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Background Posterolateral rotator instability (PLRI) is the most common pattern of recurrent elbow instability and current imaging to aid PLRI diagnosis is limited. Thus, we sought to define use of ultrasound (US) to determine normal lateral ulnohumeral joint measurements, with and without posterolateral drawer testing to provide an insight into how US may aid diagnosis. Methods Sixty elbows were evaluated in thirty healthy volunteers. The lateral ulnohumeral gap (LUHG) was measured with US in the resting position whilst the posterolateral drawer stress test maneuver was applied. Joint laxity was calculated as the difference between maximum stress and average rest measurements. Two independent readers assessed each elbow with comparison performed between stress and rest positions. Results: differences in LUHG were evident between stress and rest conditions (Reader 1: p Conclusions This study demonstrates a dynamic US assessment for PLRI, which aimed to assess the usefulness and feasibility of a laxity measurement following the application of a posterolateral drawer stress maneuver in a healthy population. Whilst establishing concordance between readers in measuring a LUHG under stress, the utility of a laxity measurement alone is not clear as correlation of measurements is not excellent, hence an upper limit of normal (ULN) for the ulnohumeral gap under stress maybe more useful. Further evaluation of this technique is required in patients with PLRI.

Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer’s disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.

The mechanism producing psychosis appears to include hippocampal inflammation, which could be associated with the microbiome-gut-brain-axis (MGBS). To test this hypothesis we are conducting a multidisciplinary study, herein described. The procedures are illustrated with testing of a single subject and group level information on the impact of C-section birth are presented. Method Study subjects undergo research diagnostic interviews and symptom assessments to be categorized into one of 3 study groups: psychosis, nonpsychotic affective disorder or healthy control. Hippocampal volume and metabolite concentrations are assessed using 3-dimensional, multi-voxel H1 Magnetic Resonance Imaging (MRSI) encompassing all gray matter in the entire hippocampal volume. Rich self-report information is obtained with the PROMIS interview, which was developed by the NIH Commons for research in chronic conditions. Early trauma is assessed and cognition is quantitated using the MATRICS. The method also includes the most comprehensive autonomic nervous system (ANS) battery used to date in psychiatric research. Stool and oral samples are obtained for microbiome assessments and cytokines and other substances are measured in blood samples. Results Group level preliminary data shows that C-section birth is associated with higher concentrations of GLX, a glutamate related hippocampal neurotransmitter in psychotic cases, worse symptoms in affective disorder cases and smaller hippocampal volume in controls. Conclusion Mode of birth appears to have persistent influences through adulthood. The methodology described for this study will define pathways through which the MGBA may influence the risk for psychiatric disorders.

Cel pracyCelem badania była ocena skuteczności i bezpieczeństwa leczenia elektrowstrząsowego w populacji pacjentów ≥ 65 latMetodaOmawiane badanie miało charakter naturalistyczny, retrospektywny. Do badania włączono 65 pacjentów, kobiety i mężczyzn hospitalizowanych w oddziałach Instytutu Psychiatrii i Neurologii i poddawanych terapii EW. Analizowano przebieg 615 zabiegów przeprowadzonych w latach 2015-2019. Skuteczność EW oceniano z wykorzystaniem skali CGI-S. Bezpieczeństwo oceniano analizując działania niepożądane terapii, uwzględniając obciążenia somatyczne grupy badanych.WynikiAż 94 % pacjentów wyjściowo spełniało kryteria lekooporności. W badanej grupie nie odnotowano poważnych powikłań takich jak zgon, stan zagrożenia życia, konieczność hospitalizacji na innym oddziale czy trwały uszczerbek na zdrowiu. Łącznie w całej grupie działania niepożądane odnotowano u 47,7% starszych pacjentów, w większości przypadków (88%) miały one niewielkie nasilenie i ustępowały bez stosowania żadnego specyficznego postępowania. Najczęściej obserwowanym działaniem niepożądanym EW były wzrosty ciśnienia tętniczego (55,4%). Czterech pacjentów nie ukończyło terapii EW z powodu działań niepożądanych. U większości badanych (86,2%) wykonano co najmniej 8 zabiegów w serii. Zabiegi EW okazały się być skuteczną metodą leczenia w populacji pacjentów po 65 roku życia - reakcję na leczenie stwierdzono u 76,92% chorych, a remisję u 49, 23% leczonych osób. Wyjściowe nasilenie choroby w skali CGI-S wyniosło średnio 5,54, po leczeniu EW 2,67.WnioskiTolerancja zabiegów jest po 65 r.ż gorsza niż u młodszych pacjentów, większość działań niepożądanych jest związana z wyjściowymi obciążeniami somatycznymi, głównie dotyczącymi układu sercowo-naczyniowego. Nie zmienia to faktu, że terapia EW jest w tej populacji wysoce skuteczna i może stanowić bardzo dobrą alternatywę dla często nieskutecznej lub powodującej uboczne działania farmakoterapii.

Various advantages are directing the attention to modular multilevel converters (MMCs). Simple ways to balance the voltage difference of MMC modules are strongly desired but an open problem. The modular multilevel series/parallel converter (MMSPC) can be an efficient solution for this problem. However. implementing an effective control method is essential for close-to-optimum operation of MMSPCs. Generally, on the higher level of control, various modulation techniques can control the output, while a scheduler balances the module voltages on a lower control level. This paper proposes a simple yet powerful module scheduling method for MMSPCs. This scheduling method can be combined with many modulation techniques, such as nearest level modulation (NLM). It reduces the control complexity using the sensorless balancing capability, improves efficiency by minimizing the conduction loss, and achieves a compromise between balancing the module voltages and switching loss. Though applicable to other modulation methods, simulation and experiments combine the proposed method with NLM for a comparison with prior-art of scheduling. Based on the presented results and analysis, the algorithm is suited particularly for MMSPCs with low to medium number of modules. The proposed technique achieves 1855% reduction in power loss and 7.5% improvement in capacitor currents compared to other algorithms.

