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Although the physiatric community increasingly embraces evidence-based medicine (EBM), the current state of EBM training for trainees in physiatry is unclear. The purposes of this article are to report the results of the Association of Academic Physiatrists’ surveys of physiatry residency programs in the United States, to discuss the implications of their findings, and to better delineate the “baseline” upon which sound and clear recommendations for systematic EBM training can be made. The two Association of Academic Physiatrists surveys of US physiatry residency programs reveal that most survey respondents report that they include EBM training in their programs that covers the five recommended steps of EBM core competencies. However, although most respondents reported using traditional pedagogic methods of training such as journal club, very few reported that their EBM training used a structured and systematic approach. Future work is needed to support and facilitate physiatry residency programs interested in adopting structured EBM training curricula that include recommended EBM core competencies and the evaluation of their impact.

Background Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch–scratch cycle. Objective We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti–IL-31 receptor inhibitor nemolizumab. Method RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti–IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. Results Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. Conclusion These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.

With their extensive coverage, marine low clouds greatly impact global climate. Presently, marine low clouds are poorly represented in global climate models, and the response of marine low clouds to changes in atmospheric greenhouse gases and aerosols remains the major source of uncertainty in climate simulations. The eastern North Atlantic (ENA) is a region of persistent but diverse subtropical marine boundary layer clouds, whose albedo and precipitation are highly susceptible to perturbations in aerosol properties. In addition, the ENA is periodically impacted by continental aerosols, making it an excellent location to study the cloud condensation nuclei (CCN) budget in a remote marine region periodically perturbed by anthropogenic emissions, and to investigate the impacts of long-range transport of aerosols on remote marine clouds. The Aerosol and Cloud Experiments in Eastern North Atlantic (ACE-ENA) campaign was motivated by the need of comprehensive in situ measurements for improving the understanding of marine boundary layer CCN budget, cloud and drizzle microphysics, and the impact of aerosol on marine low cloud and precipitation. The airborne deployments took place from 21 June to 20 July 2017 and from 15 January to 18 February 2018 in the Azores. The flights were designed to maximize the synergy between in situ airborne measurements and ongoing long-term observations at a ground site. Here we present measurements, observation strategy, meteorological conditions during the campaign, and preliminary findings. Finally, we discuss future analyses and modeling studies that improve the understanding and representation of marine boundary layer aerosols, clouds, precipitation, and the interactions among them.

Germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) at diagnosis is associated with superior long-term outcomes compared to non-GCB-DLBCL in patients treated with conventional chemo-immunotherapy. Whether cell of origin (COO) by Hans algorithm retains its prognostic significance in patients with (R/R) relapsed/refractory DLBCL undergoing autologous hematopoietic cell transplant (auto-HCT) is not well established. Three hundred and fifty-seven patients underwent auto-HCT between 2005 and 2018. The COO status was determined in 284 patients and these were included in the analysis. One hundred ninety-four patients had GCB-DLBCL while 90 had non-GCB-DLBCL. Median follow up was 1.7 (0-13) years. The GCB-DLBCL was associated with inferior 5-year overall survival at 44% (95%CI, 36-52) versus 64% (95%CI, 54-77) (P = .004) and a higher relapse incidence at 67% (95%CI, 58-74) versus 49% (95%CI, 35-60) (P = .01) in the non-GCB-DLBCL. The difference between GCB and non-GCB-DLBCL remained statistically significant in multivariate analysis. Additionally, response at the time of transplant was an independent prognostic factor. GCB-DLBCL was enriched in double-hit and triple hit phenotype based on available fluorescence in situ hybridization data. These results suggest an enrichment of high-risk genetic rearrangements in R/R GCB-DLBCL resulting in limited efficacy of auto-HCT.

Background: Patients with end-stage renal disease (ESRD) on maintenance dialysis receive dialysis in common spaces with other patients and have a higher risk of severe SARS-CoV-2 infections. They may have persistently or intermittently positive SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) tests after infection. We describe the clinical course of SARS-CoV-2 infection and the serologic response in a convenience sample of patients with ESRD to understand the duration of infectivity. Methods: From August to November 2020, we enrolled patients on maintenance dialysis with SARS-CoV-2 infections from outpatient dialysis facilities in Atlanta, Georgia. We followed participants for approximately 42 days. We assessed COVID-19 symptoms and collected specimens. Oropharyngeal (OP), anterior nasal (AN), and saliva (SA) specimens were tested for the presence of SARS-CoV-2 RNA, using RT-PCR, and sent for viral culture. Serology, including neutralizing antibodies, was measured in blood specimens. Results: Fifteen participants with a median age of 58 (range 37‒77) years were enrolled. Median duration of RT-PCR positivity from diagnosis was 18 days (interquartile range (IQR): 8‒24 days). Ten participants had at least one, for a total of 41, positive RT-PCR specimens ≥10 days after symptoms onset. Of these 41 specimens, 21 underwent viral culture; one (5%) was positive 14 days after symptom onset. Thirteen participants developed SARS-CoV-2 specific antibodies, 11 of which included neutralizing antibodies. RT-PCRs remained positive following seroconversion in eight participants and following detection of neutralizing antibodies in four participants; however, all these samples were culture negative. Conclusions: Patients with ESRD on maintenance dialysis remained persistently and intermittently SARS-CoV-2 RT-PCR positive. However, of the 15 participants, only one had infectious virus, on day 14 after symptom onset. Most participants mounted an antibody response, including neutralizing antibodies. Participants continued having RT-PCR-positive in the presence of SARS-CoV-2 specific antibodies, but without replication-competent virus detected.

