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BACKGROUND: Rotator cuff weakness is considered an important risk factor for shoulder injuries in volleyball. OBJECTIVE: To evaluate association of shoulder preseason strength status with shoulder injury occurrence in subsequent season. METHODS: Volleyball players (N= 181; 99 men) from Slovenian 1st and 2nd national league volunteered to participate in this prospective cohort study. Preseason isokinetic testing of the shoulder was conducted at 60∘/s in the concentric mode of contraction over a RoM of 60∘ with five repetitions of internal (IR) and external (ER) rotation. During the subsequent season the players reported shoulders injuries through a weekly questionnaire. RESULTS: During the season we have registered 14 (7.7%) shoulder injuries (10 in men). All injuries affected the dominant shoulder. There was significant preseason weakness of ER and lower ER/IR strength ratio in players with shoulder injury. Normal strength ratio ER/IR was a significant protective factor (Exp (B) = 0.217, 95% C.I. 0.058–0.811) for shoulder injury occurrence when controlled for sex and previous injury. CONCLUSIONS: The inclusion of systematic strengthening of the external rotators of the shoulder is necessary, especially for male volleyball players, as part of preventive measures for the prevention of shoulder injuries.

Background Plasma cell vulvitis (PCV) is an inflammatory vulvar dermatosis that is not well characterized. Diagnosis is often delayed, and the condition can be refractory to treatment. To date, there are no systematic reviews on this topic. Objective This study aimed to provide a systematic review of PCV, including epidemiologic, clinical, and histopathologic findings, as well as associated comorbidities and treatment options. Methods A primary literature search was conducted using the PubMed, Ovid Medline, Cochrane, and CINAHL databases. Results Fifty-three publications with 196 patients (mean age: 55.3 ± 14.5 years) were included. The majority of studies were case reports and case series. Common symptoms included burning/stinging (52%), dyspareunia (44%), and pruritus (41%). Common findings included erythema (84%), glistening/shiny appearance (29%), well-demarcated lesions (25%), and erosions (22%). Common anatomic sites were the labia minora (45%), introitus (31%), and periurethral (19%). Fifty-three percent of patients had a solitary lesion. Common histologic findings were a predominant plasma cell infiltrate (88%), presence of other inflammatory cells (55%), hemosiderin/siderophages (46%), and epidermal atrophy (43%). Topical corticosteroids (64%) and tacrolimus ointment (13%) were the most frequent treatment modalities. In most reports, previous treatments were tried, and there was a diagnostic delay. Conclusion PCV is likely underrecognized and should be considered in patients with erythema of the mucous and modified mucous membranes, symptoms of burning or stinging, and a predominant plasma cell infiltrate on histopathology. First-line therapy should begin with high-potency topical corticosteroids, with the most evidence for clobetasol 0.05% or tacrolimus 0.1% ointment. Prospective studies are needed to further characterize this condition and to develop treatment guidelines.

This vignette-based study examined the willingness to feign symptoms to obtain a prescription following an analysis on who might use prescription stimulants to enhance performance ( N = 3,468). It experimentally manipulated three factors: the social disapproval of prescription stimulant use for enhancement purposes, the physicians’ diagnostic efforts, and the medical condition (attention-deficit/hyperactivity disorder and narcolepsy); respondent characteristics of self-control, personal morality, and self-efficacy were also measured. Our results showed that social disapproval of prescription drug use, a personal morality that disapproves of drug use, high self-control, and high self-efficacy were negatively associated with the willingness to use. Willingness increased especially in situations of social approval when there was a stronger personal approval of drug use, or surprisingly when physicians’ diagnostic efforts were higher. The feigning willingness was lower in situations of social disapproval and when personal morality disapproved of feigning. Thus, personal and situational characteristics are relevant to understand both behaviors.

Supplemental Digital Content is available in the text., Rationale: PCSK9 (proprotein convertase subtilisin/kexin type 9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and HDL (high-density lipoprotein) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance spectroscopy and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck study (n=656) revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein C3 (apoC3), an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk; n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 time points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apoC3 from HDL, and lower levels of small HDL as measured by nuclear magnetic resonance spectroscopy. Crosslinking mass spectrometry upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin, and apolipoprotein E within the HDL proteome that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalization and multimerization. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipemia as a driver of PCSK9 and apoC3 release from HDL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03191513; URL: https://www.isrctn.com; Unique identifier: ISRCTN20774126.

Children with Clostridioides difficile infection (CDI) can experience recurrent or severe disease. Recurrent CDI occurs in 20%-30% of children with an initial CDI episode. A careful clinical evaluation is important to distinguish recurrent CDI from other disorders that cause recurring gastrointestinal symptoms. Multiple treatment options exist for recurrent CDI, but the optimal therapeutic approach remains undefined. Severe or fulminant CDI can result in poor outcomes and significant morbidity in children. Since there is not a validated definition for severe CDI in children, physicians must use their clinical judgment to identify patients with severe CDI to institute appropriate therapy. In this review, we describe the diagnostic and management challenges in caring for children with recurrent and severe CDI.

As the global population ages, hospital administrators will need to employ a sufficient number of OR nurses to meet the demands of increasing surgical volumes. However, ORs can be intimidating working environments and undergraduate nursing programs lack formal didactic courses in perioperative nursing, leaving little to entice newly graduated nurses to the perioperative specialty. It is important for nurse leaders to employ interventions for recruiting and retaining OR nurses, particularly in specialty service lines, including cardiovascular surgery. A Periop 202 course for open-heart procedures was developed and woven into a cardiovascular OR (CVOR) orientation program for newly graduated nurses and experienced nurses who were new to the CVOR. The program aimed to increase new CVOR nurses' competencies and knowledge of protocols and guidelines for open-heart procedures and their self-efficacy to function on the CVOR team. Knowledge questionnaire and learning scale results showed increased postintervention knowledge and self-efficacy among program participants.

