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We read with interest the correspondence related to the article ‘Interleukin 6 receptor inhibition in primary Sjogren syndrome: a multicentre double-blind randomised placebo-controlled trial’ in which possible explanations for negative findings in recent phase III randomised controlled trials (RCTs) for primary Sjogren’s syndrome (pSS) are discussed, including the RCT with tocilizumab.1–3 This is an important issue to raise, since there is still an unmet need for effective treatment in pSS. As discussed in these letters,2 3 most recent RCTs used the European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) as primary endpoint. The ESSDAI is widely applied and seems suitable to assess systemic disease activity in clinical practice and in cohort studies in a standardised way. However, there are some limitations to the ESSDAI as primary endpoint in trials.4 In addition to the points made by our colleagues, it is important to note that in several RCTs, including the tocilizumab trial, large response rates for the ESSDAI minimal clinically important improvement (≥3 points decrease) were seen in both the active treatment …

Introduction: The prevalence of body dysmorphic disorder among candidates for plastic surgery may vary from 6% to 54%. Some studies report discrete benefits with the surgical results, while others show symptomatic exacerbation. Some authors even affirm that body dysmorphic disorder would be a surgical contraindication, against others who suggest satisfactory results. Objective: To describe the prevalence of body dysmorphic disorder in rhinoseptoplasty candidates and to compare outcomes among patients with and without body dysmorphic disorder symptoms. Methods: Cohort study. Individuals ≥ 16 years, candidates for aesthetic and/or functional rhinoseptoplasty were recruited at a university hospital in Brazil. The prevalence of body dysmorphic disorder was assessed through the Body Dysmorphic Disorder Examination (BDDE) and the patients divided into groups: no symptoms of body dysmorphic disorder, mild-moderate and severe symptoms. The specific quality of life outcomes, Nasal Obstruction Symptom Evaluation (NOSE) and Rhinoplasty Outcome Evaluation (ROE) were evaluated before and after 90 and 180 days of the procedure. Results: 131 individuals were included, 59.5% female. The prevalence of preoperative symptoms of body dysmorphic disorder was 38%. There was a reduction in the symptoms of body dysmorphic disorder in the preoperative body dysmorphic disorder examination versus 3 and 6 months in all groups (78.94 ± 2.46 vs. 33.63 ± 6.41 and 35.51 ± 5.92, respectively, p < 0.002). Among patients with severe body dysmorphic disorder symptoms, rhinoplasty outcome evaluation ranged from 21.24 ± 3.88 to 58.59 ± 5.83 at 3 months and 52.02 ± 5.41 at 6 months postoperatively (p < 0.001); while NOSE from 71 ± 8.47 to 36.11 ± 12.10 at 6 months postoperatively (p

Background and objectives ILD patients can be positive to highly specific autoantibodies of connective tissue diseases (CTD). Among them stand out myositis-specific and associated autoantibodies (MSA/MAA). There is limited knowledge about treatment response and prognosis of ILD patients positive to MSA/MAA (MSA/MAA-ILD). Our aim was to describe clinical, radiological and pulmonary function (PF) of MSA/MAA-ILD Latin-American patients and risk factors associated to PF at onset and long term follow up. Methods Multicentric retrospective study of MSA/MAA-ILD patients evaluated between 2016 and 2018 in 3 ILD clinics in Latin America. Clinical, functional and tomographic variables were described. Variables associated with poor baseline PF and associated with functional improvement (FI) were analyzed in a multivariate logistic regression model. Results We included 211 patients, 77.4% female, mean age 57 years old. Most frequent MSA/MAA were Ro-52 and Jo-1. Poor baseline PF was associated to ILD as initial diagnosis and NSIP/OP HRCT pattern. 121 patients were included in the follow up PF analysis: 48.8% remained stable and 33% had a significant FI. In multivariate analysis, OP pattern on HRCT was associated with FI. Systemic symptoms from the beginning and the absence of sclerodactyly showed a trend to be associated with FI. Conclusions Worse baseline PF could be related to the absence of extra-thoracic symptoms and “classic” antibodies in CTD (ANA), which causes delay in diagnosis and treatment. In contrast, FI could be related to the presence of extra-thoracic signs that allow timely diagnosis and therapy, and more acute and subacute forms of ILD, such as OP pattern.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Kyowa Kirin) of mogamulizumab (Poteligeo(R)), as part of the single technology appraisal process, to submit evidence for its clinical and cost-effectiveness for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent evidence review group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. Based on a systematic literature review, one randomised controlled trial, MAVORIC, was identified showing favourable results in patients with MF and SS. However, MAVORIC compared mogamulizumab to vorinostat, which is not standard care in the NHS, and there is uncertainty due to the study design, specifically crossover of patients. Based on a "naive comparison of results from the vorinostat arm of the MAVORIC study and the physician's choice arm (methotrexate or bexarotene i.e. United Kingdom [UK] standard treatments) of the ALCANZA study as well as comparison to Phase II bexarotene data", the company considered vorinostat to be "a reasonable proxy for current standard of care in the NHS". The ERG considered, based on the limited data available, that the comparability of vorinostat (MAVORIC) and physician's choice (ALCANZA) could not be established. In response to the Appraisal Consultation Document, the company provided an unanchored matched adjusted indirect comparison (MAIC) of mogamulizumab with UK standard care by analysing Hospital Episode Statistics (HES) data. However, given the high risk of bias of an unanchored MAIC, these results needed to be regarded with a considerable degree of caution. The economic analysis suffered from uncertainty because there was no trial evidence on the comparator in the England and Wales National Health Service (NHS), and it was unclear to what extent the trial (MAVORIC) comparator (vorinostat) was comparable to standard care, referred to as established clinical management (ECM) in the NHS. The evidence for overall survival had not reached maturity and was confounded by treatment switching, for which different crossover adjustment methods produced large variations in life years. Caregiver utilities were applied in the analysis, but there was a lack of guidance on their application and whether these were indicated in this appraisal. After consultation, the company updated the economic analysis with the MAIC. Incremental cost-effectiveness ratios comparing mogamulizumab against ECM were (depending on whether the HES or MAVORIC comparison were used) 31,030 pound or 32,634 pound per quality-adjusted life years (QALYs) gained according to the company's base case and 38,274 pound or 80,555 pound per QALY gained according to the ERG's base case. NICE did not recommend mogamulizumab for treating MF or SS in adults who have had at least one previous systemic treatment.

Bacopa monnieri(L.) Wettst. (Plantaginaceae), also known as Brahmi, has been used to improve cognitive processes and intellectual functions that are related to the preservation of memory. The objective of this research is to review the ethnobotanical applications, phytochemical composition, toxicity and activity of B. monnieriin the central nervous system. It reviewed articles on B. monnieriusing Google Scholar, SciELO, Science Direct, Lilacs, Medline, and PubMed. Saponins are the main compounds in extracts of B. monnieri. Pharmacological studies showed that B. monnieriimproves learning and memory and presents biological effects against Alzheimer’s disease, Parkinson’s disease, epilepsy, and schizophrenia. No preclinical acute toxicity was reported. However, gastrointestinal side effects were reported in some healthy elderly individuals. Most studies with B. monnierihave been preclinical evaluations of cellular mechanisms in the central nervous system and further translational clinical research needs to be performed to evaluate the safety and efficacy of the plant.