Purpose Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are devastating diseases in preterm neonates, often requiring surgical treatment. Previous studies evaluated outcomes in peritoneal drain placement versus laparotomy, but the accuracy of the presumptive diagnosis remains unknown without bowel visualization. Predictive analytics provide the opportunity to determine the etiology of perforation and guide surgical decision making. The purpose of this investigation was to build and evaluate machine learning models to differentiate NEC and SIP. Methods Neonates who underwent drain placement or laparotomy NEC or SIP were identified and grouped definitively via bowel visualization. Patient characteristics were analyzed using machine learning methodologies, which were optimized through areas under the receiver operating characteristic curve (AUROC). The model was further evaluated using a validation cohort. Results 40 patients were identified. A random forest model achieved 98% AUROC while a ridge logistic regression model reached 92% AUROC in differentiating diseases. When applying the trained random forest model to the validation cohort, outcomes were correctly predicted. Conclusions This study supports the feasibility of using a novel machine learning model to differentiate between NEC and SIP prior to any intended surgical interventions. Level of Evidence level II Type of Study Clinical Research Paper

Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) is a pathogenic coronavirus causing COVID‐19 infection. The interaction between the SARS‐CoV‐2 spike protein and the human receptor angiotensin‐converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide‐thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID‐19. However, the molecular‐level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID‐19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID‐19 infection or reducing the severity of the disease.

Congenital complete heart block (CCHB) affects 1 in 20,000 newborns. This study evaluates fetal and neonatal risk factors predictive of neonatal pacemaker placement in antibody-mediated complete heart block. The Children’s Hospital Los Angeles institutional fetal, pacemaker, and medical record databases were queried for confirmed SSA/SSB cases of CCHB between January 2004 and July 2019. Cases excluded were those with a diagnosis beyond the neonatal period, diagnosis of a channelopathy, or if maternal antibody status was unknown. We recorded the gestational age (GA), birth weight (BW), fetal heart rates (FHRs) of the last echocardiogram before delivery, specific neonatal ECG and echocardiogram findings, age at pacemaker placement, and mortality. Of 43 neonates identified with CCHB, 27 had confirmed maternal antibody exposure. Variables associated with neonatal pacemaker implantation were FHRs

Objectives The COVID-19 pandemic has had a substantial impact on health systems. The WHO Antimicrobial Resistance (AMR) Surveillance and Quality Assessment Collaborating Centres Network conducted a survey to assess the effects of COVID-19 on AMR surveillance, prevention and control. Methods From October to December 2020, WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) national focal points completed a questionnaire, including Likert scales and open-ended questions. Data were descriptively analysed, income/regional differences were assessed and free-text questions were thematically analysed. Results Seventy-three countries across income levels participated. During the COVID-19 pandemic, 67% reported limited ability to work with AMR partnerships; decreases in funding were frequently reported by low- and middle-income countries (LMICs; P Conclusions This was the first survey to explore the global impact of COVID-19 on AMR among GLASS countries. Responses highlight important actions to help ensure that AMR remains a global health priority, including engaging with GLASS to facilitate reliable AMR surveillance data, seizing the opportunity to develop more sustainable IPC programmes, promoting integrated antibiotic stewardship guidance, leveraging increased laboratory capabilities and other system-strengthening efforts.

A 21-year-old with a history of cyclic abdominal pain beginning at age 13 years and a previous diagnosis of a complex mullerian anomaly presented with abdominal pain and a finding of a right distended hemiuterus, left hematosalpinx, and cervix separate from the uterine body. After laparoscopic decompression for symptomatic relief at that time, she presented to our center for definitive management. After a diagnostic vaginoscopy and laparoscopy confirmed the diagnosis of uterine isthmus agenesis, an abdominal approach to uterocervical anastomosis was planned and undertaken. At the postsurgical clinical follow-up, the patient reported normal menses and resolution of pain, and imaging confirmed maintenance of anastomotic patency. The diagnosis and classification system of mullerian anomalies are complex, and few reports detail the management of rare mullerian anomalies. In this case report, the successful anastomosis of the uterus and the cervix is reviewed as an approach that can restore normal menses successfully and safely and potentially allow for future fertility in patients with uterine isthmus agenesis.

Repeated antigen testing of 12 severe acute respiratory coronavirus virus 2 (SARS-CoV-2)–positive nursing home residents using Abbott BinaxNOW identified 9 of 9 (100%) culture-positive specimens up to 6 days after initial positive test. Antigen positivity lasted 2–24 days. Antigen positivity might last beyond the infectious period, but it was reliable in residents with evidence of early infection.

Murine models of Neisseria gonorrhoeae lower reproductive tract infection are valuable systems for studying N. gonorrhoeae adaptation to the female host and immune responses to infection. These models have also accelerated preclinical testing of candidate therapeutic and prophylactic products against gonorrhea. However, because N. gonorrhoeae infection is restricted to the murine cervicovaginal region, there is a need for an in vivo system for translational work on N. gonorrhoeae pelvic inflammatory disease (PID). Here we discuss the need for well-characterized preclinical upper reproductive tract infection models for developing candidate products against N. gonorrhoeae PID, and report a refinement of the gonorrhea mouse model that supports sustained upper reproductive tract infection. To establish this new model for vaccine testing, we also tested the licensed meningococcal 4CMenB vaccine, which cross-protects against murine N. gonorrhoeae lower reproductive tract infection, for efficacy against N. gonorrhoeae in the endometrium and oviducts following transcervical or vaginal challenge.

Background: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. Methods: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle–specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. Results: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. Conclusions: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.