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin. Significance: By tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs. See related commentary by Cukierman, p. 296. This article is highlighted in the In This Issue feature, p. 275

Youth with type 2 diabetes might have suboptimal peak bone mass, but it is unknown whether similar effects are evident in youth with prediabetes. Results from this study suggest that diabetes-related effects on peak bone mass likely occur before disease onset, and involve the muscle-bone unit. Type 2 diabetes might adversely influence bone health around the age of peak bone mass, but it is unknown whether diabetes-related effects on areal bone mineral density (aBMD) are evident in youth with prediabetes. We compared age-related trends in aBMD and associations between lean body mass (LBM) and aBMD between children and adolescents with prediabetes vs. normal glucose regulation. Cross-sectional analysis of data from the National Health and Nutrition Examination Survey (2005–2006) in youth ages 12–20 years (49% female, 34% black) with prediabetes (n = 267) and normal glucose regulation (n = 1664). Whole body aBMD and LBM were assessed via DXA. LBM index (LBMI) and Z-scores for aBMD and LBMI were computed. Unadjusted between-group comparisons revealed greater mean weight and LBMI Z-scores in youth with prediabetes vs. normal glucose regulation, but similar bone Z-scores between the two groups. While accounting for differences in BMI Z-score, there was a significant interaction between prediabetes status and age with respect to whole body aBMD Z-score (P

Treatment of patients with severe burn injuries is complex, relying on attentive fluid resuscitation, successful management of concomitant injuries, prompt wound assessment and closure, early rehabilitation, and compassionate psychosocial care. The goal of fluid resuscitation is to maintain organ perfusion at the lowest possible physiologic cost. This requires careful, hourly titration of the infusion rate to meet individual patient needs, and no more; the risks of over-resuscitation, such as compartment syndromes, are numerous and life-threatening. Recognizing runaway resuscitations and understanding how to employ adjuncts to crystalloid resuscitation are paramount to preventing morbidity and mortality. This article provides an update on fluid resuscitation techniques in burn patients, to include choosing the initial fluid infusion rate, using alternate endpoints of resuscitation, and responding to the difficult resuscitation.

Misidentification delusions are false, fixed beliefs that assign an incorrect identity to a previously familiar or unfamiliar person or place. Such delusions are common in several neuropsychiatric disorders and place a particular burden on individuals with Major Neurocognitive Disorder and their caregivers. No standard pharmacologic or non-pharmacologic treatment approaches have been shown to be consistently effective in addressing this problem. We describe two caregiver-care recipient dyads in which an innovative non-pharmacologic, digital intervention reduced delusional misidentification, improved care recipient behavior, and decreased caregiver burden.

Bee populations are declining globally due to different environmental stressors, such as pathogens, malnutrition, and agrochemicals. Brazil is the home of hundreds of stingless bee species, some of...

Zusammenfassung Hintergrund Der Beginn und Frühwarnzeichen von Krankheitsepisoden der bipolaren Störung werden von Betroffenen häufig erst spät erkannt. Je früher eine Krankheitsepisode behandelt wird, desto prognostisch günstiger ist der Verlauf. Die Symptomüberwachung per Smartphone-Applikation (App) könnte eine innovative Möglichkeit darstellen, um Frühwarnzeichen zu erkennen und schneller mit den richtigen Strategien darauf zu reagieren. Das Ziel dieser Studie war es zu evaluieren, ob PatientInnen mit bipolarer Erkrankung und deren Angehörige eine technische Unterstützung durch eine App als sinnvoll und praktikabel in der Früherkennung sowie in der Behandlung erachten. Methoden In der vorliegenden Studie wurden 51 PatientInnen mit bipolarer Störung und 28 Angehörige befragt. Es wurde ermittelt, ob die ProbandInnen Frühwarnzeichen in Form von Verhaltensänderungen derzeit subjektiv ausreichend und rechtzeitig wahrnehmen können. Zudem wurde erhoben, ob die StudienprobandInnen ein Smartphone als Behandlungsunterstützung nutzen würden. Ergebnisse Obwohl sich 94,1% der befragten PatientInnen und 78.6% der Angehörigen gut über die Erkrankung informiert fühlten, waren 13,7% beziehungsweise 35,7% mit den derzeitigen Behandlungsmöglichkeiten nicht zufrieden. Frühwarnzeichen jeder depressiven Entwicklung wurden von 25,5% der PatientInnen wahrgenommen (Angehörige 10,7%). Jede (hypo)manische Entwicklung wurde lediglich von 11,8% der PatientInnen wahrgenommen (Angehörige 7,1%). 88,2% der PatientInnen und 85,7% ihrer Angehörigen bemerkten zu Beginn einer Depression und 70,6% beziehungsweise 67,9% zu Beginn einer (hypo)manischen Episode wiederkehrend dieselben Symptome (insbesondere Veränderungen der körperlichen Aktivität, des Kommunikationsverhaltens und des Schlaf-Wach-Rhythmus). 84,3% der PatientInnen und 89,3% der Angehörigen gaben an, dass sie eine technische Unterstützung, welche auf Veränderungen in Stimmungs- und Aktivitätslage aufmerksam macht, als sinnvoll erachten und dass sie eine Smartphone-App für die Behandlung nutzen würden. Diskussion Die derzeitigen Möglichkeiten zur Wahrnehmung von Frühwarnzeichen einer depressiven oder (hypo)manischen Episode bei bipolarer Störung sind klinisch unzureichend. Bei Betroffenen und Angehörigen besteht der Wunsch nach innovativen, technischen Unterstützungen. Die rechtzeitige Früherkennung von Krankheitssymptomen, die sich oft in Veränderungen von Verhaltens- oder Aktivitätsmustern äußert, ist für den Verlauf essentiell. Apps könnten hierbei durch objektive, kontinuierliche und individuelle Datenerhebung in der Zukunft für die klinische Behandlung und die Forschung genutzt werden.

BACKGROUND Obstructive sleep apnea is associated with increased risk of sudden cardiac death.OBJECTIVE The purpose of this study was to elucidate changes in ventricular repolarization and electromechanical interaction during obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) in pigs. We also investigated the effect of a reduced repolarization reserve in drug-induced long QT (LQT) following INAP-induced changes in ventricular repolarization.METHODS In sedated spontaneously breathing pigs, 75 seconds of INAP was applied by a negative pressure device connected to the endotracheal tube. Ventricular electromechanical coupling was determined by the electromechanical window (EMW) before (preINAP), during (INAP), and after INAP (post-INAP). Incidence rates of premature ventricular contractions (PVCs) were measured respectively. A drug-induced LQT was modeled by treating the pigs with the hERG1 Mocker dofetilide (DOE).RESULTS Whereas QT interval increased during and decreased after INAP (pre-INAP: 273 +/- 5 ms; INAP 281 +/- 6 ms; post-INAP 254 +/- 9 ms), EMW shortened progressively throughout INAP and post-INAP periods (pre-INAP 81 +/- 4 ms; post-INAP 44 +/- 7 ms). DOF shortened EMW at baseline. Throughout INAP, EMW decreased in a comparable fashion as before DOF (pre-INAP/+DOF 61 +/- 7 ms; post-INAP/+DOF 14 +/- 9 ms) but resulted in shorter absolute EMW levels. Short EMW levels were associated with increased occurrence of PVCs (pre-INAP 7 +/- 2 ms vs post-INAP 26 +/- 6 ms; P = .02), which were potentiated in DOF pigs (pre-INAP/+DOF 5 +/- 2 ms vs post-INAP/+DOF 40 +/- 8 ms; P = .006). Administration of atenolol prevented post-INAP EMW shortening and decreased occurrence of PVCs.CONCLUSION Transient dissociation of ventricular electromechanical coupling during simulated obstructive respiratory events creates a dynamic ventricular arrhythmogenic substrate, which is sympathetically mediated and aggravated by drug-induced LQT.

