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Sex differences are commonly observed in behaviors that are closely linked to adaptive function, but sex differences can also be observed in behavioral "building blocks" such as locomotor activity and reward processing. Modern neuroscientific inquiry, in pursuit of generalizable principles of functioning across sexes, has often ignored these more subtle sex differences in behavioral building blocks that may result from differences in these behavioral building blocks. A frequent assumption is that there is a default (often male) way to perform a behavior. This approach misses fundamental drivers of individual variability within and between sexes. Incomplete behavioral descriptions of both sexes can lead to an overreliance on reduced "single-variable" readouts of complex behaviors, the design of which may be based on male-biased samples. Here, we advocate that the incorporation of new machine-learning tools for collecting and analyzing multimodal "big behavior" data allows for a more holistic and richer approach to the quantification of behavior in both sexes. These new tools make behavioral description more robust and replicable across laboratories and species, and may open up new lines of neuroscientific inquiry by facilitating the discovery of novel behavioral states. Having more accurate measures of behavioral diversity in males and females could serve as a hypothesis generator for where and when we should look in the brain for meaningful neural differences.

Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell–derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1β stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.

Background Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study we used functional near-infrared spectroscopy (fNIRS) to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population. Methods Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function and autism symptoms. Functional NIRS was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects. Results Compared to the control group, girls with FXS showed significant hyper-activation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition including executive function, autism symptoms, depression and anxiety. Conclusions These findings strongly support a hypothesis of neural hyper-activation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker endpoint for improving treatment trial evaluation in girls with this condition.

Resumen Introduccion Las variantes C1236T, G2677T/A y C3435T del gen ABCB1 alteran la funcion de la glicoproteina P y el transporte de sustancias endogenas y exogenas en la barrera hematoencefalica; ademas, actuan como factores de susceptibilidad para algunas enfermedades neurodegenerativas. El objetivo del estudio fue determinar la asociacion de polimorfismos ABCB1 (C1236T, G2677T/A y C3435T), sus haplotipos y sus combinaciones de genotipos con la enfermedad desmielinizante. Metodo Se genotipifico a 199 pacientes con enfermedad desmielinizante y a 200 controles mestizos mexicanos mediante PCR-RFLP y secuenciacion Sanger para comparar las frecuencias de alelos, genotipos, haplotipos y combinaciones de genotipos entre pacientes y controles. El analisis estadistico se realizo con regresion logistica y χ2 de Pearson al 95% de confianza; se calculo la OR y se evaluo la asociacion con enfermedad desmielinizante. Resultados Los haplotipos TTT y CGC fueron los mas frecuentes en pacientes y controles. El alelo G2677 (OR = 1,79; IC 95%: 1,12-2,86; p = 0,015) muestra asociacion con enfermedad desmielinizante, asi como los genotipos GG2677 (OR = 2,72; IC 95% = 1,11-6,68; p = 0,025) y CC3435 (OR = 1,82; IC 95%: 1,15-2,90; p = 0,010) y su combinacion GG2677/CC3435 (OR = 2,02; IC 95%: 1,17-3,48; p = 0,010) y el haplotipo CAT (OR = 0,21; IC 95%: 0,05-0,66; p = 0,001). Los portadores TTTTTT presentaron la edad de inicio mas temprana (23,0 ± 7,7 vs. 31,6 ± 10,7; p = 0,0001). Conclusiones La combinacion de genotipos GG2677/CC3435 esta asociada al desarrollo de enfermedad desmielinizante en esta muestra, principalmente en el sexo masculino, en el cual puede darse acumulacion toxica de sustratos de glicoproteina P. En este estudio, la edad de inicio de la enfermedad desmielinizante podria ser modulada diferencialmente entre sexos por el alelo G2677 del gen ABCB1.

Resumen La arteriopatia autosomica dominante cerebral con infartos subcorticales y leucoencefalopatia es una enfermedad autosomica dominante de pequenos vasos causada por mutaciones del gen NOTCH3. Tipicamente se presenta con migrana, eventos isquemicos cerebrales recurrentes y trastornos cognitivos. Las crisis epilepticas son inusuales como manifestacion inicial, pero aun mas infrecuente es su presentacion como status epilepticus no convulsivo 1 . Se presenta una serie familiar de 3 casos con esta arteriopatia, entre los cuales 2 de ellos tuvieron status epilepticus como manifestacion de la enfermedad.

Background context : Low back pain is a major cause of morbidity and disability worldwide and is responsible for vast societal impact. Rates of surgical intervention for lumbar spine disorders continue to rise but poor outcomes remain common. Understanding how the social determinants of health (SDH) influence spinal surgical outcomes stands to inform appropriately tailored care practices and lead to better patient outcomes. Purpose : To determine the relationships between the SDH and pain, opioid use, disability and work absenteeism following lumbar spine surgery. Study design : Systematic review and narrative synthesis. Methods : We searched Embase, the Cochrane Library, Medline, and Web of Science from inception to 21/4/2020. Studies eligible for inclusion involved participants receiving lumbar spine surgery and investigated the relationship between at least one SDH and post-surgical pain, opioid use, disability or work absenteeism. We evaluated the risk of bias of included studies and used the PROGRESS-Plus framework to organise a narrative synthesis of findings. Results : Relevant data was extracted from twenty-three studies involving 30,987 adults from 12 countries. 107 relationships between the SDH and post-surgical outcomes were evaluated, 67 in multivariate analyses. Education was investigated in 23 analyses (14 studies): 70% revealed significant independent relationships between lower education and poorer outcomes. Socioeconomic status was investigated in nine analyses (four studies): 67% revealed independent relationships between lower socioeconomic status and poorer outcomes. Gender was investigated in 40 analyses (22 studies): indications that male versus female sex was associated with poorer outcomes were equivocal. Place of residence, race/ethnicity, and social capital were infrequently investigated. Conclusions : Low educational attainment and low income status are clear independent contributors to poorer outcomes following lumbar spine surgery. Occupational factors and work context are likely to be influential. Further research is critical to guide best-practice spinal surgery through a health equity lens. Study registration : PROSPERO registration number CRD42015015778

Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE.