SUMMARY The intermediate cleft tip rhinoplasty is frequently performed during childhood to address nasal tip anomalies in cleft patients before the most critical period of psychosocial development. The authors previously described the component restoration intermediate cleft tip rhinoplasty technique for the unilateral cleft nose, which was developed to systematically address the lining deficiency, cleft lower lateral cartilage malpositioning, and cleft lateral cartilage weakness using a combination of lower lateral cartilage release, lateral cartilage repositioning, and placement of an auricular composite chondrocutaneous graft. In this work, the authors evaluate the utility of this technique to the bilateral cleft nose. Preoperative and postoperative (mean ± SD, 18.6 ± 10.8 months) photographs of bilateral cleft patients treated with the component restoration intermediate cleft tip rhinoplasty (n = 7) were evaluated using photogrammetric measurements and aesthetic assessments. From preoperatively to postoperatively, the columella length-to-alar width ratio on basal photographs increased (0.19 ± 0.05 versus 0.28 ± 0.05; p = 0.001). On lateral view, the columella-labial angle decreased from preoperatively to postoperatively [138 degrees (interquartile range, 132 to 144 degrees) versus 123 degrees (interquartile range, 122 to 139 degrees); p = 0.04]. Aesthetic ratings performed by four blinded observers also improved from preoperatively to postoperatively (1.6 ± 0.8 versus 2.4 ± 0.7; p = 0.004). As a comparison, bilateral cleft nose patients who did not undergo intermediate cleft tip rhinoplasty (n = 3) of similar ages were subjected to the same photogrammetric and aesthetic analyses, which showed no differences from preoperatively to postoperatively. In combination, the current work suggests that the component restoration technique in the bilateral intermediate cleft tip rhinoplasty improves nasal tip support and aesthetic outcomes.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing remains essential for early identification and clinical management of cases. We compared the diagnostic performance of 3 specimen types for characterizing SARS-CoV-2 in infected nursing home residents. Methods A convenience sample of 17 residents were enrolled within 15 days of first positive SARS-CoV-2 result by real-time reverse transcription polymerase chain reaction (RT-PCR) and prospectively followed for 42 days. Anterior nasal swabs (AN), oropharyngeal swabs (OP), and saliva specimens (SA) were collected on the day of enrollment, every 3 days for the first 21 days, and then weekly for 21 days. Specimens were tested for presence of SARS-CoV-2 RNA using RT-PCR and replication-competent virus by viral culture. Results Comparing the 3 specimen types collected from each participant at each time point, the concordance of paired RT-PCR results ranged from 80% to 88%. After the first positive result, SA and OP were RT-PCR-positive for ≤48 days; AN were RT-PCR–positive for ≤33 days. AN had the highest percentage of RT-PCR–positive results (21/26 [81%]) when collected ≤10 days of participants’ first positive result. Eleven specimens were positive by viral culture: 9 AN collected ≤19 days following first positive result and 2 OP collected ≤5 days following first positive result. Conclusions AN, OP, and SA were effective methods for repeated testing in this population. More AN than OP were positive by viral culture. SA and OP remained RT-PCR-positive longer than AN, which could lead to unnecessary interventions if RT-PCR detection occurred after viral shedding has likely ceased.

To determine whether histotripsy can create human-scale transcostal ablations in porcine liver without causing severe thermal wall injuries along the beam path. Histotripsy was applied to the liver using a preclinical prototype robotic system through a transcostal window in six female swine. A 3.0 cm spherical ablation zone was prescribed. Duration of treatment (75 min) was longer than a prior subcostal treatment study (24 min, 15 s) to minimize beam path heating. Animals then underwent contrast-enhanced MRI, necropsy, and histopathology. Images and tissue were analyzed for ablation zone size, shape, completeness of necrosis, and off-target effects. Ablation zones demonstrated complete necrosis with no viable tissue remaining in 6/6 animals by histopathology. Ablation zone volume was close to prescribed (13.8 ± 1.8 cm3 vs. prescribed 14.1 cm3). Edema was noted in the body wall overlying the ablation on T2 MRI in 5/5 (one animal did not receive MRI), though there was no gross or histologic evidence of injury to the chest wall at necropsy. At gross inspection, lung discoloration in the right lower lobe was present in 5/6 animals (mean size: 1 × 2 × 4 cm) with alveolar hemorrhage, preservation of blood vessels and bronchioles, and minor injuries to pneumocytes noted at histology. Transcostal hepatic histotripsy ablation appears feasible, effective, and no severe injuries were identified in an acute porcine model when prolonged cooling time is added to minimize body wall heating.

STUDY DESIGN. Prospective, randomized, controlled preclinical study. OBJECTIVE. The objective of this study was to compare the host inflammatory response of our previously described hyperelastic, 3D-printed (3DP) hydroxyapatite (HA)-demineralized bone matrix (DBM) composite scaffold to the response elicited with the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in a preclinical rat posterolateral lumbar fusion model. SUMMARY OF BACKGROUND DATA. Our group previously found that this 3D-printed HA-DBM composite material shows promise as a bone graft substitute in a preclinical rodent model, but its safety profile had yet to be assessed. METHODS. Sixty female Sprague-Dawley rats underwent bilateral posterolateral intertransverse lumbar spinal fusion using with the following implants: 1) type I absorbable collagen sponge (ACS) alone; 2) 10 μg rhBMP-2/ACS; or 3) the 3DP HA-DBM composite scaffold (n = 20). The host inflammatory response was assessed using magnetic resonance imaging, while the local and circulating cytokine expression levels were evaluated by enzyme-linked immunosorbent assays at subsequent postoperative time points (N = 5/time point). RESULTS. At both 2 and 5 days postoperatively, treatment with the HA-DBM scaffold produced significantly less soft tissue edema at the fusion bed site relative to rhBMP-2-treated animals as quantified on magnetic resonance imaging. At every postoperative time point evaluated, the level of soft tissue edema in HA-DBM-treated animals was comparable to that of the ACS control group. At 2 days postoperatively, serum concentrations of tumor necrosis factor-α and macrophage chemoattractant protein-1 were significantly elevated in the rhBMP-2 treatment group relative to ACS controls, whereas these cytokines were not elevated in the HA-DBM-treated animals. CONCLUSION. The 3D-printed HA-DBM composite induces a significantly reduced host inflammatory response in a preclinical spinal fusion model relative to rhBMP-2. LEVEL OF EVIDENCE: N/A