Transportation is a stressful event for cattle, as it may involve various handling practices, commingling, deprivation of food and water, and fluctuating temperatures. Calves are particularly susceptible to these stressors because their physiological and immune systems are still developing. There has been no formal synthesis of the scientific literature evaluating the effect of transportation on young dairy calf health and performance; the aim of this scoping review is to describe and characterize this body of work. We targeted both descriptive and analytic studies examining transport of calves, including listing how the effect of transport has been evaluated. Eight databases were searched for relevant articles with eligible studies being primary research articles investigating transportation of calves of either sex who were younger than 60 d of age or weighed less than 100 kg. Two reviewers independently screened the title and abstracts of 6,859 articles with 361 potentially relevant articles screened at full text. Of these, 46 were relevant and had data extracted. Articles reporting study location were conducted in the United States (n = 5), Australia (n = 3), Japan (n = 3), and New Zealand (n = 3). Common transport-related variables evaluated included time in transit (n = 13), distance of transportation (n = 8), vehicle-related factors (n = 8), and age at time of transportation (n = 4). Outcome measures varied greatly, including blood parameters (n = 28), health assessments (n = 20), weight (n = 17), behavioral metrics (n = 14), mortality (n = 7), feed intake following transportation (n = 4), salivary cortisol concentrations (n = 3), morbidity (n = 3), and isolation of Salmonella Dublin in fecal samples (n = 2). Outcome parameters were measured during transport or ranged from immediately after to one year following transportation. As the transport-related risk factors and outcomes measured assessed varied widely between studies, future quantitative synthesis (e.g., meta-analysis) in this area may be limited. Several knowledge gaps were identified, including methods to prepare calves for transportation, such as improving nutrition, administering medication, or transporting calves at an older age or weight. Further research could also focus on consistent and clear reporting of key items related to study conduct and analysis, as well as the development of a core outcome set for calf transport studies.

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia and/or heart failure. Diagnosis of cardiac sarcoidosis can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of cardiac sarcoidosis. Mainstay therapy for cardiac sarcoidosis is immunosuppression, however no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in cardiac sarcoidosis call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.

At the end of 2019, an outbreak of a new coronavirus, called SARS–CoV–2, was reported in China and later in other parts of the world. First infection reported in Germany by the end of January 2020 and on March 16th, 2020 the federal government announced a partial lockdown in order to mitigate the spread. Since the dynamics of new infections started to slow down, German states started to relax the confinement measures as to May 6th, 2020. As a fall back option, a limit of 50 new infections per 100,000 inhabitants within seven days was introduced for each district in Germany. If a district exceeds this limit, measures to control the spread of the virus should be taken. Based on a multi–patch SEAIRD–type model, we will simulate the effect of choosing a specific upper limit for new infections. We investigate, whether the politically motivated bound is low enough to detect new outbreaks at an early stage. Subsequently, we introduce an optimal control problem to tackle the multi–criteria problem of finding a bound for new infections that is low enough to avoid new outbreaks, which might lead to an overload of the health care system, but is large enough to curb the expected economic losses.

Purpose Over 1 billion doses of COVID-19 vaccines have been already administered across the United States, the United Kingdom and the European Union at the time of writing. Furthermore, 1.82 million booster doses have been administered in the US since 13th August, and similar booster programmes are currently planned or under consideration in the UK and the EU beginning in the autumn of 2021. Early reports showed an association between vaccine administration and the development of ipsilateral axillary and supraclavicular lymphadenopathy, which could interfere with the diagnosis, treatment and follow-up of breast cancer patients. In this paper, we review the available evidence on vaccine-related lymphadenopathy, and we discuss the clinical implications of the same on breast cancer diagnosis and management. Methods A literature search was performed - PubMed, Ovid Medline, Scopus, CINHAL, Springer Nature, ScienceDirect, Academic Search Premier and the Directory of Open Access Journals were searched for articles reporting on regional palpable or image-detected lymphadenopathy following COVID-19 vaccination. Separately, we compiled a series of case studies from the University Hospitals of Derby and Burton, United Kingdom and the Mayo Clinic in Minnesota, United States of America, to illustrate the impact that regional lymphadenopathy post-COVID-19 vaccination can have on the diagnosis and management of patients being seen in diagnostic and therapeutic breast clinics. Results From the literature search, 15 studies met the inclusion criteria (n = 2057 patients, 737 with lymphadenopathy). The incidence of lymphadenopathy ranged between 14.5% and 53% and persisted for >6 weeks in 29% of patients. Conclusions Clinicians managing breast cancer patients should be aware that the COVID-19 vaccination may result in regional lymphadenopathy in a significant number of patients, which can result in unnecessary investigations, treatment and increased patient anxiety. An accurate COVID-19 vaccination history should be collected from all patients where regional lymphadenopathy is a clinical and/or an imaging finding and then combined with clinical judgement when managing individual cases.

Background Several authors have recently compared the outcomes and complications of surgical procedures that preserve or remove the uterus in the treatment of pelvic organ prolapse (POP) and stress urinary incontinence (SUI). Following the publication of several high quality randomized control trials on this topic we performed a new systematic review and meta analysis of this data. Methods We performed a systematic literature search in ClinicalTrials.gov, PubMed, Scopus, Ovid, EBSCO host, Science Direct, Web of Science, and Cochrane CENTRAL for randomized controlled and cohort trials of uterine sparing prolapse repair (hysteropexy) versus hysterectomy with suspension. A total of 1285 patients from 14 studies were included in our systematic review and meta-analysis. Results Uterine sparing procedures (hysteropexy) were comparable to hysterectomy with suspension for recurrence rates (RR = 0.908, 95% CI [0.385, 2.143]), reoperation rates (RR = 1.517, 95% CI [0.802, 2.868]), length of hospital stay, (SMD = − 0.159 days, 95% CI [−0.375, 0.057]), voiding dysfunction (RR = 1.089, 95% CI [0.695, 1.706]), and intraoperative blood loss (SMD = − 0.339, 95% CI [−0.631, 0.047]). However, hysteropexy had shorter operative time than hysterectomy with suspension (SMD = − 1.191 h, 95% CI [−1.836, −0.545]), and fewer visceral injuries (RR = 0.421, 95% CI [0.244, 0.725]). Conclusion We found no significant differences in the outcomes or major complications of uterine preserving surgical procedures versus those which include hysterectomy in the treatment of POP. Hysteropexy procedures may be associated with a shorter operative time and fewer visceral injuries. This is consistent with older analyses.