To define the prevalence of medical eye disease diagnoses among children enrolled in commercial insurance plans in the United States and to evaluate differences among groups based on the US census region, race/ethnicity, and familial net worth.: Retrospective study of de-identified claims data from the OptumLab® Data Warehouse (OLDW) between 2007 and 2018. All children (19 years) in the OLDW with coverage were studied and those with a claim for a significant eye disease (strabismus, amblyopia, nystagmus or structural eye disorders) with minimum 6-months follow-up were studied. Baseline characteristics were extracted for the calculation of eye disease prevalence, including age, sex, race/ethnicity, region of residence, and family net worth. The prevalence of each type of eye disease was calculated among all children and by baseline characteristics.: 10,759,066 children met the study criteria. The presence of any significant eye diagnosis was 6.7%. Disease was diagnosed more often in whites (6.9%) than blacks (5.6%) and Hispanics (5.9%). The most common eye disease diagnosed was strabismus (3.2%) followed by amblyopia (1.5%). In the North-East region, there was a 10.6% prevalence of any significant eye disease diagnosis, whereas in the Mid-West, it was 7.4% followed by the South and West (5.9% and 5.3%, respectively) (: Diagnosis of significant eye diseases is relatively common in American children. The most common medical eye disease diagnosis is strabismus. Prevalence of eye disease diagnosis from claims data varies between geographical regions and different income groups. This may reflect differences in healthcare utilization rather than true disease prevalence.

OBJECTIVE This investigation examined the impact of social networks on drinking reduction efforts following a brief alcohol intervention. In a reanalysis of data from an earlier randomized controlled trial with nonstudent emerging adult drinkers (Lau-Barraco et al., 2018), we aimed to test three domains of preintervention social network features as potential factors influencing intervention response: (a) general network characteristics (i.e., network size, network stability), (b) general network alcohol use (i.e., network alcohol abstainers, network heavy/problem drinkers), and (c) risky peers in network (i.e., proportion of drinking buddies, presence of drinking buddies identified as heavy/problem drinker). METHOD Participants were 164 emerging adult heavy drinkers recruited from the community (65.9% men; mean age = 21.98 years; 56.2% ethnic minority). Participants were randomly assigned to either a brief personalized feedback intervention (PFI) or assessment-only control and provided data at 1-month and 3-month follow-ups. RESULTS Greater network stability and greater representation of alcohol abstainers in one's social network were associated with improved initial postintervention response. Heavy/problem drinkers in the network did not moderate initial postintervention effects on drinking outcomes, but there was potentially a stronger intervention effect on risk reduction for those with higher proportions of drinking buddies in their network. CONCLUSIONS Study findings provided evidence that a PFI was efficacious in mitigating some risky social network influence. However, findings did not support a consistent impact across all the network variables examined. Future research is needed to further clarify social network influences and how they may be targeted to enhance intervention efficacy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Distal radius fractures (DRF) are the most common upper extremity fractures in adults. The purpose of this study was to determine the incidence, causes, and independent predictors for unplanned return to the operating room (URTO) in a single institution within 90 days following distal radius open reduction internal fixation (ORIF). Methods: A retrospective study of 2933 consecutive patients from January 2015 to December 2019 who underwent distal radius ORIF was undertaken. Patients who returned to the operating room within 90 days of the index procedure were identified. Patients with planned return to the operating room for staged procedures were excluded, yielding a patient cohort of those with URTO. Demographic data, causes for reoperation, and final Quick Disabilities of the Arm, Shoulder and Hand DASH (QuickDASH) scores were collected. Results: Overall, 45 patients had URTO (1.5%) occurring a mean of 44 (6-89) days from the index procedure. Reasons for reoperation included nerve complications (n = 14), loss of fixation (n = 11), hardware complications (n = 9), wound complications (n = 7), and tendon complications (n = 4). Neurologic reasons for return included carpal tunnel release (n = 13) and ulnar nerve decompression (n = 1). QuickDASH scores were higher for URTO compared with control cohort at the final follow-up (33 [range: 0-91] vs 14 [range: 0-100], P < .01). Conclusions: Mechanical hardware failure and neurologic symptoms were the most common reasons for URTO after distal fracture ORIF.

OBJECTIVES: To develop a disease stratification model for COVID-19 that updates according to changes in a patient's condition while in hospital to facilitate patient management and resource allocation. DESIGN: In this retrospective cohort study, we adopted a landmarking approach to dynamic prediction of all-cause in-hospital mortality over the next 48 hours. We accounted for informative predictor missingness and selected predictors using penalised regression. SETTING: All data used in this study were obtained from a single UK teaching hospital. PARTICIPANTS: We developed the model using 473 consecutive patients with COVID-19 presenting to a UK hospital between 1 March 2020 and 12 September 2020; and temporally validated using data on 1119 patients presenting between 13 September 2020 and 17 March 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is all-cause in-hospital mortality within 48 hours of the prediction time. We accounted for the competing risks of discharge from hospital alive and transfer to a tertiary intensive care unit for extracorporeal membrane oxygenation. RESULTS: Our final model includes age, Clinical Frailty Scale score, heart rate, respiratory rate, oxygen saturation/fractional inspired oxygen ratio, white cell count, presence of acidosis (pH, Martin Wiegand was funded by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Victoria L. Keevil was funded by the MRC/NIHR Clinical Academic Research Partnership Grant (CARP) [grant code MR/T023902/1]. Vince Taylor was funded by the Cancer Research UK Cambridge Centre. Effrossyni Gkrania-Klotsas was supported by the NIHR Clinical Research Network (CRN) Greenshoots Award. Brian D. M. Tom and Robert J. B. Goudie were funded by the UKRI Medical Research Council (MRC) [programme code MC_UU_00002/2] and supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

Chronic diffuse lung diseases involve a spectrum of nonneoplastic inflammatory conditions that affect the lung parenchyma. This chapter reviews the spectrum of disease including idiopathic interstitial pneumonias, pulmonary manifestations of systemic collagen vascular disease, diffuse eosinophilc lung disease, drug-associated lung disease, diffuse granulomatous lung disease, and a variety of miscellaneous diseases that defy classification. Individual entities are reviewed, followed by a section highlighting a practical approach to the four most common patterns of injury encountered in practice.