Study Design: Retrospective cohort. Objective: Traumatic facial fractures (FFs) often require specialty consultation with Plastic Surgery (PS) or Otolaryngology (ENT); however, referral patterns are often non-standardized and institution specific. Therefore, we sought to compare management patterns and outcomes between PS and ENT, hypothesizing no difference in operative rates, complications, or mortality. Methods: We performed a retrospective analysis of patients with FFs at a single Level I trauma center from 2014 to 2017. Patients were compared by consulting service: PS vs. ENT. Chi-square and Mann-Whitney-U tests were performed. Results: Of the 755 patients with FFs, 378 were consulted by PS and 377 by ENT. There was no difference in demographic data ( P > 0.05). Patients managed by ENT received a longer mean course of antibiotics (9.4 vs 7.0 days, P = 0.008) and had a lower rate of open reduction internal fixation (ORIF) (9.8% vs. 15.3%, P = 0.017), compared to PS patients. No difference was observed in overall operative rate (15.1% vs. 19.8%), use of computed tomography (CT) imaging (99% vs. 99%), time to surgery (65 vs. 55 hours, P = 0.198), length of stay (LOS) (4 vs. 4 days), 30-day complication rate (10.6% vs. 7.1%), or mortality (4.5% vs. 2.6%) (all P > 0.05). Conclusion: Our study demonstrated similar baseline characteristics, operative rates, complications, and mortality between FFs patients who had consultation by ENT and PS. This supports the practice of allowing both ENT and PS to care for trauma FFs patients, as there appears to be similar standardized care and outcomes. Future studies are needed to evaluate the generalizability of our findings.

Tape stripping is a minimally invasive, nonscarring method that can be utilized to assess gene expression in the skin but is infrequently used given technical constraints. By comparing different tape stripping technologies and full-thickness skin biopsy results of lesional and nonlesional psoriatic skin from the same patients, we demonstrate that tape stripping with optimized high-resolution transcriptomic profiling can be used to effectively assess and characterize inflammatory responses in the skin. Upon comparison with single-cell RNA-sequencing data from psoriatic full-thickness skin biopsies, we illustrate that tape-stripping efficiently captures the transcriptome of the upper layers of the epidermis with sufficient resolution to assess the molecular components of the feed-forward immune amplification pathway in psoriasis. Notably, nonlesional psoriatic skin sampled by tape stripping demonstrates activated, proinflammatory changes when compared to healthy control skin, suggesting a prepsoriatic state, which is not captured on full-thickness skin biopsy transcriptome profiling. This work illustrates an approach to assess inflammatory response in the epidermis by combining noninvasive sampling with high throughput RNA-sequencing, providing a foundation for biomarker discoveries and mechanism of action studies for inflammatory skin conditions.

Comparative data guiding initial therapy for Waldenstrom macroglobulinemia (WM), an infrequently encountered non-Hodgkin lymphoma, are sparse. We evaluated three commonly used frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naive patients with WM, seen at Mayo Clinic between 11/01/2000 and 10/31/2019. The median follow-up was 4.5 (95%CI: 4-5) years. The R-Benda (n=83) cohort demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n=92, ORR: 78%) or BDR (n=45, ORR: 84%) cohorts, p=0.003. Similarly, longer progression-free survival (PFS) was evident with R-Benda use [median 5.2 versus 4.3 (DRC) and 1.8 years (BDR), p=0.0003].The time-to-next therapy (TTNT) favored R-Benda [median, not-reached, versus 4.4 (DRC) and 2.6 years (BDR), p=0.0002). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p=0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naive patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status. This article is protected by copyright. All rights reserved.

Our institution established a Fontan surveillance plan, which included ambulatory rhythm monitoring (ARM) at 6, 10, 13, 16 and 19 years old, for early detection of Fontan-associated complications. We conducted a retrospective chart review of Fontan patients followed at our institution 2014–2018 to determine the utility of surveillance ARMs. 139 ARMs from 83 patients were included. ARMs with supraventricular tachycardia, sinus node dysfunction, accelerated junctional rhythm, > 1st degree atrioventricular block, and complex ventricular ectopy were classified as positive for arrhythmia. Arrhythmias were occult if detected on surveillance ARM. The ARM indication was surveillance in 78 (56%) and clinically indicated in 61 (44%). 52 (37%) ARMs in 27 (33%) patients had an arrhythmia. There was no difference in the age of patients with and without arrhythmias [median 10.9 (6.5, 17.1 years) vs. 8.8 (7, 13.6 years), p = 0.5]. Clinically indicated ARMs more frequently demonstrated arrhythmias than surveillance ARMs (52% vs. 26%, p