Die klinisch-rheumatologische Praxis ist in den letzten 2 Jahrzehnten mit einer stets steigenden Anzahl autoinflammatorischer Erkrankungen konfrontiert, deren immunologische Pathomechanismen aufgeklart wurden und die sich teilweise klinisch gut einordnen lassen. Diente die gezielte genetische Diagnostik bislang der Bestatigung der klinischen Diagnose, so hat sich heute die genetische Sequenzierungstechnik verbessert. Die Hochdurchsatzsequenzierung z. B. durch Panelsequenzierung, Whole-Exom- und Whole-Genom-Sequenzierung ermoglicht einen vollig neuen diagnostischen Ansatz. Die Entscheidung zur klinischen und/oder genetischen Diagnosestellung ist damit zur taglichen Herausforderung geworden. In dieser Arbeit werden die klinischen, immunologischen und genetischen Aspekte der autoinflammatorischen Erkrankungen gegenubergestellt.

Heterostructures made from van der Waals materials provide a template to investigate proximity effects at atomically sharp heterointerfaces. In particular, near-field charge and energy transfer in heterostructures made from semiconducting transition metal dichalcogenides (TMD) have attracted interest to design model 2D "donor-acceptor" systems and new optoelectronic components. Here, using of Raman scattering and photoluminescence spectroscopies, we report a comprehensive characterization of a molybedenum diselenide (MoSe$_2$) monolayer deposited onto hexagonal boron nitride (hBN) and capped by mono- and bilayer graphene. Along with the atomically flat hBN susbstrate, a single graphene epilayer is sufficient to passivate the MoSe$_2$ layer and provides a homogenous environment without the need for an extra capping layer. As a result, we do not observe photo-induced doping in our heterostructure and the MoSe$_2$ excitonic linewidth gets as narrow as 1.6~meV, hence approaching the homogeneous limit. The semi-metallic graphene layer neutralizes the 2D semiconductor and enables picosecond non-radiative energy transfer that quenches radiative recombination from long-lived states. Hence, emission from the neutral band edge exciton largely dominates the photoluminescence spectrum of the MoSe$_2$/graphene heterostructure. Since this exciton has a picosecond radiative lifetime at low temperature, comparable with the energy transfer time, its low-temperature photoluminescence is only quenched by a factor of $3.3 \pm 1$ and $4.4 \pm 1$ in the presence of mono- and bilayer graphene, respectively. Finally, while our bare MoSe$_2$ on hBN exhibits negligible valley polarization at low temperature and under near-resonant excitation, we show that interfacing MoSe$_2$ with graphene yields a single-line emitter with degrees of valley polarization and coherence up to $\sim 15\,\%$., version 3, 5 figures

Applications of virtual reality (VR) and augmented reality (AR) assist both health care providers and patients in cardiovascular education, complementing traditional learning methods. Interventionalists have successfully used VR to plan difficult procedures and AR to facilitate complex interventions. VR/AR has already been used to treat patients, during interventions in rehabilitation programs and in immobilized intensive care patients. There are numerous additional potential applications in the catheterization laboratory. By using AR, interventionalists could combine visual fluoroscopy information projected and registered on the patient body with data derived from preprocedural imaging and live fusion of different imaging modalities such as fluoroscopy with echocardiography. Persistent technical challenges to overcome include the integration of different imaging modalities into VR/AR and the harmonization of data flow and interfaces. Cybersickness might exclude some patients and users from the potential benefits of VR/AR. Critical ethical considerations arise in the application of VR/AR in vulnerable patients. In addition, digital applications must not distract physicians from the patient. It is our duty as physicians to participate in the development of these innovations to ensure a virtual health reality benefit for our patients in a real-world setting. The purpose of this review is to summarize the current and future role of VR and AR in different fields within cardiology, its challenges, and perspectives.

Objectives: To study the safety and feasibility of a restrictive temporary-RV-pacemaker use and to evaluate the need for temporary pacemaker insertion for failed left ventricular (LV) pacing ability (no ventricular capture) or occurrence of high-degree AV-blocks mandating continuous pacing. Background: Ventricular pacing remains an essential part of contemporary transcatheter aortic valve implantation (TAVI). A temporary-right-ventricle (RV)-pacemaker lead is the standard approach for transient pacing during TAVI but requires central venous access. Methods: An observational registry including 672 patients who underwent TAVI between June 2018 and December 2020. Patients received pacing on the wire when necessary, unless there was a high-anticipated risk for conduction disturbances post-TAVI, based on the baseline-ECG. The follow-up period was 30 days. Results: A temporary-RV-pacemaker lead (RVP-cohort) was inserted in 45 patients, pacing on the wire (LVP-cohort) in 488 patients, and no pacing (NoP-cohort) in 139 patients. A bailout temporary pacemaker was implanted in 14 patients (10.1%) in the NoP-cohort and in 24 patients (4.9%) in the LVP-cohort. One patient in the LVP-cohort needed an RV-pacemaker for incomplete ventricular capture. Procedure time was significantly longer in the RVP-cohort (68 min [IQR 52–88.] vs. 55 min [IQR 44–72] in NoP-cohort and 55 min [IQR 43–71] in the LVP-cohort [p < 0.005]). Procedural high-degree AV-block occurred most often in the RVP-cohort (45% vs. 14% in the LVP and 16% in the NoP-cohort [p ≤ 0.001]). Need for new PPI occurred in 47% in the RVP-cohort, versus 20% in the NoP-cohort and 11% in the LVP-cohort (p ≤ 0.001). Conclusion: A restricted RV-pacemaker strategy is safe and shortens procedure time. The majority of TAVI-procedures do not require a temporary-RV-pacemaker.

This study assessed the clinical performance of hydrophilic dental implants in a patient cohort with type 2 diabetes mellitus (T2DM).Subjects with T2DM of ≥2-years duration were allocated to either the well-controlled (WC; HbA1c ≤ 7.0%,) or poorly-controlled (PC; 7.5 HbA1c 10%) groups in a dual-center, prospective cohort study. Each subject received a single, titanium-zirconium (Ti-Zr) dental implant with a chemically-modified, hydrophilic (modSLA) surface in a posterior mandibular site. Postoperatively, subjects were followed at 1, 2, 4, 8, and 12-week intervals. Post-loading, subjects were followed at 3, 6, and 12-months. Clinical and radiographic parameters of implant success, and dental patient-reported outcomes were collected.Twenty-one dental patients (NElevated HbA1c levels 7.5% did not compromise 1-year success rates, or oral health-related quality of life in PC patients receiving modSLA, Ti-Zr implants. Given that implant placement up to 10% HbA1c significantly enhanced oral health-related quality of life without complications or morbidity, the safety and efficacy of implants to improve oral function in T2DM is supported, even without ideal glycemic control.

