Search

In this compelling personal narrative describing a case from the front lines of the COVID-19 pandemic, a palliative care physician harnesses the creative powers and strengths of the interdisciplinary team to provide compassionate care to a critically ill patient and his family. The author describes the process of identifying a surrogate decision maker from among the patient's many adult children-several of whom were estranged from him and each other-and facilitating weighty decisions about his end-of-life care. Over the course of this journey, the author grapples with her inner biases and struggles with the emotional trauma associated with bearing witness to extraordinary suffering and social isolation imposed by COVID-19. Not only does the ethics of care approach embodied here lead to the creation of enduring vibrant works of art for this patient and others, but it also affirms a guiding principle of palliative care in which interdisciplinary collaboration is marshalled in the service of cultivating relationships, upholding responsibilities, and intensifying empathy among persons tied together by a common narrative.

Objective: To quantify tooth volume differences from extracted teeth when using three different three-dimensional (3D) computed tomography (CT)-based imaging modalities. Design: Ex vivo study. Setting: Laboratory and clinics of the University of Alberta. Methods: Cone-beam CT (CBCT) of 12 extracted teeth were scanned using 0.25- and 0.30-mm voxel size from CBCT and a 0.06-mm voxel size from micro-CT (reference standard). 3D reconstructions for each tooth from each imaging modality were made through the software ITK-SNAP®. The mean volume differences between each pair of scanning modalities were calculated and then compared and analysed through a repeated measures ANOVA. Results: The average overestimations of the teeth volume were 15.2% for the high-resolution CBCT and 28.1% for the low-resolution CBCT compared to micro-CT measurements. The differences in absolute volume were 81.6 mm3 and 152.8 mm3, respectively. All differences were statistically significant ( P < 0.05). Conclusions: Orthodontists and researchers who assess root resorption through CBCT imaging should be aware that the depicted volumes may likely be overestimating tooth volume and camouflaging real root volumetric treatment changes.

Background The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches. Objective We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT). Design/setting/participants Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible. Interventions All patients underwent [18F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT. Outcome measurements/statistical analysis Primary endpoint was biochemical response (complete, i.e. biochemical ‘no evidence of disease’ [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon’s two-stage design was employed (null and alternate hypotheses 20% response rate, respectively), with α and β of 0.1. Results Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed. Conclusions PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/− systemic agents can expand the curative therapeutic armamentarium for PCa. Patient summary We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.

Purpose: Blunt thoracic injuries are common among elderly patients and may be a common cause of morbidity and death from blunt trauma injuries. We aimed to examine the impact of chest CT on the diagnosis and change of management plan in elderly patients with stable blunt chest trauma. We hypothesized that chest CT may play an important role in providing optimal management to this subgroup of trauma patients. Methods: A retrospective analysis was performed on all the admitted adult blunt trauma patients between January 2014 and December 2018. Stable blunt chest trauma patients with abbreviated injury severity (AIS)

Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force 'Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality.

Background In human immunodeficiency virus (HIV)–positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART. Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children Results Of 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P ≤ .03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P < .001). Conclusions One in eight children in our cohort experienced PIR despite sustained VS. While the overall rate of AIDS/death was low, children with PIR had a 4-fold increase in risk of event as compared with immune responders.

Background: The present study sought to explore the combined relationship of physical activity, screen time, consumption of sugar-sweetened beverages, infant feeding practices, and demographic fact...

Objectives The aim of this study was to identify the patterns of medication load, its medication burden, coordination of healthcare and patient’s understanding of their conventional cardiac medications and related herbal-derived preparations. Methods The study is a mixed-method both, quantitative and qualitative approach, which involved Filipino elderly patients (n=69) enrolled in the outpatient service of the National Center for Geriatric Health, Manila. Data were gathered through face-to-face surveys and interviews using a semi-structured questionnaire. Descriptive statistics were used during data analysis. Thematic analysis was also used to emphasize patterns in the responses of the participants. Results Respondents were knowledgeable on the name (86.9%), visual characteristics (78.3%), and indication and administration of their medicine (88.4%). The frequency of their doctor’s information on the possible side effects of the medicines was noted. The almost negligible difference in the proportions of those who asserted during the information dissemination on the medication side effect by their doctors was observed ( Conclusions The majority of the elderly patients recognized the purpose and extent of medication. It was noted that pharmacists play a limited role in understanding selected Filipino elderly patients on their medication. Lack of communication between the patient and the pharmacist was noted as preliminary findings in the study. Respondents were not yet informed of the responsibility of the pharmacist to provide information regarding their medication. Integration of pharmacists’ care for geriatric health must be strengthened and highly recommended. Supervision by the healthcare professionals, particularly by the pharmacists, must be fully established.

Background Mast cells (MCs) are known to contribute to both acute and chronic inflammation. Bronchial epithelial cells are the first line of defence against pathogens and a deficient anti-viral response has been suggested to play a role in the pathogenesis of asthma exacerbations. However, effects of MC mediators on bronchial epithelial immune response have been less studied. The aim of this study is to investigate the direct effects of stimulation with MC proteases, tryptase and chymase, on inflammatory and anti-viral responses in human bronchial epithelial cells (HBECs). Method Cultured BEAS-2b cells and primary HBECs from 3 asthmatic patients were stimulated with tryptase or chymase (0.1 to 0.5 μg/ml) for 1, 3, 6 and 24 h. To study the effects of MC mediators on the anti-viral response, cells were stimulated with 10 μg/ml of viral mimic Poly (I:C) for 3 and 24 h following pre-treatment with 0.5 μg/ml tryptase or chymase for 3 h. Samples were analysed for changes in pro-inflammatory and anti-viral mediators and receptors using RT-qPCR, western blot and Luminex. Results Tryptase and chymase induced release of the alarmin ATP and pro-inflammatory mediators IL-8, IL-6, IL-22 and MCP-1 from HBECs. Moreover, tryptase and chymase decreased the expression of E-cadherin and zonula occludens-1 expression from HBECs. Pre-treatment of HBECs with tryptase and chymase further increased Poly (I:C) induced IL-8 release at 3 h. Furthermore, tryptase significantly reduced type-I and III interferons (IFNs) and pattern recognition receptor (PRR) expression in HBECs. Tryptase impaired Poly (I:C) induced IFN and PRR expression which was restored by treatment of a serine protease inhibitor. Similar effects of tryptase on inflammation and anti-viral responses were also confirmed in primary HBECs from asthmatic patients. Conclusion MC localization within the epithelium and the release of their proteases may play a critical role in asthma pathology by provoking pro-inflammatory and alarmin responses and downregulating IFNs. Furthermore, MC proteases induce downregulation of epithelial junction proteins which may lead to barrier dysfunction. In summary, our data suggests that mast cells may contribute towards impaired anti-viral epithelial responses during asthma exacerbations mediated by the protease activity of tryptase.