Systemic sclerosis is a connective tissue disease that presents with significant gastrointestinal involvement, commonly in the esophagus. Dysphagia is a common clinical manifestation of systemic sclerosis and is strongly related to esophageal dysmotility. However, there are multiple other contributing factors in each step in the physiology of swallowing that may contribute to development of severe dysphagia. The oral phase of swallowing may be disrupted by poor mastication due to microstomia and poor dentition, as well as by xerostomia. In the pharyngeal phase of swallowing, pharyngeal muscle weakness due to concurrent myositis or cricopharyngeal muscle tightening due to acid reflux can cause disturbance. The esophageal phase of swallowing is most commonly disturbed by decreased peristalsis and esophageal dysmotility. However, it can also be affected by obstruction from chronic reflux changes, pill-induced esophagitis, or Candida esophagitis. Other contributing factors to dysphagia include difficulties in food preparation and gastroparesis. Understanding the anatomy and physiology of swallowing and evaluating systemic sclerosis patients presenting with dysphagia for disturbances in each step can allow for development of better treatment plans to improve dysphagia and overall quality of life.

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of apoptosis, proliferation, and DNA-damage response, is overexpressed in many cancers, including small cell lung cancer (SCLC). Here we report that LB100, a small molecule inhibitor of PP2A, when combined with platinum-based chemotherapy, synergistically elicited an antitumor response both in vitro and in vivo with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we determined quantitatively that sensitization via LB100 was mediated by increased uptake of carboplatin in SCLC cells. Treatment with LB100 alone or in combination resulted in inhibition of cell viability in two-dimensional culture and three-dimensional spheroid models of SCLC, reduced glucose uptake, and attenuated mitochondrial and glycolytic ATP production. Combining LB100 with atezolizumab increased the capacity of T cells to infiltrate and kill tumor spheroids, and combining LB100 with carboplatin caused hyperphosphorylation of the DNA repair marker γH2AX and enhanced apoptosis while attenuating MET signaling and invasion through an endothelial cell monolayer. Taken together, these data highlight the translational potential of inhibiting PP2A with LB100 in combination with platinum-based chemotherapy and immunotherapy in SCLC.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6-70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients' characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.

Contains fulltext : 235298.pdf (Publisher’s version ) (Open Access) Importance: Cardiovascular disease (CVD) is common in patients treated for breast cancer, especially in patients treated with systemic treatment and radiotherapy and in those with preexisting CVD risk factors. Coronary artery calcium (CAC), a strong independent CVD risk factor, can be automatically quantified on radiotherapy planning computed tomography (CT) scans and may help identify patients at increased CVD risk. Objective: To evaluate the association of CAC with CVD and coronary artery disease (CAD) in patients with breast cancer. Design, Setting, and Participants: In this multicenter cohort study of 15915 patients with breast cancer receiving radiotherapy between 2005 and 2016 who were followed until December 31, 2018, age, calendar year, and treatment-adjusted Cox proportional hazard models were used to evaluate the association of CAC with CVD and CAD. Exposures: Overall CAC scores were automatically extracted from planning CT scans using a deep learning algorithm. Patients were classified into Agatston risk categories (0, 1-10, 11-100, 101-399, >400 units). Main Outcomes and Measures: Occurrence of fatal and nonfatal CVD and CAD were obtained from national registries. Results: Of the 15915 participants included in this study, the mean (SD) age at CT scan was 59.0 (11.2; range, 22-95) years, and 15879 (99.8%) were women. Seventy percent (n = 11179) had no CAC. Coronary artery calcium scores of 1 to 10, 11 to 100, 101 to 400, and greater than 400 were present in 10.0% (n = 1584), 11.5% (n = 1825), 5.2% (n = 830), and 3.1% (n = 497) respectively. After a median follow-up of 51.2 months, CVD risks increased from 5.2% in patients with no CAC to 28.2% in patients with CAC scores higher than 400. After adjustment, CVD risk increased with higher CAC score (hazard ratio [HR]CAC = 1-10 = 1.1; 95% CI, 0.9-1.4; HRCAC = 11-100 = 1.8; 95% CI, 1.5-2.1; HRCAC = 101-400 = 2.1; 95% CI, 1.7-2.6; and HRCAC>400 = 3.4; 95% CI, 2.8-4.2). Coronary artery calcium was particularly strongly associated with CAD (HRCAC>400 = 7.8; 95% CI, 5.5-11.2). The association between CAC and CVD was strongest in patients treated with anthracyclines (HRCAC>400 = 5.8; 95% CI, 3.0-11.4) and patients who received a radiation boost (HRCAC>400 = 6.1; 95% CI, 3.8-9.7). Conclusions and Relevance: This cohort study found that coronary artery calcium on breast cancer radiotherapy planning CT scan results was associated with CVD, especially CAD. Automated CAC scoring on radiotherapy planning CT scans may be used as a fast and low-cost tool to identify patients with breast cancer at increased risk of CVD, allowing implementing CVD risk-mitigating strategies with the aim to reduce the risk of CVD burden after breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03206333.

Les patients atteints de pneumopathie grave dans le cadre de COVID-19 sont à haut risque de complications thrombotiques, en rapport avec une coagulopathie induite par le SARS-CoV-2, ce qui aggrave leur pronostic. Les mécanismes physiopathologiques de cette coagulopathie incluent une dysfonction endothéliale en partie expliquée par un état hyper-inflammatoire et l’activation de la coagulation qui en découle. Les bilans standards d’hémostase ne semblent pas suffisants pour évaluer ce sur-risque thrombotique et la thromboprophylaxie de ces patients doit probablement être renforcée.