This review identifies the three-dimensional knee loads that have the highest risk of injuring the anterior cruciate ligament (ACL) in the athlete. It is the combination of the muscular resistance to a large knee flexion moment, an external reaction force generating knee compression, an internal tibial torque, and a knee abduction moment during a single-leg athletic manoeuvre such as landing from a jump, abruptly changing direction, or rapidly decelerating that results in the greatest ACL loads. While there is consensus that an anterior tibial shear force is the primary ACL loading mechanism, controversy exists regarding the secondary order of importance of transverse-plane and frontal-plane loading in ACL injury scenarios. Large knee compression forces combined with a posteriorly and inferiorly sloped tibial plateau, especially the lateral plateau-an important ACL injury risk factor-causes anterior tibial translation and internal tibial rotation, which increases ACL loading. Furthermore, while the ACL can fail under a single supramaximal loading cycle, recent evidence shows that it can also fail following repeated submaximal loading cycles due to microdamage accumulating in the ligament with each cycle. This challenges the existing dogma that non-contact ACL injuries are predominantly due to a single manoeuvre that catastrophically overloads the ACL.

Background Thumb carpometacarpal (CMC) joint arthroplasty is a common procedure in the surgical management of symptomatic thumb basal joint arthritis. Following trapeziectomy, a number of suspensionplasty techniques are often used, but limited comparative evidence exists between these techniques. The central aim of this study was to prospectively compare the outcomes of 2 suspensionplasty techniques following trapeziectomy: suture button (TightRope) versus ligament reconstruction and tendon interposition (LRTI). Methods Prospective data were collected on 112 consecutive patients with Eaton stage III-IV thumb CMC arthritis who underwent open trapeziectomy and suspensionplasty. There were 53 LRTI and 59 TightRope suspensionplasty procedures. Outcomes were measured using the Quick Disabilities of the Arm, Shoulder, and Hand ( QuickDASH) questionnaire, Visual Analogue Scale (VAS) for pain, radiographic analysis, and lateral pinch strength. Patient demographic data and complications were also recorded. Results Patients undergoing TightRope suspensionplasty had significantly higher trapeziometacarpal index and thus less subsidence than the LRTI group at 2 weeks (0.22 vs 0.17 [ P < .0001]) and 3 months (0.17 vs 0.15 [ P < .05]) postoperatively. TightRope suspensionplasty also had a significantly lower QuickDASH score at 2 weeks (64.7 vs 74.6 [ P < .05]), 3 months (20.7 vs 32.5 [ P < .05]), and 1 year postoperatively (7.57 vs 21.5 [ P < .05]) compared with the LRTI group. However, there was no difference in VAS pain, lateral pinch strength, reoperation, or complications at any time point between groups. Conclusions Thumb CMC joint arthroplasty performed with a TightRope suspensionplasty versus LRTI yielded short-term improved resistance to subsidence, long-term greater improvement in clinical outcome by QuickDASH, and no difference in pain or complication rates.

Optimal specimen handling is essential for the accurate interpretation of biopsies and cytologic preparations obtained in the course of evaluating the patient with lung disease. Sampling techniques available include bronchoscopy, transthoracic needle core biopsy or aspiration, and surgical wedge biopsy of peripheral lung through a transthoracic approach. In this chapter specimen characteristics and processing steps are presented for each of the common lung samples taken in the course of clinical evaluation for pulmonary disease. Also, for each type of sample the benefits and limitations are reviewed. Such a working knowledge of specimen handling for each procedure ensures the greatest likelihood of success in establishing a specific diagnosis and, in the end, a rational treatment plan. The addition of clinical information dramatically increases the likelihood of a meaningful and accurate pathologic diagnosis, especially in the setting of biopsies for diffuse lung disease (interstitial lung disease).

Promoting the cessation of smoking in mental healthcare is a priority of international health organizations as it is the most cost-effective intervention in psychiatry.To explore the representations of psychiatrists on their role in active smoking cessation prevention in severe psychiatric disorders.Psychiatrists and residents in psychiatry were recruited at a national level by professional mailings.One thousand four hundred and sixty participants were included in the study, and only 46% reported actively promoting smoking cessation. In multivariate analyses, participants aged35years were more likely to promote cessation of tobacco smoking, as well as the two thirds who believe that psychiatry is a systemic discipline with complex interactions between brain, body and mind. Almost two thirds of those promoting tobacco cessation reported lacking time to combine psychiatric and physical examination during one session. The psychiatrists who reported not promoting tobacco smoking cessation also reported never dealing with physical health in case of the absence of a general practitioner and thinking that physical examination may have a negative impact on the therapeutic relationship. Almost all (96%) reported promoting the need for a general practitioner for their patients. We found no significant difference between the public and private sectors (P0.05).Young psychiatrists are more prone than their elders to promote smoking cessation but report lacking time to include it in their daily practice. Promotion of tobacco smoking cessation should be included in the components for quality evaluation for mental health services and specific sessions dedicated to this intervention.