International audience; There is increasing evidence that elimination strategies have resulted in better outcomes for public health, the economy, and civil liberties than have mitigation strategies throughout the first year of the COVID-19 pandemic. With vaccines that offer high protection against severe forms of COVID-19, and increasing vaccination coverage, policy makers have had to reassess the trade-offs between different options. The desirability and feasibility of eliminating SARS-CoV-2 compared with other strategies should also be re-evaluated from the perspective of different fields, including epidemiology, public health, and economics. To end the pandemic as soon as possible-be it through elimination or reaching an acceptable endemic level-several key topics have emerged centring around coordination, both locally and internationally, and vaccine distribution. Without coordination it is difficult if not impossible to sustain elimination, which is particularly relevant in highly connected regions, such as Europe. Regarding vaccination, concerns remain with respect to equitable distribution, and the risk of the emergence of new variants of concern. Looking forward, it is crucial to overcome the dichotomy between elimination and mitigation, and to jointly define a long-term objective that can accommodate different political and societal realities.

Objectives To compare stent recoil (SR) of the thin-strut durable-polymer Zotarolimus-eluting stent (dp-ZES) and the ultrathin-strut bioabsorbable-polymer Sirolimus-eluting stent (bp-SES) in chronic total occlusions (CTOs) and to investigate the predictors of high SR in CTOs. Background Newer ultrathin drug eluting stent might be associated with lower radial force and higher elastic recoil due to the thinner strut design, possibly impacting on the rate of in-stent restenosis and thrombosis. Methods Between January 2017 and November 2019, consecutive patients with CTOs undergoing percutaneous coronary intervention were evaluated. Only patients treated with dp-ZES or bp-SES were included and stratified accordingly. Quantitative coronary angiography analysis was used to assess absolute SR, relative SR, absolute focal SR, relative focal SR, high absolute, and high relative focal SR. Results A total of 128 lesions (67 treated with dp-ZES and 61 with bp-SES) in 123 patients were analyzed. Between bp-SES and dp-ZES no differences were found in absolute SR (p = .188), relative SR (p = .138), absolute focal SR (p = .069), and relative focal SR (p = .064). High absolute and high relative focal SR occurred more frequently in bp-SES than in dp-ZES (p = .004 and p = .015). Bp-SES was a predictor of high absolute focal SR (Odds ratio [OR] 3.29, 95% confidence interval [CI] 1.50-7.22, p = .003]. High-pressure postdilation and bp-SES were predictors of high relative focal SR (OR 2.22, 95% CI 1.01-4.86, p = .047; OR 2.74, 95% CI 1.24-6.02, p = .012, respectively). Conclusions Both stents showed an overall low SR. However, ultra-thin strut bp-SES was a predictor of high absolute and high relative focal SR.

Comments from S. Joseph Munchak and Robert Meneghini of NASA Goddard Space Flight Center, Charles (Chip) Helms of Universities Space Research Association, Liang Liao of Morgan State University are highly appreciated. Discussions with Norm Wood of University of Wisconsin-Madison on PIP data processing was very helpful. Leo Pio D’Adderio of National Research Council of Italy provided Figure 1 of this study. Thanks to the National Weather Service in Marquette, Michigan for hosting and maintaining the suite of instruments used in this work and sharing meteorological data. Thanks to the National Aeronautics and Space Administration Goddard Space Flight Center Wallops Flight Facility and the Global Precipitation Measurement (GPM) program for providing the PIP, Pluvio, and Parsivel instruments used in this work. Acknowledgments extend to three anonymous reviewers for their constructive comments. This study is partially supported by the NASA award (80NCCS19M0139) under Patrick N. Gatlin of NASA Marshall Space Flight Center, Principal Investigator. The instrument deployment and data processing for the observations from the Marquette, Michigan snowfall suite are supported by NASA grant number 80NSSC18K0701 and NOAA grant number NA15NES4320001. Claire Pettersen’s efforts on this work are supported by NASA grant number 80NSSC19K0712 and Mark Kulie’s efforts are supported by NASA PMM grant 80NSSC20K0982. Annakaisa von Lerber is funded by the Academy of Finland postdoctoral scholarship (333901). The scientific results and conclusions, as well as any views or opinions expressed herein, are those of the authors and do not necessarily reflect those of NOAA or the Department of Commerce.

Challenges to work-life balance, including childcare, have been cited as major barriers to career advancement for women in academic medicine.We performed a cross-sectional study to investigate the availability of onsite childcare at academic health centers (AHCs) for US medical schools and examined institutional characteristics associated with its provision. Data from the Association of American Medical Colleges (AAMC) were used to identify US medical schools by region, type (private vs. public, community-based vs. not), financial relationship to the university, and numbers of female medical students, faculty, chairs, and deans. We assessed onsite childcare from publicly available information on institutional websites, plus phone calls to human resources departments at medical centers and/or medical schools.Our study identified 144 US medical schools from the AAMC database and collected complete data for 136 (95%). Most AHCs offered onsite childcare (62%, 84/136). AHCs in the Midwest (78%) were most likely to have onsite childcare, whereas AHCs in the Southwest were least likely (14%, p .001). No associations were demonstrated between onsite childcare and the proportion of female chairs or female faculty, or the AHC's financial relationship with the parent university.Although accessible childcare is critical to the upward mobility of women in medicine, more than a third of AHCs do not offer onsite childcare. As more women in medicine navigate childcare demands, the expansion of accessible, quality onsite childcare at AHCs is needed to promote a diverse academic workforce.

Background: Mobile medical devices for self-patient use are a rapidly evolving section of telehealth. We examined the INSTINCT® ultrasound system, a portable, self-operated ultrasound device attach...

SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.

Introduction: Early detection of large vessel occlusion (LVO) is essential to facilitate fast endovascular treatment. CT angiography (CTA) is used to detect LVO in suspected stroke patients. We aimed to assess the accuracy of CTA evaluations in daily clinical practice in a large cohort of suspected stroke patients. Patients and methods: We used data from the PRESTO study, a multicenter prospective observational cohort study that included suspected stroke patients between August 2018 and September 2019. Baseline CTAs were re-evaluated by an imaging core laboratory and compared to the local assessment. LVO was defined as an occlusion of the intracranial internal carotid artery, M1 segment, or basilar artery. Medium vessel occlusion (MeVO) was defined as an A1, A2, or M2 occlusion. We calculated the accuracy, sensitivity, and specificity to detect LVO and LVO+MeVO, using the core laboratory evaluation as reference standard. Results: We included 656 patients. The core laboratory detected 89 LVOs and 74 MeVOs in 155 patients. Local observers missed 6 LVOs (7%) and 28 MeVOs (38%), of which 23 M2 occlusions. Accuracy of LVO detection was 99% (95% CI: 98–100%), sensitivity 93% (95% CI: 86–97%), and specificity 100% (95% CI: 99–100%). Accuracy of LVO+MeVO detection was 95% (95% CI: 93–96%), sensitivity 79% (95% CI: 72–85%), and specificity 99% (95% CI: 98–100%). Discussion and Conclusion: CTA evaluations in daily clinical practice are highly accurate and LVOs are adequately recognized. The detection of MeVOs seems more challenging. The evolving EVT possibilities emphasize the need to improve CTA evaluations in the acute setting.