This article describes the innovative nurse retentionist role that a large academic medical health system in the southeastern United States implemented to improve nurse retention. The program leveraged 5 key strategies to drive results. Example outcomes during the first 2 years include a 27% increase in clinical ladder participation, a 43% clinical ladder advancement, and an 187% increase in ambulatory nurse recognition. Internal promotions increased 31%. Participation in nursing career development increased 294%. Extern program increased 420%, and 77 nurse residents were retained that initially considered resignation. Nurse turnover dropped to 11.8% with the retention of 254 nurses.

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.

Bone marrow (BM) angiogenesis significantly influences disease progression in multiple myeloma (MM) patients and correlates with adverse prognosis. The present study shows a statistically significant correlation of the AP-1 family member JunB with VEGF, VEGFB, and IGF1 expression levels in MM. In contrast to the angiogenic master regulator Hif-1α, JunB protein levels were independent of hypoxia. Results in tumor-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs). Consequently, conditioned media derived from MM cells after JunB knockdown or JunB activation either inhibited or stimulated in vitro angiogenesis. The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections. In summary, in continuation of our previous study (Fan et al., 2017), the present report reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of AF transcription and consequently of MM BM angiogenesis. Our results thereby underscore worldwide efforts to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy.

The clinical differentiation of face and scalp lesions (FSLs) is challenging even for trained dermatologists. Studies comparing the diagnostic performance of a convolutional neural network (CNN) with dermatologists in FSL are lacking.A market-approved CNN (Moleanalyzer-Pro, FotoFinder Systems) was used for binary classifications of 100 dermoscopic images of FSL. The same lesions were used in a two-level reader study including 64 dermatologists (level I: dermoscopy only; level II: dermoscopy, clinical close-up images, textual information). Primary endpoints were the CNN's sensitivity and specificity in comparison with the dermatologists' management decisions in level II. Generalizability of the CNN results was tested by using four additional external data sets.The CNN's sensitivity, specificity and ROC AUC were 96.2% [87.0%-98.9%], 68.8% [54.7%-80.1%] and 0.929 [0.880-0.978], respectively. In level II, the dermatologists' management decisions showed a mean sensitivity of 84.2% [82.2%-86.2%] and specificity of 69.4% [66.0%-72.8%]. When fixing the CNN's specificity at the dermatologists' mean specificity (69.4%), the CNN's sensitivity (96.2% [87.0%-98.9%]) was significantly higher than that of dermatologists (84.2% [82.2%-86.2%]; p 0.001). Dermatologists of all training levels were outperformed by the CNN (all p 0.001). In confirmation, the CNN's accuracy (83.0%) was significantly higher than dermatologists' accuracies in level II management decisions (all p 0.001). The CNN's performance was largely confirmed in three additional external data sets but particularly showed a reduced specificity in one Australian data set including FSL on severely sun-damaged skin.When applied as an assistant system, the CNN's higher sensitivity at an equivalent specificity may result in an improved early detection of face and scalp skin cancers.

Despite increasing interest in how artificial intelligence (AI) can augment and improve healthcare delivery, the development of new AI models continues to outpace adoption in existing healthcare processes. Integration is difficult because current approaches separate the development of AI models from the complex healthcare environments in which they are intended to function, resulting in models developed without a clear and compelling use case and not tested or scalable in a clinical setting. We propose that current approaches and traditional research methods do not support successful AI implementation in healthcare and outline a repeatable mixed-methods approach, along with several examples, that facilitates uptake of AI technologies into human-driven healthcare processes. Unlike traditional research, these methods do not seek to control for variation, but rather understand it to learn how a technology will function in practice coupled with user-centered design techniques. This approach, leveraging design thinking and quality improvement methods, aims to increase the adoption of AI in healthcare and prompt further study to understand which methods are most successful for AI implementations.

PurposeTo investigate the dosimetric impact of breathing motion on robustly optimized proton therapy treatment plans for left-sided breast cancer patients with an indication for locoregional irradiation.Materials and methodsClinical Target Volumes (CTVs) (left-sided breast, level 1 to 4 axillary lymph nodes, interpectoral and internal mammary lymph node regions) and organs at risk were delineated on 4 D-CTs of ten female patients. After treatment planning to a prescribed dose of 40.05 Gy(RBE) in 15 fractions on the time-averaged CT, the dose was calculated on all ten phases of the breathing cycle. Robustness to setup (5 mm) and range errors (3%) was evaluated for those ten phases. Correlations were evaluated between the phases of the breathing cycle and the D98% of the CTV and the D-mean of the heart.ResultsCorrelations coefficients were between -0.12 and 0.29. At the most extreme values of the 28 robustness scenarios, the clinical goals were met for all but two patients. The mean heart dose was 0.41 Gy(RBE) with a standard deviation of 0.31 Gy(RBE) of proton therapy plans.ConclusionThe effect of breathing motion on the robustness of proton therapy treatment plans for this patient group is minor and not of clinical significance. Based on this patient group, a deep-inspiration breath hold seems to be unnecessary to improve robustness for these patients.

Psychologists housed in two family medicine residency clinics located in underserved communities quickly transitioned their mode of psychotherapy from in-person to completely virtual at the beginning of the COVID-19 pandemic. We share numerous successes and advantages of a telehealth model in serving our community and describe challenges we have encountered.

Background Thromboprophylaxis of COVID-19 patients is a highly debated issue. We aimed to compare the occurrence of thrombotic/ischemic events in COVID-19 patients with acute respiratory distress syndrome (ARDS) treated with either prophylactic or therapeutic dosage of heparin. All patients referred for COVID-19 ARDS in two intensive care units (ICUs) from two centers of a French tertiary hospital were included in our cohort study. Patients were compared according to their anticoagulant treatment to evaluate the risk/benefit of prophylactic anticoagulation versus therapeutic anticoagulation. Medical history, symptoms, biological data and imaging were prospectively collected. Results One hundred and seventy-nine patients (73% men) were analyzed: 108 in prophylactic group and 71 in therapeutic group. Median age and SAPS II were 62 [IQR 51; 70] years and 47 [IQR 37; 63] points. ICU mortality rate was 17.3%. Fifty-seven patients developed clinically relevant thrombotic complications during their ICU stay, less frequently in therapeutic group (adjusted OR 0.38 [0.14–0.94], p = 0.04). The occurrences of pulmonary embolism (PE), deep vein thrombosis (DVT) and ischemic stroke were significantly lower in the therapeutic group (respective adjusted OR for PE: 0.19 [0.03–0.81]; DVT: 0.13 [0.01–0.89], stroke: 0.06 [0–0.68], all p Conclusion Increasing the anticoagulation of severe COVID-19 patients to a therapeutic level might decrease thrombotic complications without increasing their bleeding risk.