OBJECTIVE The primary aims of this study were to identify latent profiles of acute stress disorder (ASD) symptoms and to evaluate postconcussive symptom differences across the identified profiles as measured by the Acute Stress Disorder Scale and the Military Acute Concussion Evaluation, respectively. METHOD Participants (N = 315) in the current study were predominantly active-duty (75.0%), enlisted (97.8%) males (97.4%) serving in the U.S. Army (87.8%). Approximately, half of the sample reported being married or engaged (51.1%) and was on average 25.94 (SD = 6.31) years old. Participants were referred to the Air Force Theater Hospital, 332nd Air Expeditionary Wing, Joint Base Balad, Iraq, to be evaluated as part of routine clinical assessment for neurocognitive and psychological symptoms following exposure to a blast. RESULTS A 3-profile solution was identified as the most parsimonious and best-fitting model based on statistical model fit indices. Blast injured service members in Profile 3 had greater ASD total and subscale severity compared to the other 2 subgroups, with effect size estimates largely differing by hyperarousal and reexperiencing symptoms. Furthermore, Profiles 2 and 3 were more likely to demonstrate postconcussive symptoms compared to Profile 1. CONCLUSIONS Findings provide novel information on heterogenous ASD symptom profiles during the acute phase following a blast injury and highlight the relationship between psychological and physical symptoms. Classification of blast-injured service members may help identify at-risk individuals who would benefit from further clinical care and mitigate long-term psychological and neurocognitive issues. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Society for Vascular Surgery has recommended immediate transfer of patients with ruptured abdominal aortic aneurysms (rAAAs) to a regional center when feasible. However, Black patients might be less likely to be transferred and more likely to be turned down for repair. We, therefore, examined the transfer rates, turndown rates, and outcomes for Black vs White patients presenting with rAAAs in two large databases.We examined all rAAA repairs in the Vascular Quality Initiative from 2003 to 2020 to evaluate the transfer rates and outcomes for Black vs White patients. We used the National Inpatient Sample from 2004 to 2015 to examine the turndown rates. Mixed effects logistic regression, Cox regression, and marginal effects modeling were used to study the interaction between race, insurance status, surgery type (open repair vs endovascular aortic aneurysm repair), and hospital volume.We identified 4935 patients with rAAAs in the Vascular Quality Initiative (6.2% Black) and 48,489 in the National Inpatient Sample (6.0% Black). The rates of transfer were high; however, Black patients were significantly less likely to undergo transfer before repair compared with White patients (49% Black vs 62% White; P = .002). The result was consistent in both crude and adjusted analyses when considering only stable patients and was not modified by insurance status, surgery type, or hospital volume. No significant differences were found in perioperative mortality (22% vs 26%; P = .098) or complications (52% vs 52%; P = .64). However, Black patients were significantly more likely to be turned down for repair (37% vs 28%; odds ratio, 1.5; 95% confidence interval, 1.2-1.9; P .001). A significant interaction was found between race and insurance status with respect to turndown. Patients with private insurance had undergone surgery at a similar rate, regardless of race. However, among patients with Medicare or Medicaid/self-pay, Black patients were less likely than were White patients to undergo repair (Medicare, 64% vs 72%; P = .001; Medicaid/self-pay, 43% vs 61%; P = .031). Patients with Medicaid/self-pay were also less likely to undergo repair than were patients of the same race with either Medicare or private insurance (P .05).We found that Black patients with rAAAs are poorly served by the current systems of interhospital transfer in the United States, because they less often undergo transfer before repair. Although the postoperative outcomes appeared similar, this finding could be falsely optimistic, because Black patients, especially the underinsured, were turned down for repair more often even after adjustment. Significant work is needed to better understand the reasons underlying these disparities and identify the targets to improve the care of Black patients with rAAAs.

Background The use of ultrasound as a viable diagnostic tool for routine office visit evaluation of rotator cuff integrity is slowly gaining acceptance in orthopedic practice. However, the reliability of accurately assessing rotator cuff tear reparability by ultrasound has limited evidence in the literature. The purpose of this study was to compare preoperative assessment of cuff tear reparability via ultrasound with the arthroscopic determination of reparability at the time of surgery. Materials and Methods We prospectively collected preoperative ultrasound and arthroscopic imaging data on 145 patients (80 or 55% male and average age of 60.7 years) who underwent arthroscopic posterior superior rotator cuff repair. Three independent experienced orthopedic surgeons retrospectively reviewed all ultrasound studies and arthroscopic imaging and determined if the posterior superior rotator cuff tendon edge was able to be viewed via ultrasound and determined with the arthroscopic images if the tear was reparable. Results Upon review of the ultrasound and arthroscopic data, if the edge of the rotator cuff tendon edge was able to be viewed on the coronal ultrasound image, it was most likely reparable with a positive predictive value (PPV) of 97.6% and a positive likelihood ratio (LR+) of 5.8. Sensitivity was 84.4% and specificity of 76.9%. The negative predictive value (NPV) was 37.5% and negative likelihood ratio (LR-) of 0.17. The interobserver reliability was 0.63 and the observers were unanimous in determining the tendon edge was able to be visualized in 99 of 145 cases (68%). Conclusions Preoperative ultrasound evaluation of the shoulder for posterior superior rotator cuff tears is a useful tool for assessing rotator cuff integrity and may help predict intraoperative reparability of the tendon. This study demonstrates that if the cuff tear edge is able to be visualized, there is a high probability of successful arthroscopic restoration of the tendon to its native attachment. Conversely, if the tear edge is unable to be visualized, there is a moderate chance of the tear being irreparable. These results help expand the knowledge base of the usefulness of in-office ultrasound performed by the surgeon in predicting the results of surgical intervention for rotator cuff tears.