The goal of this systematic review and meta-analysis was to compare nerve conduits and nerve graft for peripheral nerve regeneration. This type of lesion frequently causes disability due to pain, paresthesia and motor deficit. On the PICO process, "P" corresponded to patients with peripheral digital nerve lesions of any age, gender or ethnicity, "I" to interventions with nerve conduits or nerve graft, "C" to the control group with no treatment, placebo or receiving other treatment, and "O" to outcome assessment of nerve regeneration. Initial search found in 3859 studies, including 2001 duplicates. The remaining 1858 studies were selected by title and/or abstract; 1798 articles were excluded, leaving 60 articles for full-text review. Thirty-nine of these 60 reports were excluded as not meeting our inclusion criteria, and 21 articles were ultimately included in the systematic review. For patients older than 40 years, there was a greater mean improvement on S2PD and M2PD tests with grafting, which seemed to be the better surgical technique, positively impacting prognosis. On the M2PD test, there was significantly greater improvement in 11-17.99 mm defects with grafting (P 0.001); this finding should guide surgical strategy in peripheral nerve regeneration, to ensure better outcomes.

Chatbots are increasingly becoming important gateways to digital services and information—taken up within domains such as customer service, health, education, and work support. However, there is only limited knowledge concerning the impact of chatbots at the individual, group, and societal level. Furthermore, a number of challenges remain to be resolved before the potential of chatbots can be fully realized. In response, chatbots have emerged as a substantial research area in recent years. To help advance knowledge in this emerging research area, we propose a research agenda in the form of future directions and challenges to be addressed by chatbot research. This proposal consolidates years of discussions at the CONVERSATIONS workshop series on chatbot research. Following a deliberative research analysis process among the workshop participants, we explore future directions within six topics of interest: (a) users and implications, (b) user experience and design, (c) frameworks and platforms, (d) chatbots for collaboration, (e) democratizing chatbots, and (f) ethics and privacy. For each of these topics, we provide a brief overview of the state of the art, discuss key research challenges, and suggest promising directions for future research. The six topics are detailed with a 5-year perspective in mind and are to be considered items of an interdisciplinary research agenda produced collaboratively by avid researchers in the field.

Zusammenfassung Fragestellung (Teil-)stationäre Psychotherapie ist in Deutschland gut implementiert. Um Wirksamkeitsfaktoren und Effekte besser zu verstehen, sind Effektivitätsstudien notwendig. Diese naturalistische Studie untersucht die Effektivität stationärer und teilstationärer Psychotherapie sowie patientenzentrierte und störungsbezogene Einflussfaktoren auf individuelle Symptomverbesserungen. Methoden Analysiert werden Patient*innen einer psychosomatisch-psychotherapeutischen Universitätsklinik, die in den Jahren 2015 bis 2019 behandelt wurden und das BSI-18 entweder bei Aufnahme und Entlassung (N=1366) oder bei Aufnahme und Dreimonatskatamnese (N=497) ausfüllten. Ergebnisse Die Verbesserungen in der globalen Symptomschwere zeigen moderate Effektstärken. Deskriptiv sind diese größer bei teilstationärer als bei stationärer Behandlung–besonders im Follow-up-Vergleich (direkt nach Entlassung: dstationär=0.401, dteilstationär=0,482; drei Monate nach Entlassung: dstationär=0,403, dteilstationär=0,807). Die teilstationären unterscheiden sich signifikant von den stationären Patient*innen – gering in Alter, Beschäftigungsstatus, Arbeitsfähigkeit und initialen Symptombelastungen, moderat in der Anzahl psychischer Komorbiditäten und stark in ihren Hauptdiagnosen. Soziodemographische Faktoren zeigen keinen, die initiale Symptomschwere einen moderaten positiven und die Anzahl psychischer Komorbiditäten einen komplexen Einfluss auf die Symptomverbesserungen. Diskussion Allgemein bestätigt diese Studie die Wirksamkeit (teil-)stationärer psychosomatischer Therapie. Die Relevanz teilstationärer Angebote wird vor dem Hintergrund von Kosteneffizienz und guter Integration in den Alltag betont, unter Beachtung individueller Behandlungsindikationen.

The prevalence of adolescent depression is increasing, particularly among girls. Existing evidence-based treatments have limitations and/or may not be acceptable to all adolescents and parents. There is evidence that hatha yoga may be useful as an adjunctive treatment for depression in adults. The purpose of the current study was to assess acceptability and feasibility of hatha yoga for depression in teens. We conducted a single-arm pilot trial of 12 weeks of manualized yoga classes specifically targeted toward teens with elevated depression symptoms. We assessed acceptability and feasibility by several metrics and compared our results against a priori benchmarks. We also collected qualitative feedback on the classes. We enrolled 11 teens. We met a priori benchmarks for recruitment and retention rates, credibility of the yoga classes, satisfaction with classes, and (lack of) adverse events causally related to classes. Class attendance and amount of home practice fell below planned benchmarks. Qualitative feedback was positive from the majority, although not all, participants. Results from this study may be used to further refine yoga classes for depressed teens.

Health care workers (HCWs) are at the frontline for combatting the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. To describe recent or past infections, the novel development of serological assays enabled the assessment of the immune response developed in coronavirus disease (COVID-19). Here, we investigate SARS-CoV-2 seroprevalence in high-risk HCWs in a Belgian general hospital after both the first and the second waves. Three different immunoassays were used to determine immune response to SARS-CoV-2 in volunteer HCWs who worked in at least one COVID-19-dedicated ward [emergency department, intensive care unit (ICU) and internal medicine department] in our institution from 8 May 2020 to 19 May 2020 (n = 267) and from 18 January 2021 to 8 February 2021 (n = 189). Risk factors for seropositivity were also assessed using a questionnaire filled out by all participants. We report a steep increase in seroprevalence after the second wave and report a higher seropositivity in HCWs than in the general population. Furthermore, we show that ICU personnel and especially nurses exhibit a proportionally lower SARS-CoV-2 seroprevalence. This study documents the rapid increase in SARS-CoV-2 seroprevalence in highly exposed HCWs in a context of high viral circulation prior to vaccination campaigns. Most importantly, it suggests a lower occupational risk in ICU and illustrates the role of diagnostic labeling and use of personal protective equipment during the COVID-19 pandemic.