Background: Body mass index (BMI) has been identified as an important modifiable lifestyle risk factor for dementia, but less is known about how BMI might interact with Apolipoprotein E ɛ4 (APOE ɛ4) carrier status to predict conversion to mild cognitive impairment (MCI) and dementia. Objective: The aim of this study was to investigate the interaction between APOE ɛ4 status and baseline (bBMI) and five-year BMI change (ΔBMI) on conversion to MCI or dementia in initially cognitively healthy older adults. Methods: The associations between bBMI, ΔBMI, APOE ɛ4 status, and conversion to MCI or dementia were investigated among 1,289 cognitively healthy elders from the National Alzheimer’s Coordinating Center (NACC) database. Results: After five years, significantly more carriers (30.6%) converted to MCI or dementia than noncarriers (17.6%), p

Some conservation prioritization methods are based on the assumption that conservation needs overwhelm current resources and not all species can be conserved; therefore, a conservation triage scheme (i.e., when the system is overwhelmed, species should be divided into three groups based on likelihood of survival, and efforts should be focused on those species in the group with the best survival prospects and reduced or denied to those in the group with no survival prospects and to those in the group not needing special efforts for their conservation) is necessary to guide resource allocation. We argue that this decision-making strategy is not appropriate because resources are not as limited as often assumed, and it is not evident that there are species that cannot be conserved. Small population size alone, for example, does not doom a species to extinction; plants, reptiles, birds, and mammals offer examples. Although resources dedicated to conserving all threatened species are insufficient at present, the world's economic resources are vast, and greater resources could be dedicated toward species conservation. The political framework for species conservation has improved, with initiatives such as the UN Sustainable Development Goals and other international agreements, funding mechanisms such as The Global Environment Facility, and the rise of many nongovernmental organizations with nimble, rapid-response small grants programs. For a prioritization system to allow no extinctions, zero extinctions must be an explicit goal of the system. Extinction is not inevitable, and should not be acceptable. A goal of no human-induced extinctions is imperative given the irreversibility of species loss.Asignación de Recursos para la Conservación, Resiliencia de Poblaciones Pequeñas y la Falacia del Triaje de Conservación Resumen Algunos métodos de priorización de la conservación están basados en el supuesto de que las necesidades de la conservación superan a los actuales recursos y que no todas las especies pueden ser conservadas; por lo tanto, se necesita un esquema de triaje (esto es, cuando el sistema está abrumado, las especies deben dividirse en tres grupos con base en su probabilidad de supervivencia y los esfuerzos deben enfocarse en aquellas especies dentro del grupo con las mejores probabilidades de supervivencia y a aquellas en el grupo sin probabilidades de supervivencia o aquellas en el grupo que no necesita esfuerzos especializados para su conservación se les deben reducir o negar los esfuerzos de conservación) para dirigir la asignación de recursos. Discutimos que esta estrategia para la toma de decisiones no es apropiada porque los recursos no están tan limitados como se asume con frecuencia y tampoco es evidente que existan especies que no puedan ser conservadas. Por ejemplo, tan sólo un tamaño poblacional pequeño no es suficiente para condenar a una especie a la extinción; contamos con ejemplos en plantas, reptiles, aves y mamíferos. Aunque actualmente todos los recursos dedicados a la conservación de todas las especies amenazadas son insuficientes, los recursos económicos mundiales son vastos y se podrían dedicar mayores recursos a la conservación de especies. El marco de trabajo político para la conservación de especies ha mejorado, con iniciativas como los Objetivos de Desarrollo Sustentable de la ONU y otros acuerdos internacionales, el financiamiento de mecanismos como el Fondo para el Medio Ambiente Mundial, y el surgimiento de muchas organizaciones no gubernamentales mediante programas de subsidios pequeños hábiles y de respuesta rápida. Para que un sistema de priorización no permita las extinciones, las cero extinciones deben ser un objetivo explícito del sistema. La extinción no es inevitable y no debería ser aceptable. El objetivo de cero extinciones inducidas por humanos es imperativo dada la irreversibilidad de la pérdida de especies.

Lymphomatoid granulomatosis (LYG) is an uncommon angiocentric and angiodestructive T-cell rich, Epstein-Barr virus (EBV) positive B-cell multisystem lymphoproliferative disorder, predominately affecting the lungs. Since both clinical presentation and radiographic imaging findings, including X-ray and computed tomographic (CT), are nonspecific, the ultimate diagnosis of LYG relies on lung tissue sample diagnosis with its WHO grading based on the degree of cytologic atypia, necrosis and density of EBV positive B-cells. In addition, its histopathologic grading is correlated with clinical manifestation with high grade LYG mimicking aggressive B-cell lymphoma. Discordant grading between pulmonary and cutaneous LYG lesion has have been observed and might be a potential diagnostic and prognostic pitfall. F18-FDG PET/CT has been used to monitor disease progression and treatment response. In this study, we reviewed and summarized the clinical role of F18-FDG PET/CT in the surveillance of high grade pulmonary LYG, and examined its limitations in grading multisystem LYG.

Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.