BACKGROUND: A watch & wait strategy for patients with rectal cancer with a clinical complete response after neoadjuvant chemoradiotherapy is a valuable alternative for rectal resection. However, there are patients who will have residual tumor or regrowth during watch & wait.OBJECTIVE: The aim was to investigate safety and costs for patients who underwent delayed surgery after neoadjuvant chemoradiotherapy.DESIGN: This is a retrospective cohort study with prospectively collected data.SETTINGS: The study was conducted at a large teaching hospital.PATIENTS: Between Jan 2015 - May 2020, 622 new rectal cancer patients were seen of which 200 received neoadjuvant chemoradiotherapy. Ninety-four patients were included of which 65 patients underwent immediate surgery and 29 patients required delayed surgery after an initial watch & wait approach.MAIN OUTCOME MEASURES: This included 30-day postoperative morbidity rate, hospital costs and two-year overall and disease-free survival.RESULTS: There was no difference in length of stay (9 vs 8, p = 0.83), readmissions (27.6% vs 10.0%, p = 0.10), surgical re-interventions (15.0% vs 3.4%, p = 0.16) and stoma free rate (52.6% vs 31.0%, p = 0.09) between immediate and delayed surgery groups. Hospital costs were similar in the delayed group (€11913 vs €13769, p = 0.89). Two-year overall survival (93% vs 100%, p = 0.23) and disease-free survival (78% vs 81%, p = 0.47) rates were comparable.LIMITATIONS: Small sample size, follow-up time and retrospective design.CONCLUSION: Delayed surgery for regrowth in a watch & wait program or for persistent residual disease after a repeated assessment is not associated with an increased risk of postoperative morbidity or a significant rise in costs compared to immediate total mesorectal excision. There also appears to be no evident compromise in oncological outcome. Repeated response assessment in patients with a near complete clinical response after neoadjuvant chemoradiotherapy is a useful approach to identify more patients who can benefit from a watch & wait strategy. See Video Abstract at http://links.lww.com/DCR/B836 .

Background: Depression is a concern during pregnancy, but it is especially prevalent for pregnant adolescents. Because prenatal depression is a strong predictor of postpartum depression and other forms of psychopathology in both mothers and children, it is important to understand potential risk and protective factors for prenatal depression.Objectives: The present study examined whether social support buffered the impact of childhood trauma on prenatal depression, and whether social support exerted a stronger buffering effect for adolescents compared to adults.Method: Self-reported levels of childhood trauma, social support, and prenatal depression were collected in a racially and ethnically diverse sample of 682 first-time mothers, 58% were adolescents (n = 396; Mage = 17.38 years) and 42% were adults (n = 286; Mage = 26.29 years).Results: Using multi-group moderation analyses, we found that pregnant adolescents with more social support were buffered from the effects of childhood trauma on prenatal depression symptoms, but pregnant adults with more social support were not.Conclusion: Findings support the stress-buffering model in that those with more stressors may benefit more from social support than those with fewer stressors. These results highlight the importance of social support and inform prenatal depression prevention/intervention strategies particularly with pregnant adolescents.

BACKGROUND: The association between obesity (body mass index (BMI) ≥ 30 kg/m(2)) and pattern of medication use during pregnancy in the United States is not well-studied. Higher prepregnancy BMI may be associated with increases or decreases in medication use across pregnancy as symptoms (e.g. reflux) or comorbidities (e.g. gestational diabetes) requiring treatment that may be associated with higher BMI could also change with advancing gestation. OBJECTIVES: To determine whether prenatal medication use, by the number and types of medications, varies by pre-pregnancy obesity status. METHODS: In a secondary data analysis of a racially/ethnically diverse prospective cohort of pregnant women with low risk for fetal abnormalities enrolled in the first trimester of pregnancy and followed to delivery (singleton, 12 United States clinical sites), free text medication data were obtained at enrollment and up to five follow-up visits and abstracted from medical records at delivery. RESULTS: In 436 women with obesity and 1750 women without obesity (pre-pregnancy BMI, 19–29.9 kg/m(2)), more than 70% of pregnant women (77% of women with and 73% of women without obesity) reported taking at least one medication during pregnancy, respectively (adjusted risk ratio (aRR)=1.10, 95% confidence interval (CI)=1.01, 1.20), with 81% reporting two and 69% reporting three or more. A total of 17 classes of medications were identified. Among medication classes consumed by at least 5% of all women, the only class that differed between women with and without obesity was hormones and synthetic substitutes (including steroids, progesterone, diabetes, and thyroid medications) in which women with obesity took more medications (11 vs. 5%, aRR = 1.9, 95% CI = 1.38, 2.61) compared to women without obesity. Within this class, a higher percentage of women with obesity took diabetes medications (2.3 vs. 0.7%) and progesterone (3.4 vs. 1.3%) than their non-obese counterparts. Similar percentages of women with and without obesity reported consuming medications in the remaining medication classes including central nervous system agents (50 and 46%), gastrointestinal drugs (43 and 40%), anti-infective agents (23 and 21%), antihistamines (20 and 17%), autonomic drugs (10 and 9%), and respiratory tract agents (7 and 6%), respectively (p > 0.05 for all adjusted comparisons). There were no differences in medication use by obesity status across gestation. Since the study exclusion criteria limited the non-obese group to women without thyroid disease, in a sensitivity analysis we excluded all women who reported thyroid medication intake and still a higher proportion of women with obesity took the hormones and synthetic substitutes class compared to women without obesity. CONCLUSION: Our findings suggest that pre-pregnancy obesity in otherwise healthy women is associated with a higher use of only selected medications (such as diabetes medications and progesterone) during pregnancy, while the intake of other more common medication types such as analgesics, antibiotics, and antacids does not vary by pre-pregnancy obesity status. As medication safety information for prenatal consumption is insufficient for many medications, these findings highlight the need for a more in-depth examination of factors associated with prenatal medication use.

Leukemia and lymphoma are cancers affecting children, adolescents, and young adults and may affect reproductive outcomes and maternal metabolism. We evaluated for metabolic changes in newborns of mothers with a history of these cancers.A cross-sectional study was conducted on California births from 2007 to 2011 with linked maternal hospital discharge records, birth certificate, and newborn screening metabolites. History of leukemia or lymphoma was determined using ICD-9-CM codes from hospital discharge data and newborn metabolite data from the newborn screening program.A total of 2,068,038 women without cancer history and 906 with history of leukemia or lymphoma were included. After adjusting for differences in maternal age, infant sex, age at metabolite collection, gestational age, and birthweight, among newborns born to women with history of leukemia/lymphoma, several acylcarnitines were significantly (The varied metabolite levels suggest history of leukemia or lymphoma has metabolic impact on newborn offspring, which may have implications for future metabolic consequences such as necrotizing enterocolitis and urea cycle enzyme disorders in children born to mothers with a history of leukemia or lymphoma.