Machine learning (ML) holds great promise for impacting healthcare delivery; however, to date most methods are tested in ‘simulated’ environments that cannot recapitulate factors influencing real-world clinical practice. We prospectively deployed and evaluated a random forest algorithm for therapeutic curative-intent radiation therapy (RT) treatment planning for prostate cancer in a blinded, head-to-head study with full integration into the clinical workflow. ML- and human-generated RT treatment plans were directly compared in a retrospective simulation with retesting (n = 50) and a prospective clinical deployment (n = 50) phase. Consistently throughout the study phases, treating physicians assessed ML- and human-generated RT treatment plans in a blinded manner following a priori defined standardized criteria and peer review processes, with the selected RT plan in the prospective phase delivered for patient treatment. Overall, 89% of ML-generated RT plans were considered clinically acceptable and 72% were selected over human-generated RT plans in head-to-head comparisons. RT planning using ML reduced the median time required for the entire RT planning process by 60.1% (118 to 47 h). While ML RT plan acceptability remained stable between the simulation and deployment phases (92 versus 86%), the number of ML RT plans selected for treatment was significantly reduced (83 versus 61%, respectively). These findings highlight that retrospective or simulated evaluation of ML methods, even under expert blinded review, may not be representative of algorithm acceptance in a real-world clinical setting when patient care is at stake. An artificial intelligence system prospectively deployed to design radiation therapy plans for patients with prostate cancer illustrates the real-world impact of machine learning in clinical practice and identifies factors influencing human–algorithm interaction

Lumbar punctures (LPs) are commonly performed procedures, serving diagnostic and therapeutic purposes. They are generally safe, and serious, life-threatening complications are rare. We report a case of a patient who underwent an LP and subsequently developed shock. Imaging studies revealed a retroperitoneal hematoma with an active bleed. Interrogation of the lumbar branches in the interventional radiology suite revealed an active arterial bleed at the level of L3-L4 which was successfully embolized. We present this case to highlight the possibility of a rare complication of an LP and to emphasize the importance of early detection and resuscitative intervention.

The changes that occur during metastasis lodging is under intense research now to develop preventive new drugs to fight against the deadly metastasis. The molecular drug, all trans Retinoic Acid (ATRA) has regulatory effects on signal mediated metabolism. In this study, we have analyzed the metastasis facilitating metabolic changes in mice lung when a highly metastatic melanoma cell line (B16F10) having potency to lodge in lung was implanted via tail vein injection into C57BL/6 mice (1×106 cells/ml in PBS). One group of implanted mice were treated with 0.60 mg of ATRA per Kg body weight daily for 21 days. The alteration of protein, enzymatic and non-enzymatic antioxidants (SOD, Catalase, GPX, GSH) levels and the lipid profile with cholesterol level were evaluated in the lung tissues. The ATRA treatment caused 62.16% inhibition on metastatic nodule formation. Compared to normal mice, the cancer control mice showed an increased (p≤ 0.01**) total protein, LPO and NO and a decreased antioxidant. In ATRA treated group, all these levels were reverted to near normal levels with a high significance (p≤ 0.01**) difference from untreated cancer mice. The lipid profile and cholesterol level also were altered in cancer and were normalized in ATRA treated group with high significance (p≤ 0.01**). All these results implies that the metabolic changes induced in the lung tissue during metastatic lodging of melanoma cells were prevented and regularized by the ATRA treatment in vivo which give a scope of anti-metastatic therapy using ATRA.

In any work system design intervention—for example, a physical workplace redesign, a work process change, or an equipment upgrade—it is often emphasized how important it is to involve stakeholders in the process of analysis and design, to gain their perspectives as input to the development, and ensure their future acceptance of the solution. While the users of an artifact or workplace are most often regarded as being the most important stakeholders in a design intervention, in a work‐system context there may be additional influential stakeholders who influence and negotiate the design intervention's outcomes, resource allocation, requirements, and implementation. Literature shows that it is uncommon for empirical ergonomics and human factors (EHF) research to apply and report the use of any structured stakeholder identification method at all, leading to ad‐hoc selections of whom to consider important. Conversely, other research fields offer a plethora of stakeholder identification and analysis methods, few of which seem to have been adopted in the EHF context. This article presents the development of a structured method for identification, classification, and qualitative analysis of stakeholders in EHF‐related work system design intervention. It describes the method's EHF-related theoretical underpinnings, lessons learned from four use cases, and the incremental development of the method that has resulted in the current method procedure and visualization aids. The method, called Change Agent Infrastructure (abbreviated CHAI), has a mainly macroergonomic purpose, set on increasing the understanding of sociotechnical interactions that create the conditions for work system design intervention, and facilitating participative efforts.

Context Translational research in uro-oncology depends on the availability of high-quality biospecimens and associated data to advance precision medicine and improve clinical outcomes. Procurement, storage, and annotation of these specimens represent critical steps towards this end. Objective To review best-practice experiences gained via the McCain GU BioBank, a repository of more than 750 000 biospecimens obtained from more than 16 000 patients attending clinics at the University Health Network in Toronto, Canada. Evidence acquisition The review summarizes our experiences at a large single-institution genitourinary oncology biorepository. Evidence synthesis Key findings are placed in the context of emerging trends in genitourinary oncology, with a focus on integration of molecular profiling and clinical data with traditional biorepository management. Proposed approaches provide high-quality biospecimens with comprehensive and reliable clinical data that can fuel innovation and discovery in research. Conclusions Biorepositories are vital for improving clinical outcomes and advancing personalized medicine. High-quality biospecimens and their associated clinical data are crucial for validation of biomarkers in oncology. Efforts to procure, store, and annotate clinical specimens represent critical steps in translational research. Elements such as biobank size, biospecimen types, disease cohorts, predetermined collection protocols, broad informed consent, sample handling and storage protocols, and available infrastructure directly influence the effectiveness and capacity of a biobank. Patient summary Biorepositories, or biobanks, are facilities that store biospecimens such as blood, urine, or tissue (usually collected from humans) for use in research. Biobanks have become an important resource in medical research, as they provide high-quality specimens to support different types of contemporary research such as genomics, biomarker discovery, and personalized medicine. Clinical management and treatment of genitourinary cancers, such as prostate, kidney, and bladder cancers, are particularly suited for biomarker research. The provision of biospecimens and their associated clinical data have become crucial for validation of biomarkers in these cancers.