Ongoing pressure for public schools to prioritize academics has increased attention on after-school settings as a critical space for social-emotional learning (SEL). After-school programs are uniquely positioned to build protective and promotive factors that contribute to positive future orientation, especially within communities where systemic inequities create barriers to high school graduation, higher education, employment, and earnings. This study examines Fit2Lead Youth Enrichment and Sports (YES), a county-funded, parks-based after-school collaboration for middle schoolers that merges mental health and recreation to promote healthy trajectories. Eight Miami neighborhood parks were selected based on county data indicating high rates of violence. An open trial design (N = 9 parks, 198 youth; ages 9-15; 40.5% female; 66.5% Black/African American, 24.9% Hispanic/Latinx, and 76.3% low-income) tested hypotheses that participation for adolescents exposed to community violence would disrupt a commonly reported decline in self-regulation and self-efficacy, and mitigate risk for anxiety and depression. Youth completed questionnaires at the beginning and end of one school year. Paired t-tests revealed no changes from pre to post, and no differences by baseline levels of youth and parent mental health. Findings highlight the promise of prevention programs to disrupt downward trajectories for youth during the risky time of early adolescence.

Objective: To determine the relationship between maximum vasoactive-inotropic (VISmax) and mortality in extremely premature (30 was associated with universal mortality. Multivariable modeling that included gestational age, birth weight, and VISmax revealed significant utility to predict mortality with negative predictive value of 87.0% and positive predictive value of 84.8% [adjusted AUROC: 0.90, (0.86-0.94)] among patients that received vasoactive-inotropic treatment. Conclusion: VISmax is an objective measure of hemodynamic/cardiovascular support that was directly associated with mortality in extremely premature ELBW infants. The VISmax represents an important step towards neonatal precision medicine and risk-stratification of extremely premature ELBW infants.

Purpose To determine the contemporary educational experiences of predoctoral dental students in the United States and Canada regarding behaviour guidance (BG) of the child patient and assess trends from a previous study in 2004. Methods Data were collected from 32 predoctoral paediatric dentistry programme directors in the United States and Canada via a web-based survey. Results The didactic curriculum hours devoted to the teaching of BG techniques in 2019 are similar to 2004. A majority (60.7%) of programmes do not have a formal assessment of competency with BG techniques. Lectures (n = 28), clinical experience (n = 28) and observation (n = 26) were the most common techniques implemented to teach BG techniques, and tell-show-do (100%), non-verbal communication (82.1%), positive reinforcement (89.3%) and distraction (82.1%) were the techniques that more than 75% of dental students most commonly have hands-on experience with during their dental education. In 2019, students tended to have more hands-on experience with nitrous oxide/oxygen inhalation and less hands-on experience with aversive techniques and sedation. Conclusions The majority of dental schools do not have a formal competency in BG of the child patient. Compared with 2004, nitrous oxide/oxygen is used more by dental students and there is less predoctoral education in aversive BG techniques.

There is minimal data regarding antegrade-only accessory pathways in young patients. Given evolving recommendations and treatments, retrospective analysis of the clinical and electrophysiologic properties of antegrade-only pathways in patients

Background The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD). However, ketamine's effects on emotional processing biases remain largely unknown, and understanding these processes may help elucidate ketamine's mechanism of action. Methods Magnetoencephalography (MEG) was used to investigate ketamine's effects on early visual responses to affective stimuli in individuals with MDD (n=31) and healthy volunteers (HVs; n=24). Participants were enrolled in a double-blind, placebo-controlled, crossover clinical trial and were assessed at baseline and after subanesthetic-dose ketamine and placebo-saline infusions. During MEG recording, participants completed an emotional evaluation task in which they indicated the sex or emotional valence (happy-neutral or sad-angry) of facial stimuli. Source-localized event-related field (ERF) M100 and M170 amplitudes and latencies were extracted from regions of interest. Linear fixed effects models examined interactions between diagnosis, stimulus valence, and drug session for behavioral and MEG data. Results In baseline behavioral analyses, MDD participants exhibited higher accuracy for sad-angry than happy-neutral faces, and HVs responded faster to happy-neutral than sad-angry faces. In the MEG post-infusion analyses, calcarine M100 amplitudes were larger in MDD than HV participants post-placebo but became more similar post-ketamine. Finally, fusiform M170 amplitudes were associated with antidepressant response in MDD participants. Limitations The modest sample size and the need to collapse across responses to happy and neutral faces to increase statistical power limit the generalizability of the findings. Conclusions Ketamine rapidly altered emotional stimulus processing in MDD, laying the groundwork for future investigations of biomarkers of antidepressant treatment response. Clinical Trial Clinicaltrials.gov, NCT#00088699

To determine the preoperative characteristics and surgical results after medial rectus advancement in patients with secondary exotropia.Retrospective, interventional case series.Setting: Tertiary Care University Medical Center. PatientPopulation: 221 patients with a diagnosis of secondary exotropia who underwent medial rectus advancement surgery by a single surgeon.Preoperative demographics, exodeviation and motility, intraoperative findings, and postoperative results were recorded. MainOutcomeMeasure: Success of surgery, defined as Esotropia15 prism diopters (pd) at postoperative week 1, or any deviation of8 pd at postoperative month 2 (POM2).A total of 98 patients underwent unilateral medial rectus advancement (UMRadv), 89 underwent UMRadv with lateral rectus recession (LRc), and 34 underwent bilateral medial rectus advancement (BMRadv). POM2 success rates were 66.7% in UMRadv patients, 62.1% in UMRadv + LRc, and 56% in BMRadv. A total of 117 patients had preoperative adduction deficits, which were significantly associated with the finding of an intraoperative stretched scar (P.001). Larger preoperative duction deficits were associated with larger stretched scars (P.001). At POM2, the mean effect of surgery (pd of correction/mm) was 2.3 ± 1.4 pd/mm for UMRadv, 2.5 ± 0.8 pd/mm for UMRadv + LRc, and 2.8 ± 1.1 pd/mm for BMRadv. Patients with a stretched scar had significantly less correction per millimeter (2.2 ± 1.2 pd/mm) compared with those without (2.6 ± 1.2 pd/mm, P.001). A total of 38.6% of patients experienced exodrift greater than 10 pd. Exodrift was significantly larger in the BMRadv group (P.005).These results provide guidance for surgical correction based on preoperative deviation and ductions. Adduction deficits indicate a stretched scar, which must be treated with resection and advancement of the medial rectus. A larger amount of surgery is needed in patients with a stretched scar. Exodrift is common, and therefore aiming for approximately 10 pd of overcorrection at postoperative week 1 can improve final outcomes.Medial rectus advancement results in successful surgical results at POM2 for secondary exotropia.