PURPOSE The risk of prostate cancer among persons living with human immunodeficiency virus (PWH) is not well understood and may be obscured by different opportunities for detection. MATERIALS AND METHODS We identified 123,472 (37,819 PWH and 85,653 comparators) men enrolled in the Veterans Aging Cohort Study, a prospective national cohort of PWH and demographically matched, uninfected comparators in 2000-2015. We calculated rates of prostate specific antigen (PSA) testing by human immunodeficiency virus (HIV) status and fit multivariable Poisson models comparing the rates of PSA testing, prostate biopsy, and cancer incidence. RESULTS The mean age at enrollment was 52 years. Rates of PSA testing were lower in PWH versus uninfected comparators (0.58 versus 0.63 tests per person-year). Adjusted rates of PSA screening and prostate biopsy were lower among PWH (incidence rate ratio [IRR] 0.87, 95% CI 0.75-0.84 and IRR 0.79 95% CI 0.74-0.83, respectively). The crude IRR for prostate cancer was lower in PWH versus controls (IRR 0.90, 95% CI 0.83-0.97). However, in a multivariable model adjusting for PSA testing, cancer incidence was similar by HIV status (IRR=0.93, 95% CI 0.86-1.01, p=0.08). Among patients who received a prostate biopsy, incidence of prostate cancer did not differ significantly by HIV status (IRR 1.06, 95% CI 0.98-1.15, p=0.15). Among incident cancers, there were significant differences in the distributions of Gleason grade (p=0.05), but not cancer stage (p=0.14) by HIV status. CONCLUSIONS When accounting for less PSA testing among PWH, the incidence of prostate cancer was similar by HIV status. These findings suggest that less screening contributed to lower observed incidence of prostate cancer in PWH.

Background Long COVID, defined as the presence of coronavirus disease 2019 (COVID-19) symptoms ≥28 days after clinical onset, is an emerging challenge to healthcare systems. The objective of the current study was to explore recovery phenotypes in nonhospitalized individuals with COVID-19. Methods A dual cohort, online survey study was conducted between September 2020 and July 2021 in the neighboring European regions Tyrol (TY; Austria, n = 1157) and South Tyrol (STY; Italy, n = 893). Data were collected on demographics, comorbid conditions, COVID-19 symptoms, and recovery in adult outpatients. Phenotypes of acute COVID-19, postacute sequelae, and risk of protracted recovery were explored using semi-supervised clustering and multiparameter least absolute shrinkage and selection operator (LASSO) modeling. Results Participants in the study cohorts were predominantly working age (median age [interquartile range], 43 [31–53] years] for TY and 45 [35–55] years] for STY) and female (65.1% in TY and 68.3% in STY). Nearly half (47.6% in TY and 49.3% in STY) reported symptom persistence beyond 28 days. Two acute COVID-19 phenotypes were discerned: the nonspecific infection phenotype and the multiorgan phenotype (MOP). Acute MOP symptoms encompassing multiple neurological, cardiopulmonary, gastrointestinal, and dermatological symptoms were linked to elevated risk of protracted recovery. The major subset of individuals with long COVID (49.3% in TY; 55.6% in STY) displayed no persistent hyposmia or hypogeusia but high counts of postacute MOP symptoms and poor self-reported physical recovery. Conclusions The results of our 2-cohort analysis delineated phenotypic diversity of acute and postacute COVID-19 manifestations in home-isolated patients, which must be considered in predicting protracted convalescence and allocating medical resources.

Objective Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without. Conclusions A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

Purpose:It remains unclear whether preoperative central graft thickness (CGT) contributes to visual outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK). This retrospective cohort study examined the ability of preoperative and postoperative CGT to predict 12-month best spectacle-corrected visual acuity (BSCVA) after DSAEK for Fuchs endothelial corneal dystrophy/moderate pseudophakic bullous keratopathy/second graft.Methods:All consecutive patients who underwent DSAEK in 2015 to 2018 were included. The primary end point was 12-month BSCVA. DSAEK-CGT was measured preoperatively and 6 times between postoperative day 8 and month 12. Eyes were divided according to preoperative CGT 130 m (ultrathin-DSAEK threshold) or 6-month postoperative CGT 100 m (mean 6-month postoperative DSAEK-CGT). The t test assessed CGT evolution of the 4 groups over time. Multivariate analyses examined whether preoperative CGT or 6-month CGT categories predicted 12-month BSCVA. Multivariate analysis assessed the preoperative/perioperative factors that predicted 6-month CGT.Results:A total of 108 eyes (68 patients) underwent DSAEK. Preoperative CGT was >130 and ≤130 m in 87 and 21 eyes, respectively. Postoperative CGT was >100 and ≤100 m in 50 and 58 eyes, respectively. Thin 6-month postoperative grafts thinned significantly more relative to preoperative thickness than thick grafts (P < 0.001). Preoperative CGT subgroups did not show this difference. Six-month postoperative CGT (P = 0.01), but not preoperative CGT, predicted 12-month BSCVA. Preoperative CGT strongly predicted 6-month CGT (P = 0.0003).Conclusions:Postoperative, but not preoperative, DSAEK-CGT predicted 6-month BSCVA. The correlation between preoperative and postoperative CGT and interstudy variation in preoperative CGT measurement accuracy may explain literature disparities regarding the importance of preoperative CGT in DSAEK outcomes.