forma são planejados os cuidados preventivos para lesão por pressão em pacientes internados nas unidades de terapia intensiva (UTI). Métodos: Trata-se de uma revisão integrativa da literatura nacional, em um recorte temporal de cinco anos. Foram selecionados 11 artigos com a combinação dos descritores: “Lesão por pressão, “Unidade de Terapia Intensiva”, “Cuidados de Enfermagem”. A busca pelos artigos foi realizada nas bases de dados BVS, Lilacs, PubMed e Ibecs. Resultados: após um processo de seis etapas de filtragem de buscas, foram selecionados 11 artigos para a construção da revisão integrativa, possibilitando os autores elucidar estudos que puderam contribuir para o ajuste dos vieses da prática profissional de enfermagem. Conclusão: Com esse estudo pôde-se concluir que mediante a revisão de literatura bibliografica, os desafios são amplos em prevenir a lesão por pressão no ambiente de terapia intensiva, visto que necessitamos de qualificação profissional, desenvolvimento de competências, gerenciamento do tempo, gerenciamento de recursos humanos, adesão ao planejamento da assistência.

Background Reaching an appropriate physical activity level (PAL) in adolescence is an important public health problem. This study aimed to evaluate factors associated with PAL and changes in PAL in late adolescence. Material and Methods The sample involved 411 adolescents (201 girls) who were 16 years of age at study baseline; the participants completed a structured validated questionnaire at baseline (the beginning of the third grade of high school) and again at follow-up (the end of the fourth grade; when they were 18 years of age). Variables were obtained at both testing waves and included the following predictors: sociodemographic indices (sex, socioeconomic status, parental education), sports factors (participation in individual and team sports, competitive sports achievement, experience in sports), and PAL (the primary outcome), which was measured using the Physical Activity Questionnaire for Adolescents . Results A significant decrease in PAL between baseline and follow-up testing was evidenced (t-test = 6.17, p < 0.001). A logistic regression model calculated with a dichotomized outcome (normal PAL vs. low PAL), and sex as a covariate, showed a significant influence of participation in team sports and maternal education on PAL, both at baseline (OR = 1.56, 95% CI: 1.11–1.87; OR = 1.38, 95% CI: 1.02–1.90) and at follow-up (OR = 1.45, 95% CI: 1.01–1.90; OR = 1.35, 95% CI: 1.08–1.70, for team sports and maternal education, respectively). Conclusions The study confirmed certain associations between the studied variables and PAL, but there was no significant influence of the observed indicators on changes in PAL in late adolescence. Further studies evaluating other predictors of changes in PAL are warranted. Med Pr. 2020;71(6):637–47

Background In recent studies, convolutional neural networks (CNNs) outperformed dermatologists in distinguishing dermoscopic images of melanoma and nevi. In these studies, dermatologists and artificial intelligence were considered as opponents. However, the combination of classifiers frequently yields superior results, both in machine learning and among humans. In this study, we investigated the potential benefit of combining human and artificial intelligence for skin cancer classification. Methods Using 11,444 dermoscopic images, which were divided into five diagnostic categories, novel deep learning techniques were used to train a single CNN. Then, both 112 dermatologists of 13 German university hospitals and the trained CNN independently classified a set of 300 biopsy-verified skin lesions into those five classes. Taking into account the certainty of the decisions, the two independently determined diagnoses were combined to a new classifier with the help of a gradient boosting method. The primary end-point of the study was the correct classification of the images into five designated categories, whereas the secondary end-point was the correct classification of lesions as either benign or malignant (binary classification). Findings Regarding the multiclass task, the combination of man and machine achieved an accuracy of 82.95%. This was 1.36% higher than the best of the two individual classifiers (81.59% achieved by the CNN). Owing to the class imbalance in the binary problem, sensitivity, but not accuracy, was examined and demonstrated to be superior (89%) to the best individual classifier (CNN with 86.1%). The specificity in the combined classifier decreased from 89.2% to 84%. However, at an equal sensitivity of 89%, the CNN achieved a specificity of only 81.5% Interpretation Our findings indicate that the combination of human and artificial intelligence achieves superior results over the independent results of both of these systems.

Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2-specific CD4+ T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-γ-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2-specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.

Background Non-invasive diagnostic techniques in dermatology gained increasing popularity in the last decade. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) are meanwhile established in research and clinical routine. While OCT is mainly indicated for detecting non-melanoma skin cancer, RCM has proven its usefulness additionally in distinguishing melanocytic lesions. Line-field confocal optical coherence tomography (LC-OCT) is an emerging tool combining the principles of both above-mentioned methods. Methods Healthy skin at different body sites and exemplary skin lesions (basal cell carcinoma, malignant melanoma, actinic keratosis) were examined using dermoscopy, RCM, OCT and LC-OCT. Standard features for RCM and OCT and comparable features for LC-OCT were analysed. Results LC-OCT has a lower penetration depth but superior resolution compared to OCT. In comparison with RCM, which provides only horizontal sections, LC-OCT creates both vertical and horizontal images in real time and has nearly the same cellular resolution. Discussion Our preliminary experiences suggest that LC-OCT combines the advantages of RCM and OCT, with optimal resolution and penetration depth to diagnose all types of skin cancer. Larger systematic studies are needed to further characterize the field of use of this device and its sensitivity and specificity compared to histology.

Background The role of inpatient rehabilitation after total knee arthroplasty (TKA) remains uncertain, with evidence suggesting no better functional outcomes for those who discharge to rehabilitation to those who discharge home. The aim of this study is to develop and implement a pre-operative predictive tool, ARISE (Arthroplasty Rehabilitation Initial Screening Evaluation), that incorporated psychological, functional, and socio-demographic factors to determine discharge destination. Methods One week prior to TKA, the ARISE tool was administered to 100 patients, in addition to an EQ-5D-5L survey and other demographic data being recorded. The primary outcome was discharge destination. An enhanced recovery pathway, which included an anesthetic protocol designed to optimize early mobilization, was utilized. Univariable and multivariable logistic regression analysis was performed to determine the likelihood of discharge destination. Results Patients in the rehabilitation group were, on average, 4.5 years older than the home group (P = .036). After multivariable regression, ARISE questions were predictive of discharge destination related to beliefs around the superiority of inpatient rehabilitation (odds ratio = 9.9 [2.6-37.9]) and post-discharge level of support (odds ratio = 6.3 [1.5-26.8]). No question around self-reported physical function was predictive. Conclusion Pre-operative patient beliefs regarding rehabilitation and future home support are highly predictive of discharge destination after primary TKA. Pre-operative patient-reported functional status and demographic variables, with the exception of increasing age, were not shown to be predictive. Predicting those that are most likely to discharge to rehabilitation allows for early, targeted interventions to optimize resources and increase likelihood of home discharge.