Objective To evaluate pre - to post-season differences in individual subtests of the Visio-Vestibular Examination (VVE) in healthy middle and high school athletes. Methods This prospective cohort study recruited participants from a private suburban United States secondary school. Participants completed a demographic questionnaire prior to the start of their season. A proxy for head impact exposure was estimated by incorporating previously published head impact frequencies by team and sport. The VVE was completed pre - and post-season and consisted of 9 subtests: smooth pursuit, horizontal/vertical saccades and gaze stability, binocular convergence, left/right monocular accommodation, and complex tandem gait. Generalized estimating equations were employed to assess the relative risk of an abnormal VVE outcome based on testing session (pre - vs. post-season). Results Participants included middle and high school athletes (n = 115; female = 59 (51.3%); median age at first assessment = 14.9 years, [IQR = 13.6, 16.0]) during 2017/18 - 2019/20 school years. During pre-season testing, accommodation (10.0%) and complex tandem gait (9.2%) had the largest proportion of abnormal outcomes, while smooth pursuits (10.6%) and convergence (9.5%) had the largest proportion of abnormal outcomes post-season. When assessing the effect of testing session on the relative risk of any abnormal VVE subtest, there were no significant findings (P ≥ 0.25). Additionally, there were no significant effects of testing session when adjusting for estimated head impact exposure for any VVE subtest (P ≥ 0.25). Conclusions Visio-vestibular function as measured by the VVE does not change from pre - to post-season in otherwise healthy adolescent athletes. Our findings suggest that the VVE may be stable and robust to typical neurodevelopment occurring in this dynamic age group and help inform post-injury interpretation of visio-vestibular impairments.

BACKGROUND: Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. METHODS: Using hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli. RESULTS: In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease–promoting and interferon (IFN)-related genes, including Ackr2 and Cxcl11. CONCLUSIONS: We demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Background Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. Objective The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. Methods A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010–2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. Results From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015–2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. Conclusion The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010–2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-021-00498-3.

Aim The Enhanced Recovery After Surgery (ERAS® ) Society guidelines aim to standardise perioperative care in colorectal surgery via 25 principles. We aimed to assess the variation in uptake of these principles across an international network of colorectal units. Method An online survey was circulated amongst European Society of Coloproctology members in 2019/20. For each ERAS® principle, respondents were asked to score how frequently the principle was implemented in their hospital, from 1 ('rarely') to 4 ('always'). Respondents were also asked to recall whether practice had changed since 2017. Subgroup analyses based on hospital characteristics were conducted. Results Of hospitals approached, 58% responded to the survey (195/335), with 296 individual responses (multiple responses were received from some hospitals). The majority were European (163/195 [83.6%]). Overall, respondents indicated they 'most often' or 'always' adhered to most individual ERAS® principles (18/25 [72%]). Variability in uptake of principles was reported, with universal uptake of some principles (e.g., prophylactic antibiotics; early mobilisation) and inconsistency from 'rarely' to 'always' in others (e.g., no nasogastric intubation; no preoperative fasting and carbohydrate drinks). In alignment with 2018 ERAS® guideline updates, adherence to principles for prehabilitation, managing anaemia, and postoperative nutrition appears to have increased since 2017. Conclusions Uptake of ERAS® principles varied across hospitals, and not all 25 principles were equally adhered to. Whilst some principles exhibited a high level of acceptance, others had a wide variability in uptake indicative of controversy or barriers to uptake. Further research into specific principles is required to improve ERAS® implementation.

Background: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. Methods: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed. Results: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P

Refereed/Peer-reviewed Visceral adipose tissue (VAT) encases mesenteric lymphatic vessels and lymph nodes through which lymph is transported from the intestine and mesentery. Whether mesenteric lymphatics contribute to adipose tissue inflammation and metabolism and insulin resistance is unclear. Here we show that obesity is associated with profound and progressive dysfunction of the mesenteric lymphatic system in mice and humans. We find that lymph from mice and humans consuming a high-fat diet (HFD) stimulates lymphatic vessel growth, leading to the formation of highly branched mesenteric lymphatic vessels that ‘leak’ HFD-lymph into VAT and, thereby, promote insulin resistance. Mesenteric lymphatic dysfunction is regulated by cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-C–VEGF receptor (R)3 signalling. Lymph-targeted inhibition of COX-2 using a glyceride prodrug approach reverses mesenteric lymphatic dysfunction, visceral obesity and inflammation and restores glycaemic control in mice. Targeting obesity-associated mesenteric lymphatic dysfunction thus represents a potential therapeutic option to treat metabolic disease.

Objectives: The aim of this study was to assess the incidence of being overweight and metabolic syndrome (MS) among people living with HIV (PHIV) in three different cross-sectional studies conducted over three different periods: 2005, 2011 and 2015. Methods: This was a multi-centre, nationwide study. Data were collected in three studies from the CISAI group - SIMOne, HIV-HY and STOPSHIV - and included a total of 3014 PHIV. Logistic regression [odds ratio (OR), 95% confidence interval (CI)] was used to account for age and gender difference among three groups when comparing MS prevalence and being overweight; potential confounders were accounted for by including them in the regression equation. Results: Overall, the mean age was 46.9±10.2years, and men comprised 73.3% of participants. Comparing 2005, 2011 and 2015, MS was present in 34.5%, 33.0% and 29.3% of PHIV, respectively. Adjusted OR for MS was 0.64 (95% CI: 0.52-0.78) in 2011 and 0.56 (95% CI: 0.46-0.69) in 2015 compared with 2005, while BMI (kg/m2 ) increased from 23.6 in 2005, 24.5 in 2011 and 24.5 in 2015, with a concomitant increase of being overweight from 29.4% to 39.5% to 39.6% (p&nbsp

Background Rare diseases are chronic and life-threatening disorders affecting Results To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002–2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. Conclusions This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.