Acute injuries to the shoulder girdle are common and frequently encountered by the practicing radiologist. The type of injury is highly dependent on the age of the patient and mechanism of trauma with injuries occurring at the site of greatest mechanical weakness. In this review, we discuss the main clinical features and key imaging findings for the most common shoulder injuries. For each injury, we also provide a section on the important features that the orthopedic surgeon needs to know in order to guide surgical versus nonsurgical management.

Reports of organisms harboring multiple carbapenemase genes have increased since 2010. During October 2012–April 2019, the Centers for Disease Control and Prevention documented 151 of these isolates from 100 patients in the United States. Possible risk factors included recent history of international travel, international inpatient healthcare, and solid organ or bone marrow transplantation.

Small ruminant brucellosis is caused by the Gram negative cocci-bacillus Brucella (B.) melitensis, the most virulent Brucella species for humans. In goats and sheep, middle to late-term gestation abortion, stillbirths and the delivery of weak infected offspring are the characteristic clinical signs of the disease. Vaccination with the currently available Rev. 1 vaccine is the best option to prevent and control the disease, although it is far from ideal. In this study, we investigate the safety of the B. melitensis 16MΔvjbR strain during a 15-month period beginning at vaccination of young goats, impregnation, delivery and lactation. Forty, 4 to 6 months old, healthy female crossbreed goats were randomly divided into four groups (n = 10) and immunized subcutaneously with a single vaccine dose containing 1x109 CFU of B. melitensis 16MΔvjbR delivered in alginate microcapsules or non-encapsulated. Controls received empty capsules or the commercially available Rev.1 vaccine. Seven months post-vaccination, when animals were sexually mature, all goats were naturally bred using brucellosis-free males, and allowed to carry pregnancies to term. Blood samples to assess the humoral immune response were collected throughout the study. At two months post-delivery, all dams and their offspring were euthanized and a necropsy was performed to collect samples for bacteriology and histology. Interestingly, none of the animals that received the vaccine candidate regardless of the formulation exhibited any clinical signs associated with vaccination nor shed the vaccine strain through saliva, vagina or the milk. Gross and histopathologic changes in all nannies and offspring were unremarkable with no evidence of tissue colonization or vertical transmission to fetuses. Altogether, these data demonstrate that vaccination with the mutant strain 16MΔvjbR is safe for use in the non-pregnant primary host.

The U.S. economy and way of life are highly dependent on transportation systems, which move goods and people locally, regionally, nationally, and internationally. Major disruptions to transportation networks due to natural hazards, manmade hazards (notably terrorist and cyberattacks), accidents, or infrastructure failure can cause substantial social and economic impacts. Through qualitative and quantitative analyses, including an in-depth review of the literature and semi-structured interviews, we identify barriers to and opportunities for lowering transportation-related disaster losses and for improving infrastructure risk management including the need for better data and metrics to support resilience. Our analyses are supported by a review of transportation-related Public Assistance (PA) expenditures to understand the magnitude and variation of expenditures over time. PA is a U.S. Federal Emergency Management Agency (FEMA) program dedicated to partial reimbursement of hazard-related losses for public infrastructure. Our analyses show that the availability and significant outlays of PA after disasters inhibit risk-based loss reduction actions by infrastructure managers. Risk management tools, notably insurance and mitigation measures, can efficiently reduce disaster losses and speed recovery times. This paper concludes with recommendations for policy measures to facilitate improvements in transportation infrastructure resilience.

Background Aztreonam/avibactam is a combination agent that shows promise in treating infections caused by highly antibiotic-resistant MBL-producing Enterobacterales. This combination can be achieved by combining two FDA-approved drugs: ceftazidime/avibactam and aztreonam. It is unknown whether ceftazidime in the combination ceftazidime/aztreonam/avibactam has a synergistic or antagonistic effect on the in vitro activity of aztreonam/avibactam by significantly increasing or decreasing the MIC. Objectives To determine whether increasing ceftazidime concentrations affect the MICs of aztreonam/avibactam alone. Methods A custom 8 × 8 chequerboard broth microdilution (BMD) panel was made using a digital dispenser (Hewlett-Packard, Corvallis, OR, USA). The panel included orthogonal 2-fold dilution series of aztreonam and ceftazidime ranging from 0.5 to 64 mg/L. Avibactam concentration was kept constant at 4 mg/L throughout the chequerboard. Thirty-seven Enterobacterales isolates from the CDC & FDA Antibiotic Resistance Isolate Bank or CDC’s internal collection with intermediate or resistant interpretations to aztreonam and ceftazidime/avibactam were included for testing. All isolates harboured at least one of the following MBL genes: blaIMP, blaNDM or blaVIM. Results Regardless of the concentration of ceftazidime, aztreonam/avibactam with ceftazidime MICs for all 37 isolates were within one 2-fold doubling dilution of the aztreonam/avibactam MIC. Conclusions Ceftazidime, in the combination ceftazidime/avibactam/aztreonam, did not affect the in vitro activity of aztreonam/avibactam in this sample of isolates. These findings can help assure clinical and public health laboratories that testing of aztreonam/avibactam by BMD can act as a reliable surrogate test when the combination of ceftazidime/avibactam and aztreonam is being considered for treatment of highly antibiotic-resistant MBL-producing Enterobacterales.