BACKGROUND Stroke risk factors after blunt cerebrovascular injury (BCVI) are ill-defined. We hypothesized that factors associated with stroke for BCVI would include medical therapy (ie: Aspirin®), radiographic features, and protocolization of care. METHODS An EAST-sponsored, 16 center, prospective, observational trial was undertaken. Stroke risk factors were analyzed individually for vertebral artery (VA) and internal carotid artery (ICA) BCVI. BCVI were graded on the standard 1-5 scale. Data was from the initial hospitalization only. RESULTS 777 BCVIs were included. Stroke rate was 8.9% for all BCVI, with an 11.7% rate of stroke for ICA BCVI and a 6.7% rate for VA BCVI. Use of a management protocol (p = 0.01), management by the trauma service (p = 0.04), antiplatelet therapy over the hospital stay (p < 0.001), and Aspirin® therapy specifically over the hospital stay (p < 0.001) were more common in ICA BCVI without stroke compared with those with stroke. Antiplatelet therapy over the hospital stay (p < 0.001) and Aspirin® therapy over the hospital stay (p < 0.001) were more common in VA BCVI without stroke than with stroke. Percentage luminal stenosis was higher in both ICA BCVI (p = 0.002) and VA BCVI (p < 0.001) with stroke. Decrease in percentage luminal stenosis (p < 0.001), resolution of intraluminal thrombus (p = 0.003), and new intraluminal thrombus (p = 0.001) were more common in ICA BCVI with stroke than without, while resolution of intraluminal thrombus (p = 0.03) and new intraluminal thrombus (p = 0.01) were more common in VA BCVI with stroke than without. CONCLUSIONS Protocol driven management by the trauma service, antiplatelet therapy (specifically Aspirin®), and lower percentage luminal stenosis were associated with lower stroke rates, while resolution and development of intraluminal thrombus were associated with higher stroke rates. Further research will be needed to incorporate these risk factors into lesion specific BCVI management.Study Type/Level of EvidenceOriginal article, prognostic and epidemiological, Level III.

Introduction Linking emergency medical services (EMS) data to emergency department (ED) data enables assessing the continuum of care and evaluating patient outcomes. We developed novel methods to enhance linkage performance and analysis of EMS and ED data for opioid overdose surveillance in North Carolina. Methods We identified data on all EMS encounters in North Carolina during January 1–November 30, 2017, with documented naloxone administration and transportation to the ED. We linked these data with ED visit data in the North Carolina Disease Event Tracking and Epidemiologic Collection Tool. We manually reviewed a subset of data from 12 counties to create a gold standard that informed developing iterative linkage methods using demographic, time, and destination variables. We calculated the proportion of suspected opioid overdose EMS cases that received International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for opioid overdose in the ED. Results We identified 12 088 EMS encounters of patients treated with naloxone and transported to the ED. The 12-county subset included 1781 linkage-eligible EMS encounters, with historical linkage of 65.4% (1165 of 1781) and 1.6% false linkages. Through iterative linkage methods, performance improved to 91.0% (1620 of 1781) with 0.1% false linkages. Among statewide EMS encounters with naloxone administration, the linkage improved from 47.1% to 91.1%. We found diagnosis codes for opioid overdose in the ED among 27.2% of statewide linked records. Practice Implications Through an iterative linkage approach, EMS–ED data linkage performance improved greatly while reducing the number of false linkages. Improved EMS–ED data linkage quality can enhance surveillance activities, inform emergency response practices, and improve quality of care through evaluating initial patient presentations, field interventions, and ultimate diagnoses.

Objectives We assessed the differences between the first version of the Centers for Disease Control and Prevention (CDC) opioid surveillance definition for suspected nonfatal opioid overdoses (hereinafter, CDC definition) and the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT) surveillance definition to determine whether the North Carolina definition should include additional International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes and/or chief complaint keywords. Methods Two independent reviewers retrospectively reviewed data on North Carolina emergency department (ED) visits generated by components of the CDC definition not included in the NC DETECT definition from January 1 through July 31, 2018. Clinical reviewers identified false positives as any ED visit in which available evidence supported an alternative explanation for patient presentation deemed more likely than an opioid overdose. After individual assessment, reviewers reconciled disagreements. Results We identified 2296 ED visits under the CDC definition that were not identified under the NC DETECT definition during the study period. False-positive rates ranged from 2.6% to 41.4% for codes and keywords uniquely identifying ≥10 ED visits. Based on uniquely identifying ≥10 ED visits and a false-positive rate ≤10.0%, 4 of 16 ICD-10-CM codes evaluated were identified for NC DETECT definition inclusion. Only 2 of 25 keywords evaluated, “OD” and “overdose,” met inclusion criteria to be considered a meaningful addition to the NC DETECT definition. Practice Implications Quantitative and qualitative trends in coding and keyword use identified in this analysis may prove helpful for future evaluations of surveillance definitions.

Objective Severely uncontrolled diabetes mellitus (DM) is associated with poor long-term outcomes and may remain unrecognized. A high frequency of uncontrolled DM has been identified in the acute-care setting, including the emergency department observation unit (EDOU). We assess the use of standardized endocrine consultation in the EDOU for hemoglobin A1C (HbA1C) levels ≥9%. Methods Standard practice in our EDOU includes universal HbA1C screening and endocrine consultation for HbA1C levels ≥9.0%. As part of a quality improvement program, EDOU patients with HbA1C levels ≥9.0% had an endocrinology consult. One-month follow-up phone calls assessed the effects of consultation after discharge. Results HbA1C tests were administered to 3688 (95.7%) of 3853 EDOU patients, of which 7.0% (n = 258) were found to have an HbA1C level ≥9% (mean ± SD, 11.7 ± 1.8%; range, 9%-16.6%). Endocrine consults were completed for 73.6% (190/258) patients with severely uncontrolled DM. Among the 190 patients, 92.1% (n = 175) had discharge DM medication adjustments. For known patients with DM (n = 142), injectable diabetes medication prescriptions increased from 47.2% (67/142) on EDOU arrival to 78.2% (111/142) upon discharge. Newly diagnosed DM injectable prescriptions increased from 0% (0/48) on arrival to 72.9% (35/48) upon discharge. A total of 72.6% (n = 138) were contacted at a 1-month follow-up and 94.9% (n = 131) reported taking DM medications, compared with 68.2% (n = 94) before consult. Conclusion HbA1C screening coupled with endocrine consultation for HbA1C levels ≥9.0% was assessed as a performance improvement study and is shown to have valuable results. Further investigation is required to determine the long-term clinical impact and cost analysis for this novel approach.

