries in patients with suspected acute stroke. RACE scale administered by Emergency medicine services (EMS) technicians in the prehospital setting correlates well with NIH Stroke Scale score after patient arrival at a hospital. Despite this, the RACE scale is often characterized as too difficult for EMS technicians to accurately utilize. There are no data examining RACE scale accuracy in the prehospital setting comparing EMS technicians with neurologists. We sought to examine agreement between RACE scores calculated by EMS technicians and stroke neurologists in the prehospital setting during telestroke consultation. Methods Data for this observational cohort study were prospectively collected and retrospectively analyzed. EMS technicians in person and stroke specialized neurologists via televideo connection independently assessed suspected stroke patients and calculated RACE scores in the prehospital setting. We used a linearly weighted Cohen's kappa (kw) to estimate the extent of agreement for RACE score between EMS technicians and stroke neurologists. Results Thirty-one patients with stroke symptoms were independently examined and assessed with the RACE scale by EMS technicians and stroke neurologists in the prehospital setting. Exact agreement on the RACE score was found in 24 of 31 (77%) patients. We found very good agreement between EMS technicians and stroke neurologists, kw = .818 (95% CI, .677-.960), P Conclusions EMS technicians provide reliable RACE assessments in patients with suspected stroke, with agreement similar to stroke specialized neurologists in the prehospital setting.

Misregulation of the processes controlling eukaryotic gene expression can result in disease. Gene expression is influenced by the surrounding chromatin; hence the nuclear environment is also of vital importance. Recently, understanding of chromatin hierarchical folding has increased together with the discovery of membrane-less organelles which are distinct, dynamic liquid droplets that merge and expand within the nucleus. These 'sieve'-like regions may compartmentalize and separate functionally distinct regions of chromatin. This article aims to discuss recent studies on nuclear phase within the context of poly(ADP-ribose), ATP, and Mg

Background Congenital idiopathic clubfoot is a condition that affects, on average, approximately 1 in 1,000 infants. One broadly adopted method of management, described by Ponseti, is the performance of a percutaneous complete tenotomy when hindfoot stall occurs. The use of onabotulinum toxin A (BTX-A) along with the manipulation and cast protocol described by Ponseti has been previously reported. Our goal was to compare the clinical outcomes between BTX-A and placebo injections into the gastrocnemius-soleus muscle at the time of hindfoot stall in infants with idiopathic clubfoot treated with the Ponseti method of manipulation and cast changes. Methods This was a double-blind, placebo-controlled, parallel-group study with balanced randomization. Results At 6 weeks after the study injection (T1), 66% of the 32 feet in the BTX-A arm and 63% of the 30 in the placebo arm responded to the treatment (i.e., obtained ≥15° of dorsiflexion). Seven of the 11 patients in the BTX-A arm and all of the 11 in the placebo arm who had not responded at T1 responded to a rescue BTX-A injection at 12 weeks after the first injection (T2). The combined response rate at T2, which included the first-time responders as well as the patients who did not respond at T1 but did at T2, was 88% in the BTX-A arm and 100% in the placebo arm, culminating in a 94% response rate at T2. At T3 (2 years of age), 89% of the feet continued to respond and there was an 8% surgical rate. Conclusions There was no difference in outcomes between the BTX-A and placebo groups when the injection was performed at the time of hindfoot stall. Overall, 92% of the clubfeet in this study responded to a manipulation and cast protocol alone, with or without BTX-A injection, by 12 weeks after hindfoot stall, or we can say that 92% of the clubfeet did not require percutaneous Achilles tendon lengthening by 2 years of age. The need for tenotomy is limited to those who have not responded to treatment at this point, and the need for surgery is limited to those for whom all attempts at treatment with sequential casts, BTX-A, and percutaneous Achilles tendon lengthening have failed. Level of evidence Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Objectives Our objective was to develop population pharmacokinetic (PK) models for ceftazidime and avibactam in the plasma and epithelial lining fluid (ELF) of healthy volunteers and to compare ELF concentrations to plasma PK/pharmacodynamic (PD) targets. Methods Plasma and ELF population PK models were developed for ceftazidime and avibactam concentration data from 42 subjects (NCT01395420). Two- and three-compartment plasma PK models were fitted to ceftazidime and avibactam plasma PK data, and different plasma–ELF linked models were evaluated. Using best-fitting models, plasma and ELF concentration–time profiles were simulated for 1000 subjects. ELF concentration–time profiles for ceftazidime/avibactam 2000–500 mg every 8 h were compared with plasma PK/PD targets for ceftazidime (50% of time above [fT >] 8 mg/l) and avibactam (50% fT > 1 mg/l). Results Three-compartment PK models best fitted the plasma concentration data for ceftazidime and avibactam. ELF data for both drugs were best described by a direct response (instantaneous equilibrium) model. Ceftazidime plasma–ELF relationships were best described by a saturable Michaelis–Menten model. For avibactam, departure from plasma–ELF relationship linearity was more modest than for ceftazidime. ELF:plasma penetration ratios of both ceftazidime (52%) and avibactam (42%) at plasma concentrations relevant for efficacy (~ 8 mg/l for ceftazidime and ~ 1 mg/l for avibactam) were greater than previously calculated using non-compartmental area under the curve (AUC) methods, which average across the entire concentration range. Ceftazidime and avibactam ELF exposures exceeded their respective plasma PK/PD time-above-threshold targets by the dosing interval mid-point in most subjects. Conclusions This compartmental modelling analysis suggests ELF exposures of both ceftazidime and avibactam exceed levels required for efficacy in plasma.

