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Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic.Cross-sectional survey using four validated instruments.Sixty-two sites in Canada and the United States.Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs.None.We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures.Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Rationale: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) with a diagnosis based on clinical, radiological, and pathological findings. The evidence supporting transbronchial forceps lung biopsy (TBBx) and transbronchial lung cryobiopsy (TBLC) as sampling techniques to diagnose HP in patients with newly detected ILD has not been reviewed systematically.Objectives: A systematic review was performed to assess the diagnostic yield and complication rates of TBBx or TBLC in patients with newly detected ILD whose differential diagnosis includes HP and to inform the development of the American Thoracic Society, Japanese Respiratory Society, and Asociacion Latinoamericana del Torax clinical practice guidelines on the diagnosis of HP.Methods: Medline, Excerpta Medica Database, and the Cochrane Library were searched through October 2019. Studies that enrolled patients with ILD and reported the diagnostic yield of TBBx or TBLC were selected for inclusion. Data related to diagnostic yield and safety outcomes were extracted and then pooled across studies via meta-analysis. The quality of the evidence was appraised using the grading of recommendations, assessment, development, and evaluation (GRADE) approach.Results: The histopathologic diagnostic yields (number of procedures that yielded a histopathologic diagnosis divided by the total number of procedures performed) of TBBx and TBLC were 37% (95% confidence interval [CI], 32-42%) and 82% (95% CI, 78-86%), respectively, among patients with ILD. Among those diagnosed by TBBx, the proportion with HP could not be determined. However, among those diagnosed by TBLC, 13.4% had HP. TBBx was complicated by moderate to severe bleeding, severe bleeding, and pneumothorax in 4% (95% CI, 0-8%), 0% (95% CI, 0-1%), and 7% (95% CI, 2-13%) of patients, respectively. TBLC was complicated by any bleeding, severe bleeding, and pneumothorax in 11% (95% CI, 7-15%), 0% (95% CI, 0-1%), and 11% (95% CI, 9-14%) of patients, respectively. The quality of the evidence was very low because of the uncontrolled study designs, lack of consecutive enrollment, and inconsistent results.Conclusions: Very low-quality evidence indicated that TBLC had a higher diagnostic yield than TBBx among patients with ILD, although complications were similar.

Rationale: Hypersensitivity pneumonitis (HP) results from exposure to a variety of stimuli, which are challenging to identify. Questionnaires and serum immunoglobulin G (IgG) testing are methods to identify potentially causative exposures.Objectives: To perform a systematic review to determine the usefulness of questionnaires and serum IgG testing in identifying exposures that may have caused HP.Methods: This systematic review informed an international, multidisciplinary panel that developed a clinical practice guideline on the diagnosis of HP for the American Thoracic Society, Japanese Respiratory Society, and Asociacion Latinoamericana del Torax. MEDLINE, the Cochrane Library, and EMBASE were searched from January 1946 to October 2019 for studies that used a questionnaire or serum IgG testing to identify exposures that may have caused HP. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to appraise the quality of the evidence.Results: Searches identified 1,141 and 926 potentially relevant articles for questionnaires and serum IgG testing, respectively. The full texts of 32 and 49 articles, respectively, were reviewed. Two observational studies for questionnaires and 15 accuracy studies for serum IgG testing were selected. Questionnaires were better at detecting potentially relevant exposures than clinical history (100% vs. 26%; risk ratio [RR], 3.80; 95% confidence interval [95% CI], 1.79-8.06) and serum IgG testing (100% vs. 63%; RR, 1.58; 95% CI, 1.12-2.23) but did not differ from serum IgG testing plus bronchial challenge testing (59% vs. 65%; RR, 0.90; 95% CI, 0.65-1.24). Longer, detailed questionnaires were more likely to lead to identification of potential exposures. Only 70% of potential exposures identified by questionnaires were subsequently confirmed by environmental testing. Serum IgG testing distinguished HP from healthy exposed and unexposed control subjects with high sensitivity (90% and 92%, respectively) and high specificity (91% and 100%, respectively) but did not distinguish HP as effectively from interstitial lung diseases (ILDs; sensitivity of 83% and specificity of 68%).Conclusions: Using a questionnaire may help clinicians identify potentially relevant exposures when evaluating a patient with newly identified ILD for HP. Serum IgG testing may also lead to identification of potentially relevant exposures, but its usefulness for distinguishing HP from other types of ILD is poor.