PURPOSE KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

To analyze different variables that influence postrhinoplasty quality of life outcomes to ascertain the determinants of postoperative satisfaction.Prospective, observational study.This was a prospective, observational study where patients were divided into two groups based on the postoperative Rhinoplasty Outcome Evaluation (ROE) score: high satisfaction group, when postoperative ROE scores were50, and low satisfaction group, when postoperative ROE scores were ≤50. Patients' general characteristics, Portuguese version of the Nasal Obstruction Symptom Evaluation (NOSE-p) score, the Body Dysmorphic Disorder Examination, nasal angles, and measures from the esthetic facial analysis of postoperative photographs were compared between the groups.Seventy-eight patients were included: 19 in the low satisfaction group and 58 in the high satisfaction group. The median reduction in the NOSE-p score was -45 (interquartile range [IIQ] -20 to -60) (P .001) in the high satisfaction group and -10 (IIQ -10 to -30) in the low satisfaction group (P = .053). The high satisfaction group had a significantly higher reduction in NOSE-p scores. There was no significant difference between the groups in terms of the analyzed facial parameters, although a significant difference was found when comparing them with the ones established in the literature as a pattern. Previous rhinoplasty, preoperative crooked nose, and higher NOSE-p scores were significantly associated with lower ROE scores (P .05) in the robust Poisson regression model.Functional results play an important role in satisfaction after rhinoplasty. Neoclassical canons were not fulfilled even in a group of patients with a high postoperative satisfaction evaluation.3 Laryngoscope, 132:1569-1575, 2022.

Objective: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. Patients and Methods: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2–4; NRAS, exons 2–4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. Results: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. Conclusion: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.

Closures are a language feature supported by many mainstream languages, combining the ability to package up references to code blocks with the possibility of capturing state from the environment of the closure's declaration. Closures are powerful, but complicate understanding and formal reasoning, especially when closure invocations may mutate objects reachable from the captured state or from closure arguments. This paper presents a novel technique for the modular specification and verification of closure-manipulating code in Rust. Our technique combines Rust's type system guarantees and novel specification features to enable formal verification of rich functional properties. It encodes higher-order concerns into a first-order logic, which enables automation via SMT solvers. Our technique is implemented as an extension of the deductive verifier Prusti, with which we have successfully verified many common idioms of closure usage., Proceedings of the ACM on Programming Languages, 5 (OOPSLA), ISSN:2475-1421

Background Home health clinicians report a need for family caregiver assistance during the majority of skilled home health care episodes. Since 2018, the Medicare Conditions of Participation has required home health agencies to provide training to family caregivers. However, little is known regarding current practices of family caregiver assessment and training during home health care. Methods Qualitative research relying on semistructured key informant interviews with registered nurses and physical therapists (n = 19), hereafter "clinicians," from four home health agencies. Interviews were recorded and transcribed, then analyzed using directed content analysis to identify relevant themes and concepts. Results Three agencies were not-for-profit and one was for-profit; three were urban and one was rural; two operated on a local scale, one on a regional scale, and one on a national scale. Key informants had an average of 9.3 years of experience in home health care and an average age of 45.0 years. Clinicians described a cyclic process of family caregiver training including four major phases: initial assessment, education, reassessment, and adjustment. Initial assessment was informal and holistic; education was delivered via demonstration and teach-back; reassessment was used to evaluate caregiver progress and inform adjustments to the care plan. Clinicians noted that their perceptions regarding the success of family caregiver training efforts influenced decisions relating to clinical practice, including the number of visits provided and whether to discharge the patient. Conclusions Caregiver training is currently integrated into clinician workflows in home health care and helps determine visit intensity and discharge timing, but clinicians face a lack of structured assessment instruments or training materials. Efforts by policymakers and home health agencies to facilitate clinicians' training efforts could positively affect the cost and quality of Medicare-funded home health care.

Background Biosimilars have been used for 15 years in the European Union (EU), and have been shown to reduce costs and increase access to important biological medicines. In spite of their considerable exposure and excellent safety record, many prescribers still have doubts on the safety and interchangeability of biosimilars, especially monoclonal antibodies (mAbs) and fusion proteins. Objectives The aim of this study was to analyse the short- and long-term safety and interchangeability data of biosimilar mAbs and fusion proteins to provide unbiased information to prescribers and policy makers. Methods Data on the safety, immunogenicity and interchangeability of EU-licensed mAbs and fusion proteins were examined using European Public Assessment Reports (EPARs) and postmarketing safety surveillance reports from the European Medicines Agency (EMA). As recent biosimilar approvals allow self-administration by patients by the subcutaneous route, the administration devices were also analyzed. Results Prelicensing data of EPARs (six different biosimilar adalimumabs, three infliximabs, three etanercepts, three rituximabs, two bevacizumabs, and six trastuzumabs) revealed that the frequency of fatal treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation of treatment, serious adverse events (SAEs), and main immune-mediated adverse events (AEs) were comparable between the biosimilars and their reference products. The availability of new biosimilar presentations and administration devices may add to patient choice and be an emerging factor in the decision to switch patients. Analysis of postmarketing surveillance data covering up to 7 years of follow-up did not reveal any biosimilar-specific adverse effects. No product was withdrawn for safety reasons. This is in spite of considerable exposure to biosimilars in treatment-naïve patients and in patients switched from the reference medicinal product to the biosimilar. Analysis of data from switching studies provided in regulatory submissions showed that single or multiple switches between the originator and its biosimilar versions had no negative impact on efficacy, safety or immunogenicity. Conclusions In line with previous reports of prelicensing studies of biosimilar mAbs and etanercepts, this study demonstrated comparable efficacy, safety, and immunogenicity compared with the reference products. This is the first study to comprehensively analyze postmarketing surveillance data of the biosimilar mAbs and etanercept. An analysis of more than 1 million patient-treatment years of safety data raised no safety concerns. Based on these data, we argue that biosimilars approved in the EU are highly similar to and interchangeable with their reference products. Thus, additional systematic switch studies are not required to support the switching of patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01601-2.

Background; Emphysema is a common phenotype of chronic obstructive pulmonary disease (COPD). Although resection of emphysematous tissue can improve lung mechanics, it is invasive and fraught with adverse effects. Meanwhile, radiofrequency (RF) treatment is an extracorporeal method that leads to tissue destruction and remodeling, resulting in “volume reduction” and overall improvement in lung compliance of emphysematous lungs. Whether these changes lead to improved exercise tolerance is unknown. Here, we investigated the effectiveness of RF treatment to improve the exercise capacity of mice with emphysema.Methods;Fifty-two mice (7 weeks of age) were used in this experiment. A bilateral emphysema model was created by intratracheally instilling porcine pancreatic elastase (PPE) (1.5U/100g body weight). RF treatment (0.5W/ g body weight) was performed extracorporeally 14 days later and mice were sacrificed after another 21 days. The exercise capacity of mice was measured using a treadmill. Treadmill runs were performed just before PPE instillation (baseline), before RF treatment and before sacrifice. Following sacrifice, lung compliance and mean linear intercept (Lm) were measured and fibrosis was assessed using a modified Ashcroft score.Results; There were 3 experimental groups: controls (instilled with saline, n=12), emphysema (instilled with porcine pancreatic elastase, PPE, n=11) and emphysema + treatment (instilled with PPE and given RF, n=9). At endpoint, the maximum velocity of the emphysema + treatment group was significantly higher than that of the emphysema group, indicating improved exercise tolerance (86.29% of baseline vs 61.69% of baseline, p=0.011). Histological analysis revealed a significant reduction in emphysema as denoted by Lm between the two groups (median 29.60 µm vs 35.68 µm, p=0.033). The emphysema + treatment group also demonstrated a higher prevalence of lung fibrosis (≧Grade 3) compared with the emphysema group (11.7% vs 5.4%, p