Right ventricular function has prognostic significance in patients with pulmonary hypertension. We evaluated whether cardiac magnetic resonance-derived strain and strain rate parameters could reliably reflect right ventricular systolic and diastolic function in precapillary pulmonary hypertension. End-systolic elastance and the time constant of right ventricular relaxation tau, both derived from invasive high-fidelity micromanometer catheter measurements, were used as gold standards for assessing systolic and diastolic right ventricular function, respectively. Nineteen consecutive precapillary pulmonary hypertension patients underwent cardiac magnetic resonance and right heart catheterization prospectively. Cardiac magnetic resonance data were compared with those of 19 control subjects. In pulmonary hypertension patients, associations between strain- and strain rate-related parameters and invasive hemodynamic parameters were evaluated. Longitudinal peak systolic strain, strain rate, and early diastolic strain rate were lower in PAH patients than in controls; peak atrial-diastolic strain rate was higher in pulmonary hypertension patients. Similarly, circumferential peak systolic strain rate was lower and peak atrial-diastolic strain rate was higher in pulmonary hypertension. In pulmonary hypertension, no correlations existed between cardiac magnetic resonance-derived and hemodynamically derived measures of systolic right ventricular function. Regarding diastolic parameters, tau was significantly correlated with peak longitudinal atrial-diastolic strain rate ( r = −0.61), deceleration time ( r = 0.75), longitudinal systolic to diastolic time ratio ( r = 0.59), early diastolic strain rate ( r = −0.5), circumferential peak atrial-diastolic strain rate ( r = −0.52), and deceleration time ( r = 0.62). Strain analysis of the right ventricular diastolic phase is a reliable non-invasive method for detecting right ventricular diastolic dysfunction in PAH.

BACKGROUND Dupilumab has been demonstrated to be an effective treatment for patients with moderate-to-severe atopic dermatitis (AD) in clinical trials. However, evidence of real-world experience with dupilumab in a broader population is limited to date. METHODS Adult patients with moderate-to-severe AD, defined as an Eczema Area Severity Index (EASI) score of 24 or higher, treated with dupilumab at ten Italian academic centers, were included in the study. Physician-reported outcome measures (EASI), patient-reported outcome measures (pruritus and sleep score, Dermatology Life Quality Index, DLQI) and serological markers [immunoglobulin (Ig) E and eosinophil count] after 16 weeks were analyzed. RESULTS We enrolled 543 patients with moderate-to-severe AD. Two patients (0.4%) discontinued treatment. The median ± interquartile percentage change from baseline to 16 weeks of treatment in the EASI score was -87.5±22.0 (p

Objective: Emerging research supports the role of chronic stress in chronic disease development. This scoping review aimed to map the field of research exploring relationships between chronic stress and the development of arthritis in adult populations. Methods: Five electronic databases were systematically searched without publication limits based on three key concepts: stress, arthritis and adults. Eligible qualitative studies investigated individuals’ perceived causes of arthritis; quantitative studies investigated relationships between exposure to a chronic stressor and an arthritis presence outcome. Articles were screened by two independent reviewers and data were narratively synthesised. Results: Of 1819 unique records, 54 studies met inclusion criteria. Nine studies used qualitative methods and 45 used quantitative methods. Studies increased chronologically, with half (n = 27) published since 2010. Chronic stress exposures were heterogenous; most were categorised as adverse life events (n = 22) or adverse childhood experiences (n = 17). Self‐reported arthritis was the most frequent measure of arthritis outcome (n = 26) in quantitative studies. A majority of studies (n = 41) suggested a relationship between exposure to chronic stressors and arthritis development. Conclusion: Increasing study numbers in the past decade may reflect increasing awareness of the potential impact of chronic stress in arthritis development, consistent with a biopsychosocial approach to chronic disease aetiology and management. Further research, using precise arthritis definitions, conducted within a clearly articulated pathophysiological framework, is required to establish a causal relationship between exposure to chronic stressors and the development of specific arthritis conditions. Refereed/Peer-reviewed

Background: Pathological stage and grade of renal pelvis urothelial carcinoma (RPUC) are difficult to estimate before radical nephroureterectomy (RNU). Objective: To examine tumor size as an independent predictor of muscle-invasive and/or non–organ-confined rates of RPUC at RNU. Design, setting, and participants: Within the Surveillance, Epidemiology and End Results (SEER) database (2004–2016), we identified nonmetastatic RPUC at RNU. Outcome measurements and statistical analysis: First, we examined stage and grade distributions. Second, two separate univariable and subsequent multivariable logistic regression models (LRMs) were fitted to test the association between tumor size and the rate of (1) muscle-invasive or higher (pT2–4N0–2) and (2) non–organ-confined (pT3–4N0–2) RPUC at RNU. Results and limitations: Of 4657 patients, 3052 (65.5%) had pT2–4N0–2 and 2382 (51.2%) pT3–4N0–2 RPUC at RNU. The median tumor size was 3.7 cm (interquartile range 2.5–5.0). The high-grade RPUC rate ranged from 71.1% to 87.2% (p < 0.001) among SEER registries. Conversely, no differences were recorded for stage (p > 0.05) or tumor size (p = 0.1) across all registries. Rates of pT2–4N0–2 and pT3–4N0–2 RPUC increased with tumor size. Specifically, for tumor size intervals from 0.1–1.0 cm to 9.1–10.0 cm, the pT2–4N0–2 rate ranged from 45% to 83% and the pT3–4N0–2 rate ranged from 23% to 75%, respectively (both p < 0.001). In multivariable LRMs, tumor size (in 1-cm units) was an independent predictor of pT2–4N0–2 (odds ratio [OR] 1.25; p < 0.001) and pT3–4N0–2 (OR 1.30; p < 0.001) disease at RNU. Conclusions: Tumor size is a key predictor of muscle-invasive or non–organ-confined RPUC. Greater tumor size directly and virtually linearly predicts a higher rate of invasive or non–organ-confined RPUC at RNU. Patient summary: For patients with cancer in urinary tract cells lining the kidney, larger tumor size predicts worse stage of the disease at surgery.