Purposes We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)–targeting radioligand (+)-[18F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[18F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer’s disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding; and whether (+)-[18F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated. Methods We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [11C]PiB PET/MRI examination. (+)-[18F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. Results With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[18F]Flubatine binding of approximately 15% but also standard deviation of 0.4–70%. Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p 18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No adverse event related to (+)-[18F]Flubatine occurred. Conclusion (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[18F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR–targeting PET ligand in further clinical trials.

Background General practitioners play a vital and increasing part in the perioperative care of patients undergoing total knee replacement (TKR). Rising obesity rates, sports-related injuries and an ageing population are likely to result in a sharp increase in TKR procedures within the next decade, combined with higher cost concerns. Rehabilitation practices that show economic efficiency and produce superior patient outcomes are a major focus of current research. Objective The aim of this article is to provide an evidence-based summary of current rapid recovery protocols following TKR surgery. Discussion Rapid recovery protocols have been shown to be effective at reducing length of stay, postoperative pain and complications without compromising patient safety. These rapid recovery protocols include same-day mobilisation; blood preservation protocols; self-directed pedalling-based rehabilitation; and individualised targeted discharge to self-directed, outpatient therapist-directed or inpatient therapist-directed rehabilitation. Low-cost self-directed rehabilitation should be considered usual care, with inpatient rehabilitation reserved for the minority of at-risk patients.

The COVID-19 pandemic exposed numerous deficiencies of the U.S. primary care infrastructure. The system is overstretched with little to no surge capacity to deal with crisis situations, its reach restrained due to overreliance on brick and mortar clinics, and its behavior overwhelmingly more reactive than preventive. As delivery systems reorganize on the fly to fight COVID-19, many are turning to tools like telemedicine, pre-visit planning, and centralized population health programs. We propose how these rapid transformations happening across the country, born out of necessity, present a silver lining opportunity to fix primary care. We describe how integrating telemedicine, patient-generated data, and preventive care into a retooled intake and care optimization process is achievable through an approach powered by humans and augmentable with artificial intelligence. Primary care must retool to meet the challenge of COVID-19 and emerge in the post-crisis world better equipped to care for a wounded nation. Our collective willingness to invest in primary care teams, relaxation of rules around telemedicine reimbursement and patient-generated data sharing, workforce training, and movement to value-based payments are necessary to achieve this vision.

Pridopidine is an investigational drug in late stage development for the treatment of Huntington disease and originally postulated to act as dopamine stabilizer by modulating dopamine-dependent motor behavior. However, preclinical studies show pridopidine has highest affinity to sigma-1 receptors. Importantly, mediated by sigma-1 receptors, pridopidine has neuroprotective properties and enhances neuronal plasticity. The aim of our study was to determine the in-vivo the target engagement (receptor occupancy) of pridopidine at clinically relevant doses in healthy volunteers and Huntington disease patients. We used sigma-1 receptor-specific (S)-(-)-[18F]Fluspidine and dopamine D2/D3 receptor-specific [18F]Fallypride PET imaging to quantify the sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine. Eleven male healthy volunteers (pridopidine 0.5 to 90 mg in six dose groups) and three male Huntington disease patients (pridopidine 90 mg) were studied twice before and 2h following single oral doses of pridopidine using S-(-)-[18F]Fluspidine PET (300 MBq, 0-90min p.i.). Distribution volume VT was quantified using kinetic modeling (One-tissue compartment model; metabolite correction). Four male healthy volunteers were studied twice using [18F]Fallpride PET (200 MBq, 0-210min p.i.) before and 2h after a single oral dose of pridopidine (90 mg). Binding potential BPND was assessed by the simplified reference model. Volume-of-interest analyses were performed. For each subject/tracer, the receptor occupancy was calculated by the Lassen plot analysis. In healthy volunteers, there was high sigma-1 receptor occupancy (87 to 91%) across all brain regions at doses ranging from 22.5 to 90 mg. The sigma-1 receptor occupancy was 43% at 1 mg pridopidine. In Huntington disease patients, very similar to healthy volunteers, at 90 mg pridopidine, there was high sigma-1 receptor occupancy (87±7%, n.s.). In contrast, in healthy volunteers, there was only negligible dopamine D2/D3 receptor occupancy (3±2%) at 90 mg pridopidine. We established a sigmoid-shaped dose/sigma-1 receptor occupancy relation (Hill equation) with Hill coefficient larger than 1 in healthy volunteers, suggesting a positive cooperative binding nature of the sigma-1 receptor. Using PET, we report for the first time in the living human brain that after a single dose of 90 mg, pridopidine acts as a selective sigma-1 receptor ligand showing near to complete sigma-1 receptor occupancy (~90%) but only minimal (~3%) dopamine D2/D3 receptor occupancy. Our findings provide significant clarification about pridopidine’s mechanism of action and support further use of the 45 mg bidaily dose to achieve full and selective targeting of the sigma-1 receptor in future clinical trials in Huntington disease and amyotrophic lateral sclerosis.

Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, I-K,I-ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specificI(K,ACh)inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF.Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction.Key Results: XAF-1407 potently and selectively inhibited K(ir)3.1/3.4 and K(ir)3.4/3.4, underlying theI(K,ACh)current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (similar to 20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia.Conclusion and Implications: XAF-1407 efficiently cardioverted sustained tachypacing-induced AF of short duration in horses without notable side effects. This supportsI(K,ACh)inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.

Aims Impaired myocardial sympathetic innervation assessed by 123Iodine-Metaiodobenzylguanidine (123I-MIBG) scintigraphy is associated with cardiac events. Since regional disparities of structural abnormalities are common in inherited arrhythmia syndromes (iAS), a chamber-specific innervation assessment of the right (RV) and left ventricle (LV) could provide important insights for a patient-individual therapy. Aim of this study was to evaluate chamber-specific patterns of autonomic innervation by Single-photon emission computed tomography/computed tomography (SPECT/CT) in patients with iAS with respect to clinical outcome regarding cardiac events. Methods and results We assessed ventricular sympathetic innervation (LV, RV and planar heart/mediastinum-ratios, and washout-rates) by 123I-MIBG-SPECT/CT in 48 patients (arrhythmogenic right ventricular cardiomyopathy [ARVC], n = 26; laminopathy, n = 8; idiopathic ventricular fibrillation [iVF], n = 14) in relation to a composite clinical endpoint (ventricular arrhythmia; cardiac death; cardiac hospitalization). RV tracer uptake was lower in patients with ARVC than in laminopathy and iVF patients (1.7 ± 0.4 vs. 2.1 ± 0.7 and 2.1 ± 0.5, respectively). Over a median follow-up of 2.2 years, the combined endpoint was met in 18 patients (n = 12 ventricular tachyarrhythmias, n = 5 hospitalizations, n = 1 death). LV, but not RV H/M ratio was associated with the combined endpoint (hazard-ratio 2.82 [1.30–6.10], p Conclusion We demonstrated that chamber-specific 123MIBG-SPECT/CT imaging is feasible and that reduced LV sympathetic innervation was associated with worse outcome in iAS. These findings provide novel insights into the potential role of regional autonomic nervous system heterogeneity for the evolution of life-threatening cardiac events in iAS.