For recently licensed antibiotics, such as the cephalosporin ceftaroline fosamil, probability of target attainment (PTA) curves, showing the percentage of patients reaching a predefined pharmacokinetic (PK)/pharmacodynamic (PD) target at different bacterial minimum inhibitory concentrations (MICs), have been used to support and justify dose recommendations across patient populations. However, information on PTA for older antibiotics is limited. A retrospective analysis was conducted to construct PTA curves for 4 antibiotics against Staphylococcus aureus in patients with complicated skin and soft tissue infections (cSSTIs). PK models for vancomycin, linezolid, daptomycin, and ceftriaxone were selected from the literature based on large numbers of subjects with covariates representative of patients in Europe and/or the United States. An existing model was available for ceftaroline fosamil. Standard and high-dosage regimens were used to compare the PTA of each antibiotic at MIC values 0.03 to 64 mg/L for a simulated set of patients with cSSTI caused by S. aureus. These were compared to proportions of S. aureus isolates at each MIC from global surveillance data. Ceftaroline achieved PTAs >99.9% for bacteriostatic and bactericidal targets at the MIC90 (1 mg/L), whereas the comparators failed to achieve PTAs >90%, at bacteriostatic or bactericidal targets, even when clinical doses were increased beyond those recommended. PTA analysis can be used to compare different drugs with the same simulated patient dataset, subject to availability of an appropriate PK model and robust exposure targets. This analysis shows that some antibiotics commonly used to treat cSSTIs may fail to reach high PTAs relative to contemporary MIC90 estimates.

Background: Up to 40% of patients with idiopathic clubfoot who are treated with the Ponseti method experience recurrence of deformity. Many of these patients receive surgery (e.g., anterior tibial tendon transfer). An alternative approach for recurrent clubfoot is repeat Ponseti casting. The purpose of this study was to evaluate the outcome of repeat Ponseti casting in the treatment of recurrent clubfoot. Methods: Patients with recurrent idiopathic clubfoot who were treated at our hospital, between 2004 and 2012, with repeat serial casting and bracing (the recurrent group) were eligible for inclusion in the study. The recurrent group and a control group of randomly selected patients seen during the same period who had not had recurrence were compared with respect to demographic data, age at the time of treatment, number of casts, subsequent surgical intervention(s), and the Disease-Specific Instrument (DSI) clubfoot scale. Patients were deemed to have a successful outcome if they had a well-corrected foot (defined as dorsiflexion of ≥10°, hindfoot in valgus, and a straight lateral border) at the time of follow-up. Results: Of a total of 71 eligible patients with clubfeet, 35 patients participated. At the time of follow-up, success rates were 74% for the recurrent group and 83% for the control group. Dorsiflexion past neutral was significantly higher in the control group than the patient group (20° versus 12°, respectively; p < 0.001). Ninety-five percent of the control subjects had a straight lateral border in comparison with 78% in the recurrent group (p = 0.004). Likewise, 97% of controls had the hindfoot in valgus in comparison with 80% of the recurrent group (p = 0.02). There was a significant difference in the ability to squat (76% in the control group and 43% in the recurrent group; p = 0.03). There was no difference between groups in the total outcome of the DSI. Conclusions: Recurrence was seen in 19% (71) of 382 children who were eligible for our study who were typically discharged after the age of 5 years from our clinic, indicating the importance of continued follow-up until after that age. Treatment with casting was successful in many patients and may be a reasonable choice for recurrent idiopathic clubfeet. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