To assess whether 18F-DCFPyL PET/multiparametric (mp)MR contributes to the diagnosis of clinically significant (cs) prostate cancer (PCa) compared to mpMR in patients with suspicion of PCa, or patients being considered for focal ablative therapies (FT). This ethics review board–approved, prospective study included 55 men with suspicion of PCa and negative systematic biopsies or clinically discordant low-risk PCa (n = 21) or those being considered for FT (n = 34) who received 18F-DCFPyL PET/mpMR. Each modality, PET, mpMR, and PET/MR (using the PROMISE classification), was assessed independently. All suspicious lesions underwent PET/MR-ultrasound fusion biopsies. There were 45/55 patients (81.8%) that had histologically proven PCa and 41/55 (74.5%) were diagnosed with csPCa. Overall, 61/114 lesions (53.5%) identified on any modality were malignant; 49/61 lesions (80.3%) were csPCa. On lesion-level analysis, for detection of csPCa, the sensitivity of PET was higher than that of mpMR and PET/MR (86% vs 67% and 69% [p = 0.027 and 0.041, respectively]), but at a lower specificity (32% vs 85% and 86%, respectively [p

Background In many countries, lockdown measures were implemented to curb the COVID-19 pandemic. This situation may have an impact on mental health, tobacco smoking and alcohol consumption. The aim of this research report is therefore to describe changes in tobacco and alcohol consumption in the general French population during the first 2 weeks of lockdown and identify any associated factors. Methods Self-reported changes in smoking and alcohol consumption following the lockdown implemented in France on 17 March 2020 were collected from 2003 respondents aged 18 years and older in an online cross-sectional survey carried out from 30 March to 1 April 2020. Anxiety and depression levels were assessed using the Hospital Anxiety and Depression Scale. Results Among current smokers, 26.7% reported an increase in their tobacco consumption since lockdown and 18.6% reported a decrease, while it remained stable for 54.7%. The increase in tobacco consumption was associated with an age of 18–34 years, a high level of education, and anxiety. Among alcohol drinkers, 10.7% reported an increase in their alcohol consumption since lockdown and 24.4% reported a decrease, while it remained stable for 64.8%. The increase in alcohol consumption was associated with an age of 18–49 years, living in cities of more than 100 000 inhabitants, a high socio-professional category, and a depressive mood. Conclusions The national lockdown implemented in France during the COVID-19 pandemic influenced tobacco and alcohol consumption in different ways according to sociodemographic group and mental health.

Becoming a parent changes one’s life, and existential questions arise. Time and being oscillate between joy and powerlessness, vulnerability, and self-confidence, between harmony and unpreparedness. Breastfeeding, one of the first skills new mothers try to master, can be joyful and painful. The aim of this study was to develop a deeper understanding of the phenomenon of initial breastfeeding complications as they are lived and experienced by mothers and how these mothers can be supported. Twelve mothers were interviewed, and a phenomenological lifeworld approach was used. Nourishing an infant and having initial breastfeeding complications can be understood by the essence and its constituents. Expectations are fulfilled, and expectations come to naught when complications are experienced such as wavering between powerlessness and joy and finding solutions through resistance. The results suggest that lifeworld-led caring may lead to deepened acknowledgment and the possibility for mothers to feel supported in their extreme situations.

We sought to examine how condom use was differentially reasoned by gay, bisexual and other men who have sex with other men (GBM) in Ontario, Canada. Data were derived from a community-based study of GBM who completed an anonymous online questionnaire in 2014. Participants qualitatively described reasons a condom was used or not at their most recent anal sex event. Qualitative responses were thematically coded non-exclusively and associations with event-level and individual-level factors were determined quantitatively using manual backward stepwise multivariable logistic regression. Among 1,830 participants, 1,460 (79.8%) reported a recent anal sex event, during which 884 (60.6%) used condoms. Reasons for condom use included protection/safety (82.4%), norms (30.5%), and combination prevention (6.2%). Reasons for non-use were intentional (43.1%), trust (27.6%), unintentional (25.7%), and other strategies (19.6%). Event-level substance use was associated with all non-use reasons: e.g., more likely to be unintentional, less likely to be trust. Condom non-use with online-met partners was associated with more intentional and unintentional reasons and less trust reasons. Non-white and bisexual GBM were less likely to explain condom use as a norm. Participant-partner HIV status was an important predictor across most condom use and non-use reasons: e.g., sero-different partnerships were more likely to reason condom use as combination prevention and condom non-use as trust, unknown status partnerships were more likely to reason non-use as unintentional. Condom use among GBM is a multi-faceted practice, especially with increasing antiretroviral-based HIV prevention. Future interventions must adapt to changing GBM (sub-)cultures with targeted, differentiated, culturally-appropriate, and sustained interventions.

Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

AIMS Papaverine is indicated for abdominal pain of various aetiologies. However, data on maternal and foetal safety following gestational exposure are lacking. The aim was to examine whether first trimester exposure to papaverine is associated with increased risk for major malformation and whether gestational exposure at any stage is associated with increased risk for preterm delivery, lower birthweight, small for gestational age, caesarean section (CS), lower Apgar score and perinatal death. METHODS A retrospective comparative study consisted of pregnant women treated with papaverine between February 2010 and October 2019 at a large tertiary center. The control group comprised of livebirth deliveries randomly selected from the institutional obstetric database. RESULTS The study group consisted of 498 pregnancies, which resulted in 537/544 (98.7%) live births, of whom 46/537 (8.6%) were exposed during the first trimester. The control group consisted of 498 pregnancies and 514 live births. Rate of major malformations did not differ between study group (2/46, 4.3%) and control (25/315, 4.9%, P = .67). Papaverine exposure was associated with higher rate of preterm delivery (22.3 vs. 10.3%, P

Background: Global trend is moving towards the use of natural phytochemicals to fight against pathogens. Human cervical cancer is directly associated with onco-potent type of Human Papilloma Virus (HPV). There is no known medicine for clearance of HPV type whose persistence is the cause of occurrence and re-occurrence of cervical cancer. The different species of fig fruit and their latex are reported to have HPV associated genital warts clearance capability. Methods: In the current investigation, the effect of the methanol extract of Ficus benghalensis L. fruits on HPV type18 viral load in HeLa cell line was tested by doing PCR using HPV L1 primers (MY09/My011) and the cytotoxicity was also analysed by MTT assay. The induction of apoptotic activity in terms of DNA fragmentation and hyper-chromic effects of DNA was analysed. Results: The PCR results showed a reduction in the HPV18 DNA and also the treatment exhibited a promising cytotoxicity with IC50 value at 211.86 μg/ml. The DNA samples from treated HeLa cells showed DNA shearing and laddering as a mark of apoptotic DNA fragmentation (Fig. 2) and the UV absorbance value at 260 nm was found to be significantly (P

Little is known about how the large brains of mammals are accommodated into the dazzling diversity of their skulls. It has been suggested that brain shape is influenced by relative brain size, that it evolves or develops according to extrinsic or intrinsic mechanical constraints, and that its shape can provide insights into its proportions and function. Here, we characterise the shape variation among 84 marsupial cranial endocasts of 57 species including fossils, using 3D geometric morphometrics and virtual dissections. Statistical shape analysis revealed four main patterns: over half of endocast shape variation ranges between elongate and straight to globular and inclined; little allometric variation with respect to centroid size, and none for relative volume; no association between locomotion and endocast shape; limited association between endocast shape and previously published histological cortex volumes. Fossil species tend to have smaller cerebral hemispheres. We find divergent endocast shapes in closely related species and within species, and diverse morphologies superimposed over the main variation. An evolutionarily and individually malleable brain with a fundamental tendency to arrange into a spectrum of elongate-to-globular shapes – possibly mostly independent of brain function - may explain the accommodation of brains within the enormous diversity of mammalian skull form.

Objective The purpose of the study was to develop a short form of the revised Diabetes Family Conflict Scale (DFCS) in a racially and income diverse sample while retaining strong psychometric properties. Methods 179 youth with type 1 diabetes (ages 12-18 years) and caregivers completed the DFCS-Revised as well as assessments of adherence, psychosocial functioning, and diabetes-related stress. Hemoglobin A1c was also obtained. The sample was split at random into a development sample and validation sample. Results Confirmatory factor analyses in the validation sample supported the use of a six-item diabetes family conflict scale short form (DFCS-SF) either as a total score (6-items) or a direct (3-item) and indirect (3-item) score. Variations of the DFCS-SF (three items of the 6-item short form) also had acceptable model fit. The short-form questionnaires had acceptable internal consistency and convergent validity (6-item: Cronbach's a = 0.865, full scale DFCS r = 0.954; 3-item: Cronbach's a = 0.757, full scale DFCS r = 0.912). The DFCS-SF showed measurement invariance across both youth and caregiver respondents. Greater report of the DFCS-SF by both youth and caregivers was significantly associated with higher HbA1c, more diabetes-related stress, and more psychosocial concerns. Conclusions The DFCSȁ0SF developed in the present study shows psychometric integrity in a diverse population of youth and can be utilized by providers to rapidly assess and potentially implement interventions to reduce diabetes family conflict, a psychosocial concern which is associated with elevated HbA1c, non-optimal adherence, diabetes-related stress, and psychological distress. This article is protected by copyright. All rights reserved.

BackgroundFamotidine has been posited as a potential treatment for COVID-19. We compared the incidence of COVID-19 outcomes (i.e., death; and death or intensive services use) among hospitalized famotidine users vs. proton pump inhibitors (PPIs) users, hydroxychloroquine users or famotidine non-users separately.MethodsWe constructed a retrospective cohort study using data from COVID-19 Premier Hospital electronic health records. Study population were COVID-19 hospitalized patients aged 18 years or older. Famotidine, PPI and hydroxychloroquine exposure groups were defined as patients dispensed any medication containing one of the three drugs on the day of admission. The famotidine non-user group was derived from the same source population with no history of exposure to any drug with famotidine as an active ingredient prior to or on the day of admission. Time-at-risk was defined based on the intention-to-treat principle starting 1 day after admission to 30 days after admission. For each study comparison group, we fit a propensity score (PS) model through large-scale regularized B logistic regression. The outcome was modeled using a survival model.ResultsWe identified 2193 users of PPI, 5950 users of the hydroxychloroquine, 1816 users of famotidine and 26,820 non-famotidine users. After PS stratification, the hazard ratios for death were as follows: famotidine vs no famotidine HR 1.03 (0.89-1.18); vs PPIs: HR 1.14 (0.94-1.39); vs hydroxychloroquine:1.03 (0.85-1.24). Similar results were observed for the risk of death or intensive services use.ConclusionWe found no evidence of a reduced risk of COVID-19 outcomes among hospitalized COVID-19 patients who used famotidine compared to those who did not or compared to PPI or hydroxychloroquine users.

OBJECTIVE: To investigate the relationship between surgeon gender and stress during the Covid-19 pandemic. BACKGROUND: Although female surgeons face difficulties integrating work and home in the best of times, the Covid-19 pandemic has presented new challenges. The implications for the female surgical workforce are unknown. METHODS: This cross-sectional, multi-center telephone survey study of surgeons was conducted across 5 academic institutions (May 15-June 5, 2020). The primary outcome was maximum stress level, measured using the validated Stress Numerical Rating Scale-11. Mixed-effects generalized linear models were used to estimate the relationship between surgeon stress level and gender. RESULTS: Of 529 surgeons contacted, 337 surgeons responded and 335 surveys were complete (response rate 63.7%). The majority of female respondents were housestaff (58.1%), and the majority of male respondents were faculty (56.8%) (P = 0.008). A greater proportion of male surgeons (50.3%) than female surgeons (36.8%) had children ≤18 years (P = 0.015). The mean maximum stress level for female surgeons was 7.51 (SD 1.49) and for male surgeons was 6.71 (SD 2.15) (P < 0.001). After adjusting for the presence of children and training status, female gender was associated with a significantly higher maximum stress level (P < 0.001). CONCLUSIONS: Our findings that women experienced more stress than men during the Covid-19 pandemic, regardless of parental status, suggest that there is more to the gendered differences in the stress experience of the pandemic than the added demands of childcare. Deliberate interventions are needed to promote and support the female surgical workforce during the pandemic.