Gerhard Sattler,1 Martina Kerscher,2 Ernst Magnus Noah,3 Welf Prager,4 Tanja C Fischer,5 Patricia Ogilvie,6 Matthias Hofmann,7 Hanna Dersch,7 Gemma Odena8 1Rosenparkklinik GmbH, Darmstadt, Germany; 2Division of Biochemistry and Molecular Biology, Cosmetic Science, University of Hamburg, Hamburg, Germany; 3Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, Kassel, Germany; 4Prager & Partner Dermatologische Praxis, Hamburg, Germany; 5Haut- Und Lasercentrum Berlin-Potsdam, Potsdam, Germany; 6SkinConcept, Munich, Germany; 7Merz Pharmaceuticals GmbH, Frankfurt Am Main, Germany; 8Merz North America, Inc., Raleigh, NC, USACorrespondence: Gerhard Sattler Email gerhard.sattler@rosenparkklinik.deBackground: Facial aging is characterized by increased prominence of nasolabial folds (NLFs), marionette lines, and thinning of the lips. Cross-linked hyaluronic acid injection is a very effective method for the temporary correction of these areas.Objective: To confirm the clinical performance and the safety of Etermis 3 (ET3) and/or Etermis 4 (ET4) in the treatment of moderate and severe wrinkles/folds, as well as lip volume enhancement.Methods: Subjects were treated in at least two facial areas (NLFs, marionette lines, lips). ET3 was used in facial moderate wrinkles while ET4 was used in severe facial skin volume loss. An optional touch-up 1 month after treatment was possible. A blinded investigator assessed improvement on Merz Aesthetic Scales (MAS). Subjects were followed-up for 12 months after the last treatment.Results: In total, 154 healthy subjects were enrolled. The proportion of subjects achieving ≥ 1 score improvement in MAS after treatment was above 60% for ET4 (Month 6/7: NLFs 94.9% and marionette lines 81.4%, p≤ 0.0004; Month 3/4: lips 63.0%, p=0.39) and ET3 (Month 6/7: marionette lines 79.4%, p=0.0005; Month 3/4: lips 65.5%, p=0.31). Facial improvement was still visible at Month 12/13 for ET4 (NLFs ≥ 76.6%, marionette lines ≥ 61%, lips ≥ 36%) and ET3 (marionette lines ≥ 50% and lips ≥ 21.9%). No treatment-related serious AEs occurred. The most frequent AEs were injection-site reactions.Conclusion: Etermis 3 and Etermis 4 demonstrated good clinical performance and safety for NLFs and marionette lines volume enhancement for up to 12 months. Both products can also be used safely to treat lips for volume augmentation.Keywords: hyaluronic acid, wrinkles, facial volume enhancement

In response to the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), researchers are expeditiously searching for antiviral treatments able to alleviate the symptoms of infection, which can be life-threatening. Here, we provide a general overview of what is currently known about the structure and characteristic features of SARS-CoV-2, some of which could potentially be exploited for the purposes of antiviral therapy and vaccine development. This minireview also covers selected and noteworthy antiviral agents/supportive therapy out of hundreds of drugs that are being repurposed or tested as potential treatments for COVID-19, the disease caused by SARS-CoV-2.

Background Questionnaires provide valuable information about physical activity (PA) behaviors in older adults. Until now, no firm recommendations for the most qualified questionnaires for older adults have been provided. Objectives This review is an update of a previous systematic review, published in 2010, and aims to summarize, appraise and compare the measurement properties of all available self-administered questionnaires assessing PA in older adults. Methods We included the articles evaluated in the previous review and conducted a new search in PubMed, Embase, and SPORTDiscus from September 2008 to December 2019, using the following inclusion criteria (1) the purpose of the study was to evaluate at least one measurement property (reliability, measurement error, hypothesis testing for construct validity, responsiveness) of a self-administered questionnaire; (2) the questionnaire intended to measure PA; (3) the questionnaire covered at least one domain of PA; (4) the study was performed in the general, healthy population of older adults; (5) the mean age of the study population was > 55 years; and (6) the article was published in English. Based on the Quality Assessment of Physical Activity Questionnaires (QAPAQ) checklist, we evaluated the quality and results of the studies. The content validity of all included questionnaires was also evaluated using the reviewers’ rating. The quality of the body of evidence was evaluated for the overall construct of each questionnaire (e.g., total PA), moderate-to-vigorous physical activity (MVPA) and walking using a modified Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. Results In total, 56 articles on 40 different questionnaires (14 from the previous review and 26 from the update) were included. Reliability was assessed for 22, measurement error for four and hypotheses testing for construct validity for 38 different questionnaires. Evidence for responsiveness was available for one questionnaire. For many questionnaires, only one measurement property was assessed in only a single study. Sufficient content validity was considered for 22 questionnaires. All questionnaires displayed large measurement errors. Only versions of two questionnaires showed both sufficient reliability and hypotheses testing for construct validity, namely the Physical Activity Scale for the Elderly (PASE; English version, Turkish version) for the assessment of total PA, and the Physical Activity and Sedentary Behavior Questionnaire (PASB-Q; English version) for the assessment of MVPA. The quality of evidence for these results ranged from very low to high. Conclusions Until more high-quality evidence is available, we recommend the PASE for measuring total PA and the PASB-Q for measuring MVPA in older adults. However, they are not equally qualified among different languages. Future studies on the most promising questionnaires should cover all relevant measurement properties. We recommend using and improving existing PA questionnaires—instead of developing new ones—and considering the strengths and weaknesses of each PA measurement instrument for a particular purpose.