Modular multilevel converters (MMCs) feature an established topology for the highest voltage and power levels. For lower levels, MMCs find a wide range of applications in generation, energy storage, and electric motor drive. However, the large quantity of expensive voltage sensors as well as high data-processing requirements for the module voltage balancing remains an obstacle. Additionally, the stark cost reductions of power electronic semiconductors have reduced their share in the total cost and rendered initially uneconomical module topologies appealing in low and medium voltages. In this article, we proposed an MMC topology with an active clamping path that balances the voltage of the modules in an arm. The proposed structure can achieve sensorless voltage balancing with a minimum control effort. The sensorless operation has the added benefit of reducing the communication as well as computation demand between the modules and the central controller. As compared with the state-of-the-art voltage balancing schemes, the proposed solution achieves a balanced system operation with less power loss, fewer components, and without any measurement. The presented analysis as well as the simulation and experimental results verify the benefits of the proposed topology. The results demonstrate that even in the face of a severe imbalance, all the module voltages are maintained within tight boundaries.

Background and Objective Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin). Methods In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism. In addition, two open-label, fixed-treatment period, phase I studies in healthy male volunteers are described. Period 1: participants received oral BI 425809 25 mg (single dose) on day 1; period 2: participants received multiple doses, across 10 days, of oral itraconazole or rifampicin combined with a single dose of oral BI 425809 25 mg on day 4/7 of the itraconazole/rifampicin treatment, respectively. Pharmacokinetic and safety endpoints were assessed in the absence/presence of itraconazole/rifampicin and included area under the concentration-time curve (AUC) over the time interval 0–167 h (AUC0‒167; itraconazole), 0–168 h (AUC0‒168; rifampicin), or 0–infinity (AUC0-∞; rifampicin and itraconazole), maximum measured concentration (Cmax) of BI 425809, and adverse events. Results In vitro results suggested that CYP3A4 accounted for ≥ 90% of the metabolism of BI 425809. BI 425809 exposure (adjusted geometric mean ratio [%]) was higher in the presence of itraconazole (AUC0‒167: 265.3; AUC0−∞: 597.0; Cmax: 116.1) and lower in the presence of rifampicin (AUC0‒168: 10.3; AUC0−∞: 9.8; Cmax: 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated. Conclusions Systemic exposure of BI 425809 was altered in the presence of strong CYP3A4 modulators, corroborating in vitro results that CYP3A4 mediates a major metabolic pathway for BI 425809. Trial Registration Number NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017) Supplementary Information The online version contains supplementary material available at 10.1007/s13318-021-00723-y.

Background Type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) are two chronic diseases that cause a tremendous burden. To reduce this burden, several programmes for optimising the care for these diseases have been developed. In Germany, so-called disease management programmes (DMPs), which combine components of Disease Management and the Chronic Care Model, are applied. These DMPs have proven effective. Nevertheless, there are opportunities for improvement. Current DMPs rarely address self-management of the disease, make no use of peer support, and provide no special assistance for persons with low health literacy and/or low patient activation. The study protocol presented here is for the evaluation of a programme that addresses these possible shortcomings and can be combined with current German DMPs for T2DM and CHD. This programme consists of four components: Meetings of peer support groups Personalised telephone-based health coaching for patients with low literacy and/or low patient activation Personalised patient feedback A browser-based web portal Methods Study participants will be adults enrolled in a DMP for T2DM and/or CHD and living in North Rhine-Westphalia, a state of the Federal Republic of Germany. Study participants will be recruited with the assistance of their general practitioners by the end of June 2021. Evaluation will be performed as a pragmatic randomised controlled trial with one intervention group and one waiting control group. The intervention group will receive the intervention for 18 months. During this time, the waiting control group will continue with usual care and the usual measures of their DMPs. After 18 months, the waiting control group will also receive a shortened intervention. The primary outcome is number of hospital days. In addition, the effects on self-reported health-state, physical activity, nutrition, and eight different psychological variables will be investigated. Differences between values at month 18 and at the beginning will be compared to judge the effectiveness of the intervention. Discussion If the intervention proves effective, it may be included into the DMPs for T2DM and CHD. Trial registration The study was registered in the German Clinical Trials Registry (Deutsches Register Klinischer Studien (DRKS)) in early 2019 under the number 00020592. This registry has been affiliated with the WHO Clinical Trials Network (https://www.drks.de/drks_web/setLocale_EN.do) since 2008. It is based on the WHO template, but contains some additional categories for which information has to be given (https://www.drks.de/drks_web/navigate.do?navigationId=entryfields&messageDE=Beschreibung%20der%20Eingabefelder&messageEN=Description%20of%20entry%20fields ). A release and subsequent number assignment only take place when information for all categories has been given.

Bernard Stiegler highlights many of the problems faced by education with respect to the ‘bringing forth’ of knowledge on an individual, collective, and technical level in the Anthropocene. These pr...

Aim: The purpose of this study was to use computational modeling to determine if surgical correction of hip dysplasia restores hip contact mechanics to those of asymptomatic, radiographically normal hips. Methods: Discrete element analysis (DEA) was used to compute joint contact stresses during the stance phase of normal walking gait for 10 individuals with radiographically normal, asymptomatic hips and 10 age- and weight-matched patients with acetabular dysplasia who underwent periacetabular osteotomy (PAO). Results: Mean and peak contact stresses were higher ( p 2 (IQR 378–496 mm2) to 595 mm2 (IQR 474–660 mm2), but remained significantly smaller ( p = 0.001) than that for radiographically normal hips (median 1120 mm2, IQR 853–1444 mm2). Conclusions: While contact mechanics in dysplastic hips more closely resembled those of normal hips after PAO, the elevated contact stresses and smaller contact areas remaining after PAO indicate ongoing mechanical abnormalities should be expected even after radiographically successful surgical correction.