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants. Mouse models of hyperoxia-induced lung injury are often used to study pathogenesis and potential therapeutic approaches of BPD. Beside histological studies, gene expression analysis of lung tissue is typically used as experimental readout. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is the standard method for gene expression analysis; however, the accuracy of the quantitative data depends on the appropriate selection of reference genes. No data on validated reference genes for hyperoxia-induced neonatal lung injury in mice are available. In this study, 12 potential reference genes were systematically analyzed for their expression stability in lung tissue of neonatal mice exposed to room air or hyperoxia and healthy adult controls using published software algorithms. Analysis of gene expression data identified Hprt, Tbp, and Hmbs as the most stable reference genes and proposed combinations of Hprt/Sdha or Hprt/Rpl13a as potential normalization factors. These reference genes and normalization factors were validated by comparing Il6 gene and protein expression and may facilitate accurate gene expression analysis in lung tissues of similar designed studies.

Chromosomal microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism array, are widely applied in the diagnostic evaluation for both constitutional and neoplastic disorders. In a constitutional setting, this technology is accepted as the first-tier test for the evaluation of chromosomal imbalances associated with intellectual disability, autism, and/or multiple congenital anomalies. Furthermore, chromosomal microarray analysis is recommended for patients undergoing invasive prenatal diagnosis with one or more major fetal structural abnormalities identified by ultrasonographic examination, and in the evaluation of intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired. This technology also provides important genomic data in the diagnosis, prognosis, and therapy of neoplastic disorders, including both hematologic malignancies and solid tumors. To assist clinical laboratories in the validation of chromosomal microarray methodologies for constitutional and neoplastic applications, the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has developed these updated technical laboratory standards, which replace the ACMG technical standards and guidelines for microarray analysis in constitutional and neoplastic disorders previously published in 2013.

Introduction Appendectomy is a common emergency surgery performed globally. Despite the frequency of laparoscopic appendectomy, consensus does not exist on the best way to perform each procedural step. We identified literature on key intraoperative steps to inform best technical practice during laparoscopic appendectomy. Methods Research questions were framed using the population, indication, comparison, outcome (PICO) format for 6 key operative steps of laparoscopic appendectomy: abdominal entry, placement of laparoscopic ports, division of mesoappendix, division of appendix, removal of appendix, and fascial closure. These questions were used to build literature queries in PubMed, EMBASE, and the Cochrane Library databases. Evidence quality and certainty was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) definitions. Results Recommendations were rendered for 6 PICO questions based on 28 full length articles. Low quality evidence favors direct trocar insertion for abdominal entry and establishment of pneumoperitoneum. Single port appendectomy results in improved cosmesis with unclear clinical implications. There was insufficient data to determine the optimal method of appendiceal stump closure, but use of a specimen extraction bag reduces rates of superficial surgical site infection and intra-abdominal abscess. Port sites made with radially dilating trocars are less likely to necessitate closure and are less likely to result in port site hernia. When port sites are closed, a closure device should be used. Conclusion Key operative steps of laparoscopic appendectomy have sufficient data to encourage standardized practice.

Purpose: To better understand the impact of cancer and treatment on outcomes and guide program development, we evaluated breast cancer survivors at risk for long-term medical and psychosocial issues who participated in survivorship care visits (SVs) at Johns Hopkins Hospital.Methods: We conducted a prospective survey study of women with stage I-III breast cancer who participated in SVs from 2010-2016. The same 56-item questionnaire administered at SV and follow-up included an assessment of symptoms, social factors, demographics, anxiety, depression, and comorbidities. We added the Godin Exercise questionnaire to the follow-up. Results: In 2018, 74 participants were identified as disease-free and mailed a follow up survey; 52 (70.3%) completed the survey. At a median follow-up time of 3.1 years after diagnosis, participants were less likely to be employed (54% vs. 67%) than at the SV. About two thirds were sedentary, and this was associated with high body mass index (p=0.02). Sufficiently active participants (≥150 minutes per week of moderate intensity activity) were less likely to report pain (p=0.02) or fatigue (p=0.001). Although 20% had moderate/severe anxiety or depression at follow up, participants who reported employment satisfaction were less likely to be depressed (p=0.02). Conclusions: Awareness of issues faced by survivors is critical for enhancing care and developing models to identify patients who might benefit most from targeted long term interventions.Implications for Cancer Survivors: Interventions to address physical activity, persistent symptoms and mental health are critical for breast cancer survivors.

Zusammenfassung Hintergrund Friseur*innen arbeiten häufig in strukturbelastenden Körperhaltungen und haben ein erhöhtes Risiko für arbeitsbedingte Muskel-Skelett-Beschwerden (MSB). MSB verursachen in Deutschland circa ein Fünftel der Arbeitsunfähigkeitstage im Friseurhandwerk. Um das Ausmaß der Verbreitung von MSB bei Friseur*innen in Deutschland zu bestimmen, wurde eine Prävalenzstudie durchgeführt. Methode Die Studie war eine bundesweite Befragung im Querschnittsdesign, woran 889 Friseur*innen teilnahmen (Rücklauf 41 %). Die 12-Monate-Prävalenz von MSB wurde mit dem Standardised Nordic Questionnaire erfasst. Die Analyse der erhobenen Daten erfolgte deskriptiv und interferenzstatistisch. Ergebnisse Insgesamt 91 % der Befragten hatten in mindestens einer Körperregion MSB. Die am häufigsten von MSB bzw. schweren MSB (mind. 30 Tage/Jahr und beruflich beeinträchtigt) betroffenen Körperregionen sind Nacken (70 %; 25 %), unterer Rücken (65 %; 25 %), Schultern (61 %; 23 %) und oberer Rücken (58 %; 22 %). Beschwerden in diesen Bereichen führten auch am häufigsten zu beruflichen Beeinträchtigungen. Faktoren wie das weibliche Geschlecht, ein hohes Alter, Adipositas, viele Berufsjahre und Selbstständigkeit sind mit schweren MSB assoziiert. Schlussfolgerung Diese Studie liefert erste Daten für die Prävalenz von MSB in verschiedenen Körperregionen bei Friseur*innen in Deutschland. Die Ergebnisse weisen auf eine hohe Belastung des Muskel-Skelett-Systems bei Friseur*innen hin. Daraus resultiert ein hoher Bedarf an Prävention von arbeitsbedingten MSB im Friseurhandwerk.