Study Objective Limited data exist on the morphologic and physiologic effect on the remaining ovary after unilateral oophorectomy, especially in the pediatric population. Our aim is to evaluate ovarian volumes following unilateral oophorectomy to determine whether compensatory ovarian hypertrophy occurs in the remaining contralateral ovary. Design This was a retrospective chart review of ovarian volume measured on ultrasounds that were completed after unilateral oophorectomy. Postoperative ovarian volumes were compared to established radiologic standards. Setting Large tertiary care academic children's hospital in Atlanta, GA. Participants Female patients less than 21 years old who underwent unilateral oophorectomy. Main Outcome Measures Ovarian volumes measured on postoperative ultrasounds. Results A total of 93 patients met inclusion criteria for this study. Serial ultrasounds were performed in slightly more than half of the patients (n = 48, 51.6%), totaling 193 postoperative ovarian volumes. The average age of oophorectomy was 10.8 years. Prior to surgery, the majority of patients presented with abdominal pain (n = 51, 54.8%) or pelvic mass (n = 51, 54.8%), and most (n = 77, 82.8%) had benign final pathology. Ovarian volumes were compared to 4 published radiologic ultrasound standards. More than 62.2% of ovarian volumes from girls who had previously had unilateral oophorectomy were larger than age-matched standard ovarian volumes. Conclusion Ovarian enlargement occurs in the contralateral ovary following unilateral oophorectomy in the pediatric and adolescent population. This supports the concept of compensatory ovarian hypertrophy. This knowledge provides valuable information for interpretation of radiologic images in young female individuals who have undergone oophorectomy, and can assist with counseling on the risk of adnexal complications due to ovarian hypertrophy after unilateral oophorectomy.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published

Introduction Low-calorie sweeteners are increasingly prevalent in the food supply and their consumption has increased in recent decades. Although low-calorie sweeteners approved for use are considered safe from a toxicological perspective, their short- and long-term impacts on chronic disease risk remain uncertain. The aim of this review was to summarize the evidence from systematic reviews on low-calorie sweetener use and chronic conditions and risk factors in children and adults. Methods MEDLINE and the Cochrane Database of Systematic Reviews were searched to identify systematic reviews of randomized and nonrandomized studies that considered low-calorie sweeteners in relation to type 2 diabetes, cardiovascular disease, cancer, anthropometric measures, hypertension, hyperglycemia, hyperlipidemia, insulin resistance, and dental caries. Data were extracted from 9 reviews deemed of moderate or high quality on the basis of AMSTAR-2. Results Narrative synthesis suggested inconsistent evidence on low-calorie sweetener use in relation to chronic conditions and associated risk factors, with nonrandomized studies suggesting positive associations and randomized studies suggesting negative or no associations. Conclusion Continued research on the long-term health impacts of low-calorie sweeteners across all life stages is warranted.

Background It is important to foster active participation in online graduate nursing courses through creative teaching strategies, such as virtual synchronous debates. Method A free videoconferencing system was used to complete the virtual synchronous debates. Demographic information and survey data were obtained to assess the impact of an online debate on critical thinking and presentation skills. Results Seven of the 10 scored survey items had statistically significant differences in preimplementation and postimplementation ranked scores. Five qualitative themes were revealed: predebate anxiety/nervousness, technical issues/online format, learning experience, improved presentation skills, and group work. Conclusion Through virtual synchronous debates, graduate nursing students can gain a stronger appreciation for ethical issues in health care, learn to succinctly convey their views, and increase their confidence in presenting a professional argument.

Mantle cell lymphoma (MCL) is a clinically heterogeneous B cell malignancy for which a variety of prognostic factors have been proposed. Previously, a digital gene expression profiling “proliferation signature” capable of risk stratifying MCL was identified and subsequently developed into a multi-analyte prognostic assay, known as the “MCL35” assay. In this study, we sought to explore the performance characteristics of the MCL35 assay in a clinical laboratory and compare results with the Ki67 proliferation marker. The results describe the clinical validation of the MCL35 assay for molecular risk stratification of MCL including accuracy, sensitivity, specificity, use in acid-decalcified bone marrow core biopsies, fixatives, lower limit of RNA input, quality metrics, and other laboratory parameters. The resulting data indicate that this is a robust technique with outstanding reproducibility. Overall, the data support the concept of molecular signatures, as assessed with digital gene expression profiling, for improved standardization and reproducibility for proliferation assessment in MCL. Electronic supplementary material The online version of this article (10.1007/s12308-020-00418-4) contains supplementary material, which is available to authorized users.

Rationale: Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo. Objective: We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. Methods and Results: We prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRβ (platelet-derived growth factor receptor β). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD ( Lactobacillus casei cell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction upon Lactobacillus casei cell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRβ inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in Conclusions: Platelet-derived miR-223 (through PDGFRβ inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRβ represents potential therapeutic strategies to alleviate coronary pathology in KD. Graphic Abstract: A graphic abstract is available for this article.

Ectopic pregnancy represents a potentially life-threatening diagnosis. The risk factors for recurrent ectopic pregnancy have been enumerated but are not yet clearly defined. Understanding which risk factors are perhaps more common may allow providers to counsel and manage patients with a higher level of scrutiny.