Background In MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR] 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial. Methods The premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n = 72; placebo plus fulvestrant, n = 42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS). Results At the primary objective cutoff (February 14, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR 0.415; 95% CI 0.246–0.698). At the pre-specified OS interim cutoff (20-June-2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR 0.477; 95% CI 0.302–0.755). A numerical OS benefit was observed with abemaciclib plus fulvestrant compared to fulvestrant alone (HR 0.689; 95% CI 0.379–1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR 0.599), TTC (HR 0.674), and CFS (HR 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously. Conclusions Results of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant. Clinical trial registration: NCT02107703. Registered April 08, 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02107703.

Modular multilevel converters (MMCs) enjoy the benefits of modularity and scalability. In particular, MMCs with symmetrical half-bridge submodules enable bipolar operation yet with a simple structure and low conduction losses. However, bulky dc capacitors in MMC submodules act as one major obstacle that retards the further improvement of system size, weight, and cost performance. Additionally, tight regulation and balance of dc capacitor voltages necessitate expensive voltage sensors paired with dedicated voltage controllers. This article proposes an effective hardware-based strategy that achieves MMC capacitance reduction through parallelization of symmetrical half-bridge submodules. On top of capacitance saving, the proposed strategy balances capacitor voltages in a sensorless fashion, which translates into the removal of voltage sensors and great simplification of control efforts. In addition, the proposed strategy allows fault-tolerant operation of MMCs. Finally, simulation and experimental results validate the effectiveness of the proposed strategy in capacitance reduction and capacitor voltage balancing of MMCs as static compensators.

Background Predicting Parkinson's disease (PD) progression may enable better adaptive and targeted treatment planning. Objective Develop a prognostic model using multiple, easily acquired longitudinal measures to predict temporal clinical progression from Hoehn and Yahr (H&Y) stage 1 or 2 to stage 3 in early PD. Methods Predictive longitudinal measures of PD progression were identified by the joint modeling method. Measures were extracted by multivariate functional principal component analysis methods and used as covariates in Cox proportional hazards models. The optimal model was developed from the Parkinson's Progression Marker Initiative (PPMI) data set and confirmed with external validation from the Longitudinal and Biomarker Study in PD (LABS-PD) study. Results The proposed prognostic model with longitudinal information of selected clinical measures showed significant advantages in predicting PD temporal progression in comparison to a model with only baseline information (iAUC = 0.812 vs. 0.743). The modeling results allowed the development of a prognostic index for categorizing PD patients into low, mid, and high risk of progression to HY 3 that is offered to facilitate physician-patient discussion on prognosis. Conclusion Incorporating longitudinal information of multiple clinical measures significantly enhances predictive performance of prognostic models. Furthermore, the proposed prognostic index enables clinicians to classify patients into different risk groups, which could be adaptively updated as new longitudinal information becomes available. Modeling of this type allows clinicians to utilize observational data sets that inform on disease natural history and specifically, for precision medicine, allows the insertion of a patient's clinical data to calculate prognostic estimates at the individual case level. © 2021 International Parkinson and Movement Disorder Society.

BACKGROUND In 2016, SSO Choosing Wisely guidelines recommended against routine sentinel lymph node (SLN) surgery in women ≥ 70 with HR+ cN0 breast cancer. Following this, we identified a group of women at low-risk of nodal positivity where SLN may be omitted (grade 1, cT1mi-T1c, or grade 2, cT1mi-T1b). This study evaluates the impact of these changes on our practice. METHODS Retrospective chart review of women aged ≥ 70 years with HR+ cN0 breast cancer at our institution from 2010 to 2020. We compared SLN use before (2010-2016)/after (2017-2020) guideline release according to clinical risk and the association with adjuvant therapy. RESULTS A total of 1015 breast cancers in 987 women identified. SLN surgery rate significantly decreased from 90.6% (2010-2016) to 62.8% in 2020 (p < 0.001). This was driven by breast-conserving surgery (BCS) with SLN rates of 88.2% (2010-2016) and 46.7% in 2020. During 2017-2020, SLN use varied by risk within BCS patients: 52.2% low-risk, 81.9% higher-risk, p < 0.001. In contrast, in mastectomy patients SLN was performed in ≥ 98% regardless of risk level. SLN positivity was 13.4% overall: 7.4% in low-risk and 20.8% in higher-risk, p < 0.001. After adjusting for age and clinical risk, SLN use was not associated with adjuvant radiation [odds ratio (OR) 1.61, p = 0.11] or endocrine therapy (OR 1.12, p = 0.71). CONCLUSIONS The Society of Surgical Oncology guideline release, followed by implementation of a clinical tool to stratify by nodal risk, was associated with decreased SLN use in women aged ≥ 70 years, in those with clinically low-risk HR+ disease surgically treated with BCS. Adjusting for confounders, omission of SLN surgery was not associated with use of subsequent adjuvant radiation or hormonal therapy.

Background Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. Methods This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3–5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. Discussion In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. Trial registration ClinicalTrials.gov NCT04397718. Registered on May 21, 2020

OBJECTIVES Pancreatic transplantation is usually performed simultaneously with renal transplantation in the setting of end-stage nephropathy and type 1 diabetes. Surgical methods for dealing with exocrine secretions include bladder drainage, direct duodenojejunostomy and Roux-en-Y (ReY) enteric drainage. Roux-en-Y may confer an advantage over duodenojejunostomy because it distances enteric content from the transplant duodenal anastomosis. We examined the effect of enteric drainage method on transplant outcomes. METHODS Data were obtained from the UK transplant registry on 2172 consecutive pancreatic transplants. Early graft loss was the primary endpoint. Secondary endpoints included return to theater, length of inpatient stay, readmission with pancreatitis, graft survival, and patient survival. RESULTS There was no protective effect of ReY drainage (early graft loss, 4.6% vs 3.1%, P = 0.30; hazard ratio, 0.98; 95% confidence interval, 0.63-1.52; P = 0.91). There was a significant association between ReY and return to theater, reflecting either the technique or indication for ReY (multivariate odds ratio, 2.05; 95% confidence interval, 1.38-3.06; P < 0.01). The effect of transplant center on graft survival was assessed and adjusted for. CONCLUSIONS There was no evidence of a protective benefit of ReY drainage over duodenojejunostomy, but there was an increased risk of return to theater.