The mean potential of lordosis restoration by transforaminal lumbar interbody fusion (TLIF) is supposed to be low in general. In contrast, clinical experience shows a wide range of segmental lordosis correction. In this study, the predictability of lordosis correction should be investigated. Prospectively collected register data were analyzed retrospectively. One hundred twenty-one consecutive patients (2014–2016) operated with single-level TLIF L4/5 (10°-lordotic cage). Segmental lordosis (L4/5) and overall lordosis (L1–S1) were measured on lumbar X-rays: preoperatively (pre), after 3–5 days (post), at least 24 months postoperatively (2yFU). Outcome and satisfaction of patients were assessed. Parameters were statistically compared by students t-tests (a = 0.05). In addition, predictors of correction were analyzed. Age was 60.7 years, rate of 2yFU 41.3% (n = 50). Lordosis correction L4/5 was statistically significant with (post–pre) 4.9 ± 5.7° (p

ObjectiveFollowing the Journal of Pediatric Psychology’s special edition on health disparities, calling for Phase 2 research exploring mechanisms of racial groups in health disparities, this study aims to explore social information processing predictors of longitudinal hemoglobin A1c (HbA1c) trajectories in a racially diverse group of adolescents. The social information processing model of glycemic control in type 1 diabetes (T1D) posits that adolescents who make negative attributions about reactions of friends are likely to find adherence difficult in social situations, have increased stress, and have suboptimal glycemic control.MethodsOne hundred eighty-four youth with T1D completed self-report measures and HbA1c at three time points within 1 year was extracted from medical records. Growth mixture modeling empirically derived classes of HbA1c trajectories and explored predictive relationships of social information processing variables, demographics, and diabetes characteristics.ResultsThree classes emerged: High Decelerating, Mid-High Accelerating, and Near-Optimal Accelerating. Black/African American participants were highly likely to be in the High and Mid-High groups. Higher anticipated adherence difficulties in social situations predicted increased odds of being in the Mid-High versus Near-Optimal HbA1c group. Increased diabetes stress predicted increased odds of being in the High versus Near-Optimal and Mid-High groups.ConclusionsContinuing research on mechanisms behind this health disparity is necessary with more representation from varied racial and ethnic groups. Equal access to diabetes technology and psychosocial treatments are recommended and implications for clinical intervention development are discussed.

Introduction: Extrapulmonary small-cell cancer (EPSCC) is a relatively rare malignancy. The management of EPSCC is usually extrapolated from small-cell lung cancer (SCLC). In spite of the morphological similarity of the 2 malignancies, there are many differences in clinical features, prognosis, and recommendations of treatment of these disorders. The data on the correlation of clinical-pathological characteristics of EPSCC and treatment results is scarce. Materials and Methods: This retrospective analysis of 41 consecutively treated patients diagnosed with EPSCC in 2015–2018 was performed in a tertiary medical center. The correlation between the clinical and pathological characteristics and the treatment outcome (response rate, disease-free interval, and overall medial survival) was done using the standard statistics, Kaplan-Meier method, and multivariate analyses. The stratification was done on the stage of the disease, Ki-67 proliferative index, the location of the tumor, and smoking. Results: Forty-one patients were included with a median age of 66.3 years. The most common primary site was the gastrointestinal tract (28, 68.3%) including the pancreas. The most common distant metastasis site was the liver (23, 56.1%). Only 2 patients (4.9%) had brain metastases. Unlike in SCLC, most patients did not have any history of smoking (23, 56.1%). Nineteen patients with metastatic disease received systemic treatment, mostly cisplatin-based chemotherapy, with a response rate of 57.9%. The results of treatment were significantly better in patients with disseminated EPSCC with Ki-67 Discussion: The results of our study show the unique entity of EPSCC. The rarity of brain metastases proves that prophylactic brain irradiation should not be recommended in practice. The provocative idea of prophylactic liver irradiation in limited-stage EPSCC of gastrointestinal origin can be evaluated in future studies. The predictive role of Ki-67 is important in metastatic EPSCC. There is probably no role of smoking in developing EPSCC.

Hepatic metastases are a major cause of morbidity and mortality for patients with cancer. Apart from curative resection, which offers patients the potential for long-term survival, an array of locoregional therapies, with limited evidence of improving survival, are used to treat them. The authors use examples from the realm of gastrointestinal cancer, largely focusing on the experience of patients with neuroendocrine cancer, hepatobiliary cancer, and colorectal cancer, to suggest that current systemic therapies offer, at minimum, similar survival outcomes for patients compared with these locoregional approaches.

Summary Background Although acellular dermal matrix (ADM) is widely used in expander-implant-based breast reconstructions, previous analyses have been unable to demonstrate improvements in patient-reported outcomes (PROs) with this approach over non-ADM procedures. This study aims to develop a more selective, evidence-based approach to the use of ADM in expander-implant-based breast reconstruction by identifying patient subgroups in which ADM improved clinical outcomes and PROs. Study design The Mastectomy Reconstruction Outcomes Consortium Study prospectively evaluated immediate expander-implant reconstructions at 11 centers from 2012 to 2015. Complications (any/overall and major), and PROs (satisfaction, physical, psychosocial, and sexual well-being) were assessed two years postoperatively using medical records and the BREAST-Q, respectively. Using mixed-models accounting for centers and with interaction terms, we analyzed for differential ADM effects across various clinical subgroups, including age, body mass index, radiation timing, and chemotherapy. Results Expander-implant-based breast reconstruction was performed in 1451 patients, 738 with and 713 without ADM. Major complication risk was higher in ADM users vs. nonusers (22.9% vs. 16.4% and p = 0.04). Major complication risk with ADM increased with higher BMI (BMI=30, OR=1.70; BMI=35, OR=2.29, interaction p = 0.02). No significant ADM effects were observed for breast satisfaction, psychosocial, sexual, and physical well-being within any subgroups. Conclusion In immediate expander-implant-based breast reconstruction, ADM was associated with a greater risk of major complications, particularly in high-BMI patients. We were unable to identify patient subgroups where ADM was associated with significant improvements in PROs. Given these findings and the financial costs of ADM, a more critical approach to the use of ADM in expander-implant reconstruction may be warranted.