HighlightsPeptidyl arginine deiminase 2 (PADI2) citrullinates arginine1810 (cit1810) present at carboxy-terminal domain of RNA polymerase II (RNAP2-CTD).PADI2 and R1810 of RNAP2-CTD regulate transcription and proliferation of breast cancer cells.Absence of cit1810 at RNAP2-CTD leads to RNAP2 accumulation at proximal promoter regions.Cit1810 at RNAP2-CTD facilitate interaction with P-TFEb complex.SUMMARYThe post-translational modification of key residues at the carboxy-terminal domain of RNA polymerase II (RNAP2-CTD), coordinates transcription, splicing, and RNA processing by modulating its capacity to act as a landing platform for a variety of protein complexes. Here, we identify a new modification at the CTD, the deimination of arginine and its conversion to citrulline by peptidyl arginine deiminase 2 (PADI2), an enzyme that has been associated with several diseases including cancer. We show that among PADI family members, only PADI2 citrullinates R1810 (Cit1810) at repeat 31 of the CTD. Depletion of PADI2 or loss of R1810 result in accumulation of RNAP2 at transcription start sites, reduced gene expression and inhibition of cell proliferation. Cit1810 is needed for interaction with the P-TEFb (positive transcription elongation factor b) kinase complex and for its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells.

Aims High-quality clinical research in children’s orthopaedic surgery has lagged behind other surgical subspecialties. This study used a consensus-based approach to identify research priorities for clinical trials in children’s orthopaedics. Methods A modified Delphi technique was used, which involved an initial scoping survey, a two-round Delphi process and an expert panel formed of members of the British Society of Children’s Orthopaedic Surgery. The survey was conducted amongst orthopaedic surgeons treating children in the United Kingdom and Ireland. Results A total of 86 clinicians contributed to both rounds of the Delphi process, scoring priorities from one (low priority) to five (high priority). Elective topics were ranked higher than those relating to trauma, with the top ten elective research questions scoring higher than the top question for trauma. Ten elective, and five trauma research priorities were identified, with the three highest ranked questions relating to the treatment of slipped capital femoral epiphysis (mean score 4.6/ 5), Perthes’ disease (4.5) and bone infection (4.5). Conclusion This consensus-based research agenda will guide surgeons, academics and funders to improve the evidence in children’s orthopaedic surgery and encourage the development of multicentre clinical trials. Cite this article: Bone Joint J 2018;100-B:680–4.

Hepsin is a membrane-anchored serine protease whose role in hepatocyte growth factor (HGF) signaling and epithelial integrity makes it a target of therapeutic interest in carcinogenesis and metastasis. Using an integrated design, synthesis, and screening platform, we were able to rapidly develop potent and selective inhibitors of hepsin. In progressing from the initial hit 7 to compound 53, the IC50 value against hepsin was improved from ∼1 μM to 22 nM, and the selectivity over urokinase-type plasminogen activator (uPA) was increased from 30-fold to >6000-fold. Subsequent in vitro ADMET profiling and cellular studies confirmed that the leading compounds are useful tools for interrogating the role of hepsin in breast tumorigenesis.

Aims To analyse outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with radium 223 (Ra-223) across the Yorkshire and Humber Cancer Network. Materials and methods A regional, multicentre, retrospective cohort study of 189 men undergoing Ra-223 for mCRPC between March 2014 and April 2017 was undertaken. Factors predicting overall survival and completion of planned treatment were assessed. Results The median overall survival for the entire cohort was 10.5 months. Those completing five to six cycles of Ra-223 had a higher overall survival of 18.6 months. On multivariable analysis, four factors remained independent significant predictors of overall survival: age (P = 0.005, hazard ratio 1.07 [1.02–1.12]); number of cycles of Ra-223: 5–6 versus 1–4 (P ≤ 0.001, hazard ratio 0.10 [0.005–0.20]); baseline alkaline phosphatase (P = 0.044, hazard ratio 1.06 [1.002–1.12]); neutrophil-to-lymphocyte ratio (P = 0.033, hazard ratio 1.19 [1.01–1.40]). Baseline performance status 0 versus 2 (P = 0.026, odds ratio 0.080 [0.001–0.74]) and higher baseline haemoglobin (P = 0.028, odds ratio 1.04 [1.004–1.074]) were independent predictors of the completion of five to six cycles of Ra-223. Conclusions Younger age, completion of five to six cycles of Ra-223, lower alkaline phosphatase and neutrophil-to-lymphocyte ratio are predictors of overall survival. This is the first study to report neutrophil-to-lymphocyte ratio as an independent predictor of overall survival in a Ra-223 cohort. Good performance status and higher baseline haemoglobin predict the completion of five to six cycles of Ra-223.