Background Despite numerous benefits for both mom and baby, few infants are exclusively breastfed for the recommended first six months. Additionally, infants are given solids too early. Prenatal education increases rates of breastfeeding initiation and we hypothesize it can also improve exclusive breastfeeding rates and prevent the early introduction of solids. We conducted a randomized controlled pilot and feasibility trial to understand the feasibility and maternal acceptance of a prenatal behavioral lifestyle intervention (PBLI) delivered via group based phone counseling (GBPC) and its effectiveness on rates of exclusive breastfeeding up to six months postpartum. Secondary aims included rates of any breastfeeding up to six months, rates of early introduction of solids, and infant feeding progression. Methods Forty-one pregnant women were recruited from a Kansas City Metropolitan Obstetrics and Gynecology office and randomly assigned to a usual care group or a PBLI. Women in the PBLI participated in six GBPC sessions where they learned about breastfeeding and introducing solids. Feeding questionnaires to assess breastfeeding and introduction of solids were sent at two weeks, two months, four months, and six months postpartum. Structured interviews were also conducted after the intervention and at six months postpartum to assess maternal acceptance and intervention feasibility. Results Participants overwhelmingly found the intervention acceptable and beneficial. Rates of exclusive breastfeeding and any breastfeeding did not differ between groups at any time point. No between group differences were found for early introduction of solids or infant feeding progression. Conclusions Mothers discontinue breastfeeding earlier than recommended despite high rates of initiation. A PBLI delivered via GBP is feasible, acceptable to participants, and showed positive impacts such as maternal empowerment for both breastfeeding and introducing solids. Future interventions should incorporate both prenatal and postpartum components. Trial registration Study protocols were approved by the University of Kansas Medical Center’s Human Subjects Committee (STUDY00140506) and registered at ClinicalTrials.gov on 02/22/2018 (NCT03442517, retrospectively registered). All participants gave written informed consent prior to data collection.

Cascaded H-bridge and modular multilevel converters (MMC) are on the rise with emerging applications in renewable energy generation, energy storage, and electric motor drives. However, their well-known advantages come at the price of complicated balancing, high-bandwidth isolated monitoring, and numerous sensors that can prevent MMCs from expanding into highly cost-driven markets. Therefore, an obvious trend in research is developing control and topologies that depend less on measurements and benefit from simpler control. Diode-clamped topologies are considered among the more applicable solutions. The main problem with a diode-clamped topology is that it can only balance the module voltages of a string in one direction; therefore, it cannot provide a completely balanced operation. This article proposes an effective balancing technique for the diode-clamped topology. The proposed solution exploits the dc component of the arm current by introducing a symmetrically level-adjusted phase-shifted modulation scheme, and ensures the balancing current flow is always in the correct direction. The advantages of this method are sensorless operation, reduced computation, and control effort, lower communication requirement, removing the voltage sensors, and low overall cost. Analysis and detailed simulations provide insight into the operation of the new balancing technique and the experimental results confirm the provided discussions.

High-power silicon field-effect transistors as well as insulated gate bipolar transistors and particularly wide-bandgap semiconductor transistors typically need negative turn- off voltage for a secure off -state, resilience to spurious turn on , and rapid transition through the saturation mode. We present a gate driver configuration with compact and very efficient supply of the high and low sides of power transistor bridges with asymmetric bipolar control voltages without the need for costly and lossy isolated dc–dc converter and only low-voltage active components. The underlying negative voltage gate driver supply circuit consists of only a few cost-efficient components, its electrical potential is referenced to the source of the controlled semiconductor power switch, and its operation is synchronized with the gate driver output. It outcompetes the established use of isolated dc–dc converters in gate circuits with negative voltage needs with respect to cost, size, reliability, and efficiency. Importantly, the proposed negative voltage supply allows bootstrapping without the need for controllable high-voltage semiconductors for the sake of further cost reduction. We present detailed design rules of the circuit and experimentally validate circuit and control. In the automotive prototype implementation, size of the gate driver supply was reduced by 61%, cost by 57%, and loss by more than 16%.

Background and Aim: Upper gastrointestinal tumors account for 5% of upper gastrointestinal bleeds. These patients are challenging to treat due to the diffuse nature of the neoplastic bleeding lesions, high rebleeding rates, and significant transfusion requirements. TC-325 (Cook Medical, North Carolina, USA) is a hemostatic powder for gastrointestinal bleeding. The aim of this study was to examine the outcomes of upper gastrointestinal bleeds secondary to tumors treated with Hemospray therapy. Methods: Data were prospectively collected on the use of Hemospray from 17 centers. Hemospray was used during emergency endoscopy for upper gastrointestinal bleeds secondary to tumors at the discretion of the endoscopist as a monotherapy, dual therapy with standard hemostatic techniques, or rescue therapy. Results: One hundred and five patients with upper gastrointestinal bleeds secondary to tumors were recruited. The median Blatchford score at baseline was 10 (interquartile range [IQR], 7–12). The median Rockall score was 8 (IQR, 7–9). Immediate hemostasis was achieved in 102/105 (97%) patients, 15% of patients had a 30-day rebleed, 20% of patients died within 30 days (all-cause mortality). There was a significant improvement in transfusion requirements following treatment (P