Objective: To explore the impact of the Covid-19 pandemic on the stress levels and experience of academic surgeons by training status (eg, housestaff or faculty). Background: Covid-19 has uniquely challenged and changed the United States healthcare system. A better understanding of the surgeon experience is necessary to inform proactive workforce management and support. Methods: A multi-institutional, cross-sectional telephone survey of surgeons was conducted across 5 academic medical centers from May 15 to June 5, 2020. The exposure of interest was training status. The primary outcome was maximum stress level, measured using the validated Stress Numerical Rating Scale-11 (range 0–10). Results: A total of 335 surveys were completed (49.3% housestaff, 50.7% faculty; response rate 63.7%). The mean maximum stress level of faculty was 7.21 (SD 1.81) and of housestaff was 6.86 (SD 2.06) (P = 0.102). Mean stress levels at the time of the survey trended lower amongst housestaff (4.17, SD 1.89) than faculty (4.56, SD 2.15) (P = 0.076). More housestaff (63.6%) than faculty (40.0%) reported exposure to individuals with Covid-19 (P < 0.001). Subjects reported inadequate personal protective equipment in approximately a third of professional exposures, with no difference by training status (P = 0.557). Conclusions: During the early months of the Covid-19 pandemic, the personal and professional experiences of housestaff and faculty differed, in part due to a difference in exposure as well as non-work-related stressors. Workforce safety, including adequate personal protective equipment, expanded benefits (eg, emergency childcare), and deliberate staffing models may help to alleviate the stress associated with disease resurgence or future disasters.

Key Clinical Points Evaluation and Management of Severe Covid-19 Patients with severe coronavirus disease 2019 (Covid-19) may become critically ill with acute respiratory distress syndrome that typ...

Aims: The first year after childbirth involves a major transition for women, which can accentuate inadequacies and feelings of powerlessness, making them vulnerable to depression. The aim of this study was to investigate the prevalence and frequency of maternal postpartum depressive symptoms at different times after giving birth (0–21 months). Methods: Data were collected cross-sectionally using a web questionnaire containing the Edinburgh Postnatal Depression Scale (EPDS). A total of 888 mothers with children in the age range 0–21 months responded. Results: The results showed different levels of depression over the range of months included in the study. The overall prevalence using EPDS ⩾ 12 was 27.8%. There were higher levels at 9–12 months and 17–21 months. The highest levels of symptoms of depression were found at nine, 12, and 17 months after birth, and the lowest levels at two and 16 months. Conclusions: Many mothers experience symptoms of depression after giving birth that can continue well beyond the child’s first year. We have identified different levels of depression at different points in time after giving birth, with highs and lows throughout the first 21 months. This highlights a need to screen for depression more than once during the first years, as well as a closer cooperation between midwives and child healthcare nurses in supporting mothers in the transition to motherhood. This is an important aspect of public health, which not only involves mothers with symptoms of depression, but also their ability to care for their child and a possible negative impact on the child’s development.

This study focused on evaluating the potency of Methyl Palmitate in reducing in vivo toxicity with enhancement of anti-cancer effects of Sorafenib. In vitro anti-cancer effects on human Hep-G2 cell line were analysed by MTT, Trypan blue, clonogenic, wound scratch migration and TUNEL assays. An in vivo study for anti-angiogenesis effect, toxicity and teratogenicity was analysed in Zebrafish embryos. The combination of Sorafenib (4.5 µmol/L) with Methyl Palmitate (3 mmol/L) significantly enhanced anti-cancer effects on Hep-G2 cell line by increasing cytotoxicity (P ≤ .05 in MTT assay; P ≤ .01 in Trypan blue assay), apoptosis (P ≤ .05) and decreasing the metastatic migration (P ≤ .01) than Sorafenib alone treatment. A prominent inhibition of angiogenesis in vivo was observed for combination treatment. At 5 dpf, only

National data on patient characteristics, treatment, and outcomes of critically ill coronavirus disease 2019 (COVID-19) solid organ transplant (SOT) patients are limited. We analyzed data from a multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units (ICUs) at 68 hospitals across the United States from March 4 to May 8, 2020. From 4153 patients, we created a propensity score matched cohort of 386 patients, including 98 SOT patients and 288 non-SOT patients. We used a binomial generalized linear model (log-binomial model) to examine the association of SOT status with death and other clinical outcomes. Among the 386 patients, the median age was 60 years, 72% were male, and 41% were black. Death within 28 days of ICU admission was similar in SOT and non-SOT patients (40% and 43%, respectively; relative risk [RR] 0.92; 95% confidence interval [CI]: 0.70-1.22). Other outcomes and requirement for organ support including receipt of mechanical ventilation, development of acute respiratory distress syndrome, and receipt of vasopressors were also similar between groups. There was a trend toward higher risk of acute kidney injury requiring renal replacement therapy in SOT vs. non-SOT patients (37% vs. 27%; RR [95% CI]: 1.34 [0.97-1.85]). Death and organ support requirement were similar between SOT and non-SOT critically ill patients with COVID-19.