Chemotherapy for tuberculosis (TB) is lengthy and could benefit from synergistic adjuvant therapeutics that enhance current and novel drug regimens. To identify genetic determinants of intrinsic antibiotic susceptibility in Mycobacterium tuberculosis , we applied a chemical genetic interaction (CGI) profiling approach. We screened a saturated transposon mutant library and identified mutants that exhibit altered fitness in the presence of partially inhibitory concentrations of rifampin, ethambutol, isoniazid, vancomycin, and meropenem, antibiotics with diverse mechanisms of action. This screen identified the M. tuberculosis cell envelope to be a major determinant of antibiotic susceptibility but did not yield mutants whose increase in susceptibility was due to transposon insertions in genes encoding efflux pumps. Intrinsic antibiotic resistance determinants affecting resistance to multiple antibiotics included the peptidoglycan-arabinogalactan ligase Lcp1, the mycolic acid synthase MmaA4, the protein translocase SecA2, the mannosyltransferase PimE, the cell envelope-associated protease CaeA/Hip1, and FecB, a putative iron dicitrate-binding protein. Characterization of a deletion mutant confirmed FecB to be involved in the intrinsic resistance to every antibiotic analyzed. In contrast to its predicted function, FecB was dispensable for growth in low-iron medium and instead functioned as a critical mediator of envelope integrity.

Recruitment of individuals into clinical trials is a critical step in completing studies. Reports examining the effectiveness of different recruitment strategies, and specifically in infertile couples, are limited.We investigated recruitment methods used in two NIH sponsored trials, Pregnancy in Polycystic Ovary Syndrome (PPCOS II) and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), and examined which strategies yielded the greatest number of participants completing the trials.3683 couples were eligible for screening. 1650 participants were randomized and 1339 completed the trials. 750 women were randomized in PPCOS II; 212 of the participants who completed the trial were referred by physicians. Participants recruited from radio ads (84/750) and the internet (81/750) resulted in similar rates of trial completion in PPCOS II. 900 participants were randomized in AMIGOS. 440 participants who completed the trial were referred to the study by physicians. The next most successful method in AMIGOS was the use of the internet, achieving 78 completed participants. Radio ads proved the most successful strategy in both trials for participants who earned$50,000 annually. Radio ads were most successful in enrolling white patients in PPCOS II and black patients in AMIGOS. Seven ancillary Clinical Research Scientist Training (CREST) sites enrolled 324 of the participants who completed the trials.Physician referral was the most successful recruitment strategy. Radio ads and the internet were the next most successful strategies, particularly for women of limited income. Ancillary clinical sites were important for overall recruitment.

Background and objectives Recombinant human erythropoietin (epoetin) is used routinely to increase blood hemoglobin levels in patients with ESRD and anemia. Although lower doses of epoetin are required to achieve equivalent hemoglobin responses when administered subcutaneously rather than intravenously, standard practice has been to administer epoetin to patients on hemodialysis intravenously. Randomized trials of alternative epoetin treatment regimens in patients with kidney failure have shown that risks of cardiovascular complications and death are related to the dose levels of epoetin used. Therefore, given the dose-sparing advantages of subcutaneous epoetin administration, the possibility that treatment of patients on hemodialysis with subcutaneous epoetin might be associated with more favorable outcomes compared with intravenous treatment was investigated. Design, setting, participants, & measurements A retrospective cohort study of 62,710 adult patients on hemodialysis treated with either intravenous or subcutaneous epoetin-α and enrolled in the Centers for Medicare and Medicaid Services ESRD Clinical Performance Measures Project from 1997 to 2005 was carried out. Risks of death and/or hospitalization for cardiovascular complications (adverse composite event outcomes) during 2 years of follow-up were determined in relationship to epoetin dose and route of administration (intravenous versus subcutaneous) by multivariate Cox proportional hazard modeling adjusted for demographics and clinical parameters. Results Epoetin doses used to achieve equivalent hemoglobin responses in study patients were, on average, 25% higher when epoetin was administered intravenously rather than subcutaneously (as expected). Moreover, adverse composite event outcomes were found to be significantly more likely to occur during follow-up for patients on hemodialysis managed with intravenous rather than subcutaneous epoetin (adjusted hazard ratio for adverse events within 1 year [intravenous versus subcutaneous] was 1.11 [95% confidence interval, 1.04 to 1.18]). Conclusions This study finds that treatment of patients on hemodialysis with subcutaneous epoetin is associated with more favorable clinical outcomes than those associated with intravenous epoetin treatment.