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the preferred method for diagnosing pancreatic masses. While the diagnostic success of EUS-FNA is widely accepted, the actual performance of EUS-FNA is not known. This study sought to define the EUS-FNA accuracy compared with the gold standard, surgically resected specimens. The study was a single institution, retrospective, and chart review of patients with surgically resected pancreatic specimens from 2005 to 2015 with a preoperative EUS-FNA or biliary brushing. Cytological reports were organized from least concerning (i.e., low chance of malignancy) to most concerning (high chance of malignancy) into eight cytologic categories. We identified 741 cytologic cases: 530 EUS-FNA and 211 endoscopic brushings. For EUS-FNA samples, 62.5% of "benign" samples proved to be "benign" on surgical pathology. A cytologic diagnosis of "suspicious for malignancy" or "positive for malignancy" were concordant with a cancer diagnosis on surgical pathology 93.3% and 98.0% of cases, respectively. EUS-FNA proved to be highly reliable at diagnosing malignancy for cytologic samples that were "suspicious" or "positive" for malignancy. Paired with supportive clinical data, these interpretations may be used to justify cancer treatment.

BACKGROUND Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking. METHODS More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8+ cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results. RESULTS At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%; p

Background Understanding the safety of vaccines is critical to inform decisions about vaccination. Our objective was to conduct a systematic review of the safety of vaccines recommended for children, adults, and pregnant women in the United States. Methods We searched the literature in November 2020 to update a 2014 Agency for Healthcare Research and Quality review by integrating newly available data. Studies of vaccines that used a comparator and reported the presence or absence of key adverse events were eligible. Adhering to Evidence-based Practice Center methodology, we assessed the strength of evidence (SoE) for all evidence statements. The systematic review is registered in PROSPERO (CRD42020180089). Results Of 56,603 reviewed citations, 338 studies reported in 518 publications met inclusion criteria. For children, SoE was high for no increased risk of autism following measles, mumps, and rubella (MMR) vaccine. SoE was high for increased risk of febrile seizures with MMR. There was no evidence of increased risk of intussusception with rotavirus vaccine at the latest follow-up (moderate SoE), nor of diabetes (high SoE). There was no evidence of increased risk or insufficient evidence for key adverse events for newer vaccines such as 9-valent human papillomavirus and meningococcal B vaccines. For adults, there was no evidence of increased risk (varied SoE) or insufficient evidence for key adverse events for the new adjuvanted inactivated influenza vaccine and recombinant adjuvanted zoster vaccine. We found no evidence of increased risk (varied SoE) for key adverse events among pregnant women following tetanus, diphtheria, and acellular pertussis vaccine, including stillbirth (moderate SoE). Conclusions Across a large body of research we found few associations of vaccines and serious key adverse events; however, rare events are challenging to study. Any adverse events should be weighed against the protective benefits that vaccines provide.

In MONARCH 3, continuous dosing of abemaciclib with an aromatase inhibitor (AI) conferred significant clinical benefit to postmenopausal women with HR+, HER2− advanced breast cancer. We report data for clinically prognostic subgroups: liver metastases, progesterone receptor status, tumor grade, bone-only disease, ECOG performance status, and treatment-free interval (TFI) from an additional 12-month follow-up (after final progression-free survival [PFS] readout). In the intent-to-treat population, after median follow-up of approximately 39 months, the updated PFS was 28.2 versus 14.8 months (hazard ratio [HR], 0.525; 95% confidence interval, 0.415–0.665) in abemaciclib versus placebo arms, respectively. Time to chemotherapy (HR, 0.513), time to second disease progression (HR, 0.637), and duration of response (HR, 0.466) were also statistically significantly prolonged with the addition of abemaciclib to AI. Treatment benefit was observed across all subgroups, as evidenced by objective response rate change from the addition of abemaciclib to AI, with the largest effects observed in patients with liver metastases, progesterone receptor-negative tumors, high-grade tumors, or TFI

Electrification has been a key component of technological progress and economic development since the industrial revolution. It has improved living conditions, spurred innovation, and increased efficiency across all sectors of our economy and all aspects of our lives. During the coming decades, electrification is expected to reach further and deeper into the transportation, building, and industry sectors, mainly motivated by the energy transition to a zero-carbonemission-based economy to mitigate climate change.

Aim Osteoporosis is a major risk factor for fractures. Poor persistence with osteoporosis medication hampers outcomes. This study assessed whether encouraging the formation of patient-led follow-up cooperatives between general practitioners (GPs) and community pharmacists improved medication persistence. Methods All consecutive patients who attended an osteoporosis patient education program were invited to participate. They were given a logbook containing questionnaires they would bring to 6-monthly visits to their GP and pharmacist. The effect of this 3-year cooperative follow-up on persistence with medication and lifestyle changes was assessed. Results In total, 121 patients (average age, 67 years; 93% female) participated. Poor cooperation between GPs and pharmacists was noted. Nevertheless, medication persistence ranged from 83% to 91% over the 6 visits. However, since patient drop-out rates were high and questionnaire return rates were low, a post-study medical chart review was performed. This confirmed that persistence was high (74%-83%) at 3 years post-enrollment, even for oral bisphosphonate-treated patients (73%-76%). However, adoption of anti-osteoporosis lifestyle changes was poor throughout the study: one- to two-thirds of the patients did not alter their diet, physical activity, or surroundings to prevent falls. Conclusion One study goal, namely, to encourage GPs and pharmacists to cooperate in patient follow-up, was not achieved. However, high medication persistence was observed. This may reflect the education program, patient empowerment, personalized attention from study personnel, and being in a study. Patient-centered approaches can thus significantly increase medication persistence in osteoporosis. Ongoing education may be needed to improve patient adoption of and persistence with lifestyle changes.