BACKGROUND: Cardiac arrhythmias in horses are diagnosed by auscultation or electrocardiogram (ECG), which results in a low sensitivity for detecting arrhythmias that occur sporadically. Implantable loop recorders (ILRs) are small ECG devices placed subcutaneously, to automatically detect arrhythmias in human patients.OBJECTIVES: To test ILRs ability to detect atrial fibrillation (AF) in horses. Further, we hypothesised that anatomical location of the implant site might influence signal quality. Signal quality was evaluated both during exercise and over time.STUDY DESIGN: Experimental study.METHODS: In five Standardbred mares, eleven ILRs were implanted subcutaneously in up to three different positions (Front: pectoral region, Left-6: sixth left intercostal space, Ventral: xiphoid region) and AF induced. The R and T wave amplitudes were measured in all positions over time during AF. AF burden automatically registered by the ILRs over a 2-month period were compared with selected Holter ECG recordings.RESULTS: All three positions had stable R and T wave amplitudes during the study period and were of sufficient quality to allow AF detection at rest. The position Left-6 showed significantly higher R and T wave amplitudes compared to the other positions. During submaximal exercise only the Left-6 position was able to record ECG signals of diagnostic quality. No position yielded diagnostic signals at maximum exercise due to artefacts.MAIN LIMITATIONS: Few horses and ILRs included and no spontaneous AF episodes were studied.CONCLUSIONS: This preliminary study indicates that ILRs can be used for AF detection in horses, but the anatomical location is important for optimal ECG quality. Despite insufficient quality during exercise, ILRs were suitable for AF detection at rest. Therefore, the ILR may be a valuable diagnostic tool for detecting paroxysmal AF in horses.

Early life stress influences adult psychopathology and is associated with an increase in the propensity for drug use/seeking throughout the lifespan. Animal models corroborate that stress exposure exacerbates maladaptive reactivity to stressful stimuli while also shifting the rewarding properties of many drugs of abuse, including nicotine (NIC), a stimulant commonly misused by adolescents. Interestingly, NIC treatment can also normalize some stress-induced behavioral deficits in adult rodents; however, little is known about NIC's therapeutic efficacy following stress experienced during adolescence. The goal of the following experiments was to elucidate NIC's ability to buffer the negative consequences of stress exposure, and to further assess behavioral responsivity while on the drug. Given that stress often occurs in both physical and non-physical forms, we employed the vicarious social defeat stress (VSDS) model which allows for investigation of both physical (PS) and emotional stress (ES) exposure. After 10 days, exposure to PS and ES decreased interaction with a social target in the social interaction test (SIT), confirming social avoidance. Groups were further divided and given NIC (0.0 or 160 mg/L) in their drinking water. After 1 month of NIC consumption, the mice were exposed to the SIT, elevated plus maze (EPM), and the forced swim test (FST), respectively. NIC-treated mice showed a reversal of stress-induced deficits in the EPM and FST. Surprisingly, the mice did not show improvement in the SIT regardless of treatment condition. Together, these data confirm NIC's ability to normalize some stress-induced behavioral deficits; however, NIC's effects on social behavior need further investigation.

The vitamin D receptor (VDR), primarily known as a crucial mediator of calcium homeostasis and metabolism, has been shown to play a significant role in various cancer entities. Previous studies have focused on vitamin D and its receptor in gynecological cancers, noting that the receptor is upregulated in epithelial ovarian cancer (EOC). The aim of this study is to analyze the prognostic impact of VDR and its functional significance in ovarian cancer. Through immunohistochemistry, VDR staining was examined in 156 ovarian cancer samples. Evaluation of VDR staining was conducted in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score, and the scores were classified into high- and low-level expressions. Expression levels were correlated with clinical and pathological parameters as well as with overall survival to assess for prognostic impact. Differences in cytoplasmic VDR expression were identified between the histological subtypes (p = 0.001). Serous, clear cell, and endometrioid subtypes showed the highest staining, while the mucinous subtype showed the lowest. Cytoplasmic VDR correlated with higher FIGO stage (p = 0.013;Cc = 0.203), positive lymph node status (p = 0.023;Cc = 0.236), high-grade serous histology (p = 0.000;Cc = 0.298) and grading from the distinct histological subtypes (p = 0.006;Cc = − 0.225). Nuclear VDR did not correlate with clinicopathological data. High cytoplasmic expression of VDR was associated with impaired overall survival (HR 2.218, 32.5 months vs. median not reached;p

OBJECTIVE Study the effect of coronary artery calcium (CAC) on resting coronary physiological indices. BACKGROUND Prior studies found no correlation between angiographic stenosis and fractional flow reserve (FFR) in heavily calcified arteries. METHODS Two hundred consecutive patients undergoing whole-cycle resting Pd/Pa and FFR evaluation of a single lesion of intermediate severity (40-80%) had CAC quantified based upon radiopacities at the site of the stenosis, where 0 = none or mild calcium, 1 = moderate calcium, and 2 = severe calcium. RESULTS Mean age was 61 ± 11 years and 34% were female. The mean degree of stenosis, FFR, and resting Pd/Pa were 60 ± 12%, 0.83 ± 0.08, and 0.93 ± 0.05, respectively. Resting Pd/Pa correlated with degree of angiographic diameter stenosis (DS) as determined by quantitative coronary angiography (QCA) or visual estimation in arteries with calcium score of 0 or 1, but there was no correlation in severely calcified arteries. The diagnostic accuracy of DS ≥70% by QCA to predict hemodynamic significance was 68% with calcium scores of 0/1, but only 43% with calcium score = 2. Resting Pd/Pa was highly correlated with FFR irrespective of the degree of CAC (R2 = 0.68, p

Purpose Thyroid hormone receptors (THR) have manifold functions and are involved in the carcinogenesis of several tumor types. Within this study, we aimed to investigate the expression pattern (nuclear versus cytoplasmic) of the THR alpha and its impact on patients survival in ovarian cancer (OvCa). Methods The presence of the thyroid hormone receptors THRα, THRα1 and − 2 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated with clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS). Results Among all subtypes of OvCa, clear cell carcinomas showed the highest THRα expression. Furthermore, nuclear THRα was associated with a reduced survival in this subtype. However, nuclear expressed THRα1 turned out to be a positive prognosticator for all subtypes of OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. In contrast, cytoplasmic expression THRα2 was associated with a reduced OS in all subtypes of OvCa patients; while, cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates with gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin. Conclusion Depending on nuclear or cytoplasmic expression, our study shows that THRα and its isoforms 1 and 2 provide different prognostic information for ovarian cancer patients. Further investigations should analyze if THRs may represent new endocrine targets for the treatment of ovarian cancer.