The association between inferior vena cava (IVC) filter presence and subsequent bloodstream infection (BSI) is unknown. We hypothesized among patients with a new diagnosis of venous thromboembolism (VTE), incidence of BSI after 1 year would be higher in patients who had presence of an IVC filter.We performed a retrospective cohort study of patients with newly diagnosed VTE but no IVC filter (N = 4,053) and patients with IVC filter (N = 635) admitted to a metropolitan hospital system from 2006 to 2009 comparing incidence of BSI within 1 year of inclusion. Multivariable regression modeling was used to evaluate the association of IVC filter placement with BSI 1 year after placement.Patients with an IVC filter placed were more likely to be older with higher Charlson co-morbidity score (median 4 vs 1; P.001). The incidence of BSI was not different between the group with IVC filter and the group without (10.7% vs 8.8%; P = .12). There was no association with IVC filter placement and BSI before or after multivariable adjustment.In patients newly diagnosed with VTE, we found no association between IVC filter placement and increased incidence of BSI after 1 year.

Rationale: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by inflammation and/or fibrosis in response to an inhalational exposure.Objectives: To determine the...

Background Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. Methods An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. Results The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. Conclusions The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities., For patients with acute COVID-19 pneumonia who require oxygen support, the International Task Force made suggestions for remdesivir and dexamethasone, but against hydroxychloroquine. Post-discharge management of COVID-19 survivors is a research priority. https://bit.ly/32B96uI

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS., Author Summary Cornelia de Lange Syndrome (CdLS) is a genetic disease marked by growth retardation, cognitive and neurological problems, and structural defects in many organ systems. The majority of CdLS cases are due to mutation of one copy of the Nipped B-like (NIPBL) gene, the product of which regulates a complex of chromosomal proteins called cohesin. How reduction of NIPBL function gives rise to pervasive developmental defects in CdLS is not understood, so a model of CdLS was developed by generating mice that carry one null allele of Nipbl. Developmental defects in these mice show remarkable similarity to those observed in individuals with CdLS, including small stature, craniofacial abnormalities, reduced body fat, behavioral disturbances, and high perinatal mortality. Molecular analysis of tissues and cells from Nipbl mutant mice provide the first evidence that the major role of Nipbl in the etiology of CdLS is to exert modest, but significant, effects on the expression of diverse sets of genes, some of which are located in characteristic arrangements along the DNA. Among affected genes is a set involved in the development of adipocytes, the cells that make and accumulate body fat, potentially explaining reductions in body fat accumulation commonly observed in individuals with CdLS.

Adolescents and young adult females who are hypoestrogenic need gonadal hormone therapy for sexual development, enhancement of growth, and maintenance of reproductive tissues, cyclic menses, and psychosocial health. In addition, prevention of chronic disease, specifically bone loss and possibly early heart disease, needs to be addressed in these patients. The etiology of hypopituitarism should also be considered when evaluating therapeutic options. The issues concerning estrogen replacement therapy (ERT), including the doses used and the length of therapy, are different for young patients than for postmenopausal women. The highly publicized findings of the Women's Health Initiative have identified risks of combined progestin-estrogen therapy; these risks, found in much older women, have raised questions regarding the appropriateness of ERT in adolescents with hypopituitarism and Turner syndrome. It is therefore appropriate to examine the relative risks and benefits of ERT in these populations.