To examine cancer prevalence in men with and without military service history, using national-level self-reported outcomes. A cross-sectional survey-based US study, including men aged 18 and above from the Health Information National Trends Survey database between 2011 and 2014. The primary endpoint was self-reported cancer prevalence. Multivariable logistic regression analyses assessed the association of various covariates with the prevalence of cancer. A total of 4,527 men were analyzed, with 1,352 (29.9%) reporting a history of military service. Compared to men with no military service history, men with a military service history were older (median of 65 [IQR 56, 74] vs. 53 [IQR 41, 62] years, p

Purpose Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long‐term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. Methods We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. Results Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. Conclusion This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

OBJECTIVES To assess whether free PSA ratio (FPSAR) at biochemical recurrence (BCR) can predict metastasis, castrate-resistant prostate cancer (CRPC), and cancer-specific survival (CSS), following therapy for localised disease. PATIENTS AND METHODS A single-centre retrospective cohort study (NCT03927287) including a discovery cohort composed of patients with an FPSAR after radical prostatectomy (RP) or radiotherapy (RT) between 2000 and 2017. For validation, an independent Biobank cohort of patients with BCR after RP was tested. Using a defined FPSAR cut-off, the metastasis-free-survival (MFS), CRPC-free survival, and CSS were compared. Multivariable Cox models determined the association between post-treatment FPSAR, metastases, and CRPC. RESULTS Overall, 822 patients (305 RP- and 363 RT-treated patients and 154 Biobank patients) were analysed. In the RP cohort, a total of 272/305 (89.1%) and 33/305 (10.9%) had a FPSAR test incidentally and reflexively, respectively. In the RT cohort, 155/363 (42.7%) and 208/263 (57.3%) had a FPSAR test incidentally and reflexively, respectively. However, in the prospective Biobank RP cohort, FPSAR testing was done on all samples of patients diagnosed with BCR. A FPSAR cut-off of 0.10 was determined using receiver operating characteristic analyses in both the RP and RT cohorts. A FPSAR of

Fur das pathologische Verstandnis retinaler Veranderungen sind direkte Vergleiche von hochaufgeloster In-vivo-Bildgebung und histologischer Darstellung wunschenswert. Dargestellt wird der methodische Aufbau zur multimodalen In-vivo- und Ex-vivo-Bildgebung eines Spenderauges mit sekundaren Veranderungen nach einem retinalen Zentralarterienverschluss. Die sich anschliesende Korrelation mit der Histologie erfolgt an identischen Gewebelokalisationen. Mit entsprechenden Vorrichtungen lassen sich In-vivo- und Ex-vivo-Bildgebung korrelieren und an den herkommlichen Geraten zur retinalen Bildgebung – wie am Beispiel des SD-OCTs („spectral domain“ optische Koharenztomographie) gezeigt – aufnehmen. Die prazise Ausrichtung des Gewebes ermoglicht eine histologische Analyse an identischen Aufnahmeorten. Durch die direkte Korrelation von klinischer Bildgebung mit Ex-vivo-Darstellung und Histologie lassen sich Erkenntnisse zur Pathogenese unterschiedlicher ophthalmologischer Krankheiten gewinnen. Die groste Herausforderung ist derzeit die eingeschrankte Verfugbarkeit von Spendergewebe.

Objective To determine reliability and validity of the acceptance and action diabetes questionnaire (AADQ) and the diabetes acceptance and action scale for children and adolescents (DAAS), measures of diabetes-specific psychological flexibility. Methods One hundred and eight-one youth with type 1 diabetes completed the AADQ, DAAS, and measures of mindfulness, cognitive fusion, and health-related quality of life. HbA1c was extracted from medical records. Confirmatory factor analysis (CFA) was used to cull items and evaluate the factor structures of the AADQ and DAAS. Bivariate correlations were conducted between all measures to explore content validity. Results CFAs supported a one-factor structure of the AADQ (for youth and parent report) and a second-order DAAS solution with a total score indicated by avoidance, values impairment, and avoidance subscales. All scales and subscales displayed strong internal consistency (α = .86-.95). The AADQ and DAAS evidence good content validity based on associations with other measures. Conclusions The AADQ and DAAS are reliable, valid measures of diabetes-specific psychological flexibility.

Background Matrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma. Patients and Methods This phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed. Results Andecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9−11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed. Conclusion Andecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma. Implications for Practice The combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.

A proposal for the use of porcine pancreatic elastase (PPE) to develop a mouse model of pulmonary emphysema raised concerns about introducing contaminating porcine viruses into our barrier facility. Porcine Circovirus (PCV) is a known contaminant of vaccines and cell cultures that have been exposed to porcine-derived reagents. Endemic infection of PCV3 in laboratory mice has been reported, and some evidence supports natural PCV infection in wild mice. PPE samples from 2 different vendors tested positive for DNA from both PCV2 and 3. To allow model development with these reagents to proceed, we developed a protocol that would meet scientific objectives, minimize exposure of mice, and provide information on the potential for the virus to spread. Five d after BALB/c mice received intralaryngeal administration of PPE, lungs were harvested and analyzed for evidence of disease. Tissues from other major organs were submitted to test for disseminated PCV2 and 3 DNA. Similarly, tissues (including lungs) from direct contact nude sentinel mice were analyzed for the presence of the virus. To evaluate the possibility of endemic PCV2/3 infection, we also surveyed non-porcine reagent exposed mice on other studies. PCV2 and 3 was not detected in any of the tissues submitted. Although this study provided no evidence of infection and transmission of PCV2/3 from the contaminated PPE sample over the 5 d study, further work is needed to understand the risks and impact of introducing PCV contaminated cells or reagents into barrier maintained rodent colonies.

Evidence points to an indispensable function of macrophages in tissue regeneration, yet the underlying molecular mechanisms remain elusive. Here we demonstrate a protective function for the IL-33-ST2 axis in bronchial epithelial repair, and implicate ST2 in myeloid cell differentiation. ST2 deficiency in mice leads to reduced lung myeloid cell infiltration, abnormal alternatively activated macrophage (AAM) function, and impaired epithelial repair post naphthalene-induced injury. Reconstitution of wild type (WT) AAMs to ST2-deficient mice completely restores bronchial re-epithelialization. Central to this mechanism is the direct effect of IL-33-ST2 signaling on monocyte/macrophage differentiation, self-renewal and repairing ability, as evidenced by the downregulation of key pathways regulating myeloid cell cycle, maturation and regenerative function of the epithelial niche in ST2−/− mice. Thus, the IL-33-ST2 axis controls epithelial niche regeneration by activating a large multi-cellular circuit, including monocyte differentiation into competent repairing AAMs, as well as group-2 innate lymphoid cell (ILC2)-mediated AAM activation., Signaling of IL-33 via its receptor, ST2, has been implicated in macrophage function in tissue repair. Here the authors show, using genetic mouse models and single-cell transcriptomic data, that the IL-33/ST2 axis regulates both ILC2-derived IL-13 and macrophage differentiation/reparative function required for club cell regeneration.