Disruptions of varying severity often occur in the course of an organization’s work to implement new programs or projects. These disruptions may slow their progress or even derail the work altogether. Resilient organizations must be prepared to respond in a thoughtful and timely way to disruptions. Readiness, Resilience and Recovery is an adaptable readiness assessment tool that organizations can use to proceed with their work with insight about their readiness status and how their readiness has been impacted by a disruption. The resulting information can then be used to guide the development of solutions for recovery and build the organization’s overall capacity for resilience. Based on our early experience, the Readiness, Resilience and Recovery approach is emerging as a tool that can be useful when organizations face significant disruptions. We have found it to be adaptable to different types of projects, at various points in the implementation cycle, and with multiple types of disruptions. To demonstrate its use, this illustrative paper provides five examples from different projects and settings: Substance Abuse Treatment Services, Multi-Site Sexual Assault Prevention Initiative, Serve and Connect (a Police-Community Relationships Initiative), Carolina Family Engagement Center (family engagement in schools), and Action for Equity (an equity intervention). Practical uses of the tool and conceptualizing it within important implementation science concepts are discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s43477-021-00011-6.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double‐blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent‐to‐treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression‐free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P, Abemaciclib in combination with endocrine therapy (ET) in the East Asian populations of MONARCH 2 and MONARCH 3 improved efficacy for patients with HR+, HER2− advanced breast cancer.

Summary Stem cell-based embryo models by cultured pluripotent and extra-embryonic lineage stem cells are novel platforms to model early postimplantation development. We showed that induced pluripotent stem cells (iPSCs) could form ITS (iPSCs and trophectoderm stem cells) and ITX (iPSCs, trophectoderm stem cells, and XEN cells) embryos, resembling the early gastrula embryo developed in vivo. To facilitate the efficient and unbiased analysis of the stem cell-based embryo model, we set up a machine learning workflow to extract multi-dimensional features and perform quantification of ITS embryos using 3D images collected from a high-content screening system. We found that different PSC lines differ in their ability to form embryo-like structures. Through high-content screening of small molecules and cytokines, we identified that BMP4 best promoted the morphogenesis of the ITS embryo. Our study established an innovative strategy to analyze stem cell-based embryo models and uncovered new roles of BMP4 in stem cell-based embryo models., Graphical abstract, Highlights • Set up machine learning-assisted image analysis to study stem cell-based embryos • Mouse iPSCs can form ITS or ITX embryos with TSCs and XEN cells • Different PSC lines differ in their abilities to form embryo-like structures • High-content screen identified BMP4 best promoted the morphogenesis of ITS embryos, In this article, Dr. J. Na and colleagues established a machine learning-assisted image analysis method to perform unbiased and automated analysis of stem cell-based embryos. With this powerful technology, the authors compared different pluripotent stem cell lines, optimized culture conditions, and conducted a small-molecule and cytokine screen to identify factors that can promote the development of stem cell-based embryos.

Background. In 2008, the Movement Disorders Society published the Unified Dyskinesia Rating Scale (UDysRS). This has become the established tool for assessing the severity and disability associated with dyskinesia in patients with Parkinson’s Disease (PD). We translated and validated the Polish version of the UDysRS, explored its dimensionality, and compared it to the Spanish version, which is the Reference Standard for UDysRS translations. Material and methods. The UDysRS was translated into Polish by a team led by JS and GO. The back-translation, completed by colleagues fluent in both Polish and English who were not involved in the original translation, was reviewed and approved by the Executive Committee of the MDS Rating Scales Programme. Then the translated version of the UDysRS underwent cognitive pretesting, and the translation was modified based on the results. The approved version was considered to be the Official Working Document of the Polish UDysRS and was tested on 250 Polish PD patients recruited at movement disorder centres. Data was compared to the Reference Standard used for validating UDysRS translations. Results. The overall factor structure of the Polish version was consistent with that of the Reference Standard version, as evidenced by the high Confirmatory Fit Index score (CFI = 0.98). The Polish UDysRS was thus confirmed to share a common factor structure with the Reference Standard. Conclusions. The Official Polish UDysRS translation is recommended for use in clinical and research settings. Worldwide use of uniform rating measures offers a common ground to study similarities and differences in disease manifestations and progression across cultures.

Objective:To assess the effectiveness and acceptability of antimicrobial stewardship-focused implementation strategies on inpatient fluoroquinolones.Methods:Stewardship champions at 15 hospitals were surveyed regarding the use and acceptability of strategies to improve fluoroquinolone prescribing. Antibiotic days of therapy (DOT) per 1,000 days present (DP) for sites with and without prospective audit and feedback (PAF) and/or prior approval were compared.Results:Among all of the sites, 60% had PAF or prior approval implemented for fluoroquinolones. Compared to sites using neither strategy (64.2 ± 34.4 DOT/DP), fluoroquinolone prescribing rates were lower for sites that employed PAF and/or prior approval (35.5 ± 9.8; P = .03) and decreased from 2017 to 2018 (P < .001). This decrease occurred without an increase in advanced-generation cephalosporins. Total antibiotic rates were 13% lower for sites with PAF and/or prior approval, but this difference did not reach statistical significance (P = .20). Sites reporting that PAF and/or prior approval were “completely” accepted had lower fluoroquinolone rates than sites where it was “moderately” accepted (34.2 ± 5.7 vs 48.7 ± 4.5; P < .01). Sites reported that clinical pathways and/or local guidelines (93%), prior approval (93%), and order forms (80%) “would” or “may” be effective in improving fluoroquinolone use. Although most sites (73%) indicated that requiring infectious disease consults would or may be effective in improving fluoroquinolones, 87% perceived implementation to be difficult.Conclusions:PAF and prior approval implementation strategies focused on fluoroquinolones were associated with significantly lower fluoroquinolone prescribing rates and nonsignificant decreases in total antibiotic use, suggesting limited evidence for class substitution. The association of acceptability of strategies with lower rates highlights the importance of culture. These results may indicate increased acceptability of implementation strategies and/or sensitivity to FDA warnings.

Residential segregation by income has become an emerging concern in Chinese cities. Existing literature on residential segregation has mostly focused on the informal rental market, and little is kn...