S / Developmental Biology 295 (2006) 349 – 353 reported to participate in both the retinoid signaling pathway and the transforming growth factor-beta (TGF-beta) pathway. Smad2 is a intracellular mediator of the TGF-beta signaling cascade, regulating gene transcription. Depending upon the co- activator, Smad2 can function as either an enhancer or repressor. Research has indicated that mice harboring Tgif mutations are more susceptible to teratogenesis induced by exogenous all – trans retinoic acid (RA), resulting in HPE and exencephaly. Smad2 heterozygous embryos are also suscepti- ble to exogenous RA. In addition, the use of a Smad2 hypomorphic allele reinforces the observation that Smad2 is involved in susceptibility, as hypomorphic heterozygous are less susceptible to the effects of RA than hypomorphic homozygotes. There are many factors involved in retinoid signaling, including both the retinoid cascade and RA synthesis and degradation. Analysis of gene transcription to determine the inherent susceptibility to RA in the Smad2+/ embryos was undertaken. Results indicate that Adh4 and Cyp26A1 are affected in early development. When the promoters of these genes were analyzed, many Smad Binding Elements (SBEs) were observed, indicating potential interaction of TGF-beta signaling in the synthesis and degradation of RA. doi:10.1016/j.ydbio.2006.04.082 Developmental defects in multiple organ systems in a mouse model of Cornelia de Lange Syndrome Shimako Kawauchi 1 , Rosaysela Santos 1 , Martha Lopez-Burks 2 , Abigail Chua 2 , Leonard M. Kitzes 1 , Arthur D. Lander 2 , L. Calof 1 Department of Anatomy and Neurobiology, University of California, Irvine, USA Department of Developmental and Cell Biology, University of California, Irvine, USA Cornelia de Lange Syndrome (CdLS) is a dominantly- inherited, multi-system birth defects syndrome with highly variable presen- tation. Individuals with CdLS have characteristic facial features, hirsutism, limb defects, heart defects, gastrointestinal system defects, and growth and cognitive retardation. Recent work has shown that CdLS is caused by heterozygous mutation of a gene, NIPBL (Nipped-B like), whose product is involved in regulation of the cohesin system of chromosomal structural proteins (Krantz et al., 2003, Nat. Genet. 36:631). We have developed a mouse model for CdLS, using mice heterozygous for a gene-trap mutation in Nipbl. Surviving Nipbl+/ mice exhibit a number of organ system defects characteristic of CdLS, including small body and head size, heart defects, hearing abnormalities, and delayed bone maturation. Nipbl+/ mice also show a very high incidence (¨75%) of perinatal mortality, indicating that these animals have other, as yet undetected, abnormalities. RNase protection assays demonstrate that the phenotypes of Nipbl+/ mice are associated with a decrease in Nipbl transcript levels to only ¨75% of wildtype, implying that these developmental events are extremely sensitive to small changes in Nipbl function. Supported by seed grants from the Cornelia de Lange Syndrome Foundation and the Center for Hearing Research at the University of California, Irvine. doi:10.1016/j.ydbio.2006.04.083 Contribution of aberrant placentation to fetal alcohol syndrome Garen S. Wolff 1 , Po J. Chiang 1 , Susan S. Smith 2 , Roberto Romero 3 , D. Randall Armant 1 Department of OB/GYN, Wayne State University, Detroit, MI, USA Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA Perinatology Research Branch, NICHHD, NIH, DHHS, Bethesda, MD, USA The teratogen ethanol causes fetal alcohol syndrome, which is associated with intrauterine growth retardation (IUGR) and neurological birth defects. A contributing factor to IUGR is cytotrophoblast cell (CTC) apoptosis during placentation. Using a human first trimester CTC line (HTR-8/SVneo), we examined the relationship between CTC apoptosis and exposure to ethanol. Exposure for 0– 2 h to 0, 25, 50 or 100 mM ethanol demonstrated a significant time-and dose-depen- dent increase in CTC death measured by TUNEL. Prolifera- tion (expression of nuclear antigen Ki-67) was also inhibited by ethanol. Increased externalization of phosphatidyl serine, the presence of pyknotic, TUNEL-positive nuclei and preven- tion of cell death by caspase inhibitors suggested that ethanol caused apoptosis, as opposed to necrosis. Moreover, there was no evidence of cell rupture and the release of lactate dehydrogenase. Production of heparin-binding EGF-like growth factor (HBEGF), which prevents CTC apoptosis due to low oxygen in the first trimester, increased with exposure to 25– 50 mM ethanol. During treatment with 100 mM ethanol, 1 nM HBEGF eliminated cell death and 5 nM restored CTC proliferation. HBEGF antagonists confirmed its specificity. We conclude that CTC apoptosis due to maternal alcohol abuse could cause IUGR; however, ethanol-induced production of HBEGF could provide an endogenous protective mechanism. Supported by NIH grants AA12057, AA11085 and AA014535 and the intramural research program of NICHHD. doi:10.1016/j.ydbio.2006.04.084 Influence of hormones on growth and differentiation of cells that do not express neurofibromin Kate F. Barald, Therese M. Roth, Poornapriya Ramamurthy University of Michigan Medical School, Department of Cell and Developmental Biology, Ann Arbor, MI, USA The tumor suppressor gene, Neurofibromatosis Type 1 (NF1) is responsible for one of the most common autosomal