The concept that exposure in utero to maternal anti-brain antibodies contributes to the development of autism spectrum disorders (ASD) has been entertained for over a decade. We determined that antibodies targeting Caspr2 are present at high frequency in mothers with brain-reactive serology and a child with ASD, and further demonstrated that exposure in utero to a monoclonal anti-Caspr2 antibody, derived from a mother of an ASD child, led to an-ASD like phenotype in male offspring. Now we propose a new model to study the effects of in utero exposure to anti-Caspr2 antibody. Dams immunized with the extracellular portion of Caspr2 express anti-Caspr2 antibodies throughout gestation to better mimic the human condition. Male but not female mice born to dams harboring polyclonal anti-Caspr2 antibodies showed abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as repetitive behaviors and impairments in novelty interest in the social preference test as adults. These data supporting the pathogenicity of anti-Caspr2 antibodies are consistent with the concept that anti-brain antibodies present in women during gestation can alter fetal brain development, and confirm that males are peculiarly susceptible.

To reduce episode spending for twenty-nine predefined clinical conditions, the Centers for Medicare and Medicaid Services (CMS) implemented the voluntary Bundled Payments for Care Improvement (BPCI...

Aims/hypothesis Chronic stimulation of β2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of β2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p −1 day−1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p p p p p Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective β2-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans.

BACKGROUND: Multiple studies have demonstrated the safety of omitting therapies in older women with breast cancer. Despite de-implementation guidelines, up to 65% of older women continue to receive one or more of these low-value services. Previous work has investigated the role of both provider and patient attitudes as barriers to de-implementation; however, the importance of the patient’s maximizing-minimizing preferences within this context remains unclear. METHODS: In this qualitative study, we conducted thirty (n = 30) semi-structured interviews with women ≥ 70 years old without a previous diagnosis of breast cancer to elicit perspectives on breast cancer treatment in relation to their medical maximizing-minimizing preferences, as determined by the single-item maximizer-minimizer elicitation question (MM1). We used an interpretive description approach in analysis to produce a thematic survey. RESULTS: Participants were relatively evenly distributed across the MM1 (minimizer n = 8, neutral n = 13, maximizer n = 9). Despite being told of recommendations allowing for the safe omission of SLNB and post-lumpectomy radiotherapy, maximizers consistently stated preferences for more medical intervention and aggressive therapies over minimizers and neutral individuals. CONCLUSION: Medical maximizing-minimizing preferences in older women correspond with preferences for breast cancer treatment options that guidelines identify as potentially unnecessary. Increased awareness of patient-level variability in maximizing-minimizing preferences may be valuable in developing optimal intervention strategies to reduce utilization of low-value care.

OBJECTIVES: To evaluate the employment possibilities of Lithuanian dental hygienists. METHODS: The questionnaire asked about the demographics of dental hygienists, characteristics of practice, patient load, career intentions, opinion about dental hygienists workforce and the need of governmental workforce regulation. The study consisted of all licensed dental hygienists in Lithuania in 2018 (N = 1109). RESULTS: The final response rate was 52.1% (n = 578), 64% (n = 370) of respondents lived in the country's five main cities, and 73.5% (n = 425) worked in these population centres, with 94.3% (n = 545) worked in private sector. Over two-thirds of respondents said there was an excess of dental hygienists in Lithuania. Nearly 80% "always" or "sometimes" reported that they had insufficient patients, which may account for the prevalence of supplementary work (48.4%, n = 280), that is work as a dental assistant (67.9%, n = 190). Data obtained show that dental hygienists with less than ten years' experience were likely to work as a dental assistant (P

Recent studies have questioned the use of high-throughput sequencing of the nuclear ribosomal internal transcribed spacer (ITS) region to derive a semi-quantitative representation of fungal community composition. However, comprehensive studies that quantify biases occurring during PCR and sequencing of ITS amplicons are still lacking. We used artificially assembled communities consisting of 10 ITS-like fragments of varying lengths and guanine-cytosine (GC) contents to evaluate and quantify biases during PCR and sequencing with Illumina MiSeq, PacBio RS II and PacBio Sequel I technologies. Fragment length variation was the main source of bias in observed community composition relative to the template, with longer fragments generally being under-represented for all sequencing platforms. This bias was three times higher for Illumina MiSeq than for PacBio RS II and Sequel I. All 10 fragments in the artificial community were recovered when sequenced with PacBio technologies, whereas the three longest fragments (> 447 bases) were lost when sequenced with Illumina MiSeq. Fragment length bias also increased linearly with increasing number of PCR cycles but could be mitigated by optimization of the PCR setup. No significant biases related to GC content were observed. Despite lower sequencing output, PacBio sequencing was better able to reflect the community composition of the template than Illumina MiSeq sequencing.

Proton pump inhibitors (PPIs) are commonly prescribed medications that have been shown to have contradicting effects on cancer. We aimed to investigate the effect of pantoprazole and other PPIs on prostate cancer (PCa) specific mortality (PCSM), use of androgen deprivation therapy (ADT), and PCa diagnosis using a large Canadian population-based cohort. We identified 21,512 men aged ≥ 66, with a history of a single negative prostate biopsy and no previous use of any of the analyzed medications between 1994 and 2016. Multivariable Cox regression models with time-dependent covariates were used to assess the associations of PPIs with PCa outcomes. All models included other medications with a putative chemopreventative effect on PCa-outcomes, and were adjusted for age, rurality, comorbidity, and study inclusion year. Over a mean follow-up of 8.06 years (SD 5.44 years), 10,999 patients (51.1%) used a PPI, 5187 patients (24.1%) had PCa, 2043 patients (9.5%) were treated with ADT, and 805 patients (3.7%) died from PCa. For every 6 months of cumulative use, pantoprazole was associated with a 3.0% (95% CI 0.3–6.0%) increased rate of ADT use, while any use of other PPIs was associated with a 39.0% (95% CI 18.0–64.0%) increased risk of PCSM. No association was found with PCa diagnosis. Upon validation of the potentially negative association of PPIs with PCa, PPI use may need to be reassessed in PCa patients.