Marine propeller design can be carried out with the aid of automated optimization, but experience shows that a such an approach has still been inferior to manual design in industrial scenarios. In this study, the automated propeller design optimization is evolved by integrating human–computer interaction as an intermediate step. An interactive optimization methodology, based on interactive genetic algorithms (IGAs), has been developed, where the blade designers systematically guide a genetic algorithm towards the objectives. The designers visualize and assess the shape of the blade cavitation and this evaluation is integrated in the optimization method. The IGA is further integrated with a support-vector machine model, in order to avoid user fatigue, IGA's main disadvantage. The results of the present study show that the IGA optimization searches solutions in a more targeted manner and eventually finds more non-dominated feasible designs that also show a good cavitation behaviour in agreement with designer preference.

Background The first wave of COVID-19 in South Africa peaked in July, 2020, and a larger second wave peaked in January, 2021, in which the SARS-CoV-2 501Y.V2 (Beta) lineage predominated. We aimed to compare in-hospital mortality and other patient characteristics between the first and second waves. Methods In this prospective cohort study, we analysed data from the DATCOV national active surveillance system for COVID-19 admissions to hospital from March 5, 2020, to March 27, 2021. The system contained data from all hospitals in South Africa that have admitted a patient with COVID-19. We used incidence risk for admission to hospital and determined cutoff dates to define five wave periods: pre-wave 1, wave 1, post-wave 1, wave 2, and post-wave 2. We compared the characteristics of patients with COVID-19 who were admitted to hospital in wave 1 and wave 2, and risk factors for in-hospital mortality accounting for wave period using random-effect multivariable logistic regression. Findings Peak rates of COVID-19 cases, admissions, and in-hospital deaths in the second wave exceeded rates in the first wave: COVID-19 cases, 240·4 cases per 100 000 people vs 136·0 cases per 100 000 people; admissions, 27·9 admissions per 100 000 people vs 16·1 admissions per 100 000 people; deaths, 8·3 deaths per 100 000 people vs 3·6 deaths per 100 000 people. The weekly average growth rate in hospital admissions was 20% in wave 1 and 43% in wave 2 (ratio of growth rate in wave 2 compared with wave 1 was 1·19, 95% CI 1·18–1·20). Compared with the first wave, individuals admitted to hospital in the second wave were more likely to be age 40–64 years (adjusted odds ratio [aOR] 1·22, 95% CI 1·14–1·31), and older than 65 years (aOR 1·38, 1·25–1·52), compared with younger than 40 years; of Mixed race (aOR 1·21, 1·06–1·38) compared with White race; and admitted in the public sector (aOR 1·65, 1·41–1·92); and less likely to be Black (aOR 0·53, 0·47–0·60) and Indian (aOR 0·77, 0·66–0·91), compared with White; and have a comorbid condition (aOR 0·60, 0·55–0·67). For multivariable analysis, after adjusting for weekly COVID-19 hospital admissions, there was a 31% increased risk of in-hospital mortality in the second wave (aOR 1·31, 95% CI 1·28–1·35). In-hospital case-fatality risk increased from 17·7% in weeks of low admission (8000 admissions; aOR 1·24, 1·17–1·32). Interpretation In South Africa, the second wave was associated with higher incidence of COVID-19, more rapid increase in admissions to hospital, and increased in-hospital mortality. Although some of the increased mortality can be explained by admissions in the second wave being more likely in older individuals, in the public sector, and by the increased health system pressure, a residual increase in mortality of patients admitted to hospital could be related to the new Beta lineage. Funding DATCOV as a national surveillance system is funded by the National Institute for Communicable Diseases and the South African National Government.

Background/aim Adverse event (AE) frequencies observed in interventional clinical trials are difficult to interpret when the placebo control is missing. Materials and methods Systematic literature review of AEs reported from the placebo arms of randomized cancer trials between 2008 and 2021. Imputation of missing values assuming normal distribution of hemoglobin values. Results Anemia grade 1 or higher was reported in 46 of 100 placebo monotherapy cohorts with a mean frequency of 23.4% (SD=27%) of the enrolled patients. The reported frequency depended on the type of cancer; other demographic variables had no significant influence on anemia frequency. Conclusion External controls for anemia in clinical trials should be disease specific.

Ahmed Omar Kaseb,1 S Cheenu Kappadath,2 Sunyoung S Lee,1 Kanwal Pratap Raghav,1 Yehia I Mohamed,1 Lianchun Xiao,3 Jeffrey S Morris,4 Chimela Ohaji,1 Rony Avritscher,5 Bruno C Odisio,5 Joshua Kuban,5 Mohamed E Abdelsalam,5 Beth Chasen,6 Khaled M Elsayes,7 Mohamed Elbanan,7 Robert A Wolff,1 James C Yao,1 Armeen Mahvash2 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 5Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USACorrespondence: Ahmed Omar Kaseb Email akaseb@mdanderson.orgPurpose: The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres (90Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors.Methods: We enrolled 38 Child–Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by 90Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival.Results: A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III–IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8– 14.4) and 13.2 months (95% CI 7.9– 18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3– 90) weeks, and average dose was 622 (466– 800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-90Y treatment.Conclusion: This is the first prospective study to evaluate sorafenib followed by 90Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC.Clinical Trial Registration Number: NCT01900002.Keywords: HCC, sorafenib, yttrium 90, BCLC, hepatocellular carcinoma

PURPOSE Primary care physicians have an important role in encouraging adequate cancer screening. Disparities in cancer screening by socioeconomic status (SES) may affect presentation stage and cancer survival. This study aimed to examine whether breast, colorectal, and cervical cancer screening rates in women differed by SES and age, and whether screening rates and SES disparities changed after introduction of a primary care–based national quality indicator program. METHODS This repeated cross-sectional study spanning 2002-2017 included all female Israeli residents in age ranges appropriate for each cancer screening assessed. SES was measured both as an individual-level variable based on exemption from copayments and as an area-level variable using census data. RESULTS In 2017, the most recent year in the study period, screening rates among 1,529,233 women were highest for breast cancer (70.5%), followed by colorectal cancer (64.3%) and cervical cancer (49.6%). Women in the highest area-level SES were more likely to undergo cervical cancer screening compared with those in the lowest (odds ratio = 3.56; 99.9% CI, 3.47-3.65). Temporal trends showed that after introduction of quality indicators for breast and colorectal cancer screening in 2004 and 2005, respectively, rates of screening for these cancers increased, with greater reductions in disparities for the former. The quality indicator for cervical cancer screening was introduced in 2015, and no substantial changes have occurred yet for this screening. CONCLUSIONS We found increased uptake and reduced socioeconomic disparities after introduction of cancer screening indicators. Recent introduction of a cervical cancer screening indicator may increase participation and reduce disparities, as has occurred for breast and colorectal cancer screening. These findings related to Israel’s quality indicators program highlight the importance of primary care clinicians in increasing cancer screening rates to improve outcomes and reduce disparities.