We performed a retrospective analysis of the patients assessed at our memory unit for whom Alzheimer disease (AD) cerebrospinal fluid biomarker results were available. We selected patients diagnosed with mild cognitive impairment due to AD (National Institute on Aging-Alzheimer's Association clinical criteria), confirmed neuropsychological deficit, a Global Deterioration Scale score of 3, and an abnormal profile of cerebrospinal fluid biomarkers. Of the 588 cases reviewed, 110 met the inclusion criteria. During follow-up, 50 cases (45.45%) progressed to dementia due to AD. Baseline levels of total and phosphorylated tau were higher in the group of patients that progressed to dementia than in those remaining with mild cognitive impairment. After adjusting for age, sex, history of hypertension, diabetes, and educational level, a 10% increase in total tau protein values was associated with a 7.60% increase in the risk of progression to dementia (hazard ratio: 2.22; 95% confidence interval, 1.28-3.84]; P = .004). Among patients with mild cognitive impairment due to AD and abnormal cerebrospinal fluid biomarker profiles, progressively higher concentrations of total or phosphorylated tau were associated with increased risk of progression to dementia.

Resumen En junio de 2019 se organizo en Sevilla el primer curso de resonancia magnetica (RM) fetal, con el aval de las sociedades espanolas de Radiologia Medica (SERAM) y Radiologia Pediatrica (SERPE), y se fundo el grupo espanol de RM fetal. Para establecer este grupo, se diseno un cuestionario para radiologos que se dediquen a la imagen prenatal en Espana que anuncio la Sociedad Espanola de Radiologia a sus socios. Las preguntas estaban relacionadas con el tipo de hospital, con los estudios de RM (campo magnetico, edad gestacional, uso de sedacion, numero de estudios por ano, proporcion de estudios de neuroimagen fetal) y con la docencia e investigacion de la RM fetal. Recogimos 41 respuestas de 25 provincias (88% hospitales publicos). Muy pocos radiologos realizan ecografia (7%) o tomografia computarizada prenatal en Espana. La RM se realiza en el segundo trimestre (34%) o tercer trimestre (44%). En el 95% de los centros predominan los estudios del cerebro fetal. El 41% de los centros tienen la posibilidad de realizar sus estudios en RM 3 Tesla. La sedacion materna se usa en el 17% de los centros. El numero de estudios de RM fetal por ano es muy variable, siendo mucho mayor en Barcelona y Madrid que en el resto de Espana.

It is hard to construct an optimal classifier for high-dimensional imbalanced data, on which the performance of classifiers is seriously affected and becomes poor. Although many approaches, such as resampling, cost-sensitive, and ensemble learning methods, have been proposed to deal with the skewed data, they are constrained by high-dimensional data with noise and redundancy. In this study, we propose an adaptive subspace optimization ensemble method (ASOEM) for high-dimensional imbalanced data classification to overcome the above limitations. To construct accurate and diverse base classifiers, a novel adaptive subspace optimization (ASO) method based on adaptive subspace generation (ASG) process and rotated subspace optimization (RSO) process is designed to generate multiple robust and discriminative subspaces. Then a resampling scheme is applied on the optimized subspace to build a class-balanced data for each base classifier. To verify the effectiveness, our ASOEM is implemented based on different resampling strategies on 24 real-world high-dimensional imbalanced datasets. Experimental results demonstrate that our proposed methods outperform other mainstream imbalance learning approaches and classifier ensemble methods.

Summary Objectives A whole body vibration platform using vertical oscillation has been shown to be efficacious in reducing vocal fatigue in adults. This study aimed to investigate whether this platform-generated whole body vibration was unique in reducing vocal fatigue by comparing it with self-generated whole body vibration. Methods Twenty-four female adults (mean age = 23.96 years) were randomly assigned to one of the following three groups: a machine-generated whole body vibration group (N = 8), a self-generated whole body vibration group (N = 8), and a placebo vocal resting group (N = 8). All participants performed a karaoke singing task for at least 95 minutes. Each participant received 10 minutes of platform-generated vibration, self-vibration, or sham localised vibration (placebo group with basically voice rest only), according to their group allocation. Vocal function ability, measured by the highest fundamental frequency produced, and a self-reported vocal fatigue score were evaluated at three time points: baseline (prefatigue), after the singing task (post-fatigue) and post-vibration. Results The study revealed that machine-generated whole body vibration was significantly better at improving vocal fatigue than self-generated whole body vibration or voice rest. Conclusion The findings support previous research that machine-generated whole body vibration is effective in reducing vocal fatigue. The non-significant results of self-generated whole body vibration in terms of relieving vocal fatigue suggest that inadequate vibration frequency or amplitude together with leg muscle fatigue may have been the main factor of ineffectiveness.

Objective Chronic skin wounds are one of the most devastating complications in diabetic patients due to the formation of advanced glycation end products (AGEs) resulting from non-enzymatic glycation of proteins and lipids in hyperglycemia. AGEs, upon binding their receptors (RAGEs), trigger pro-inflammatory signals that impair wound healing in diabetes and contribute to the pathology of chronic skin wounds. Approach We previously developed a recombinant fusion protein containing the binding domain of RAGE (vRAGE) linked to elastin-like polypeptides (ELPs) that acts as a competitive inhibitor of AGEs, and another ELP fusion protein containing stromal cell-derived factor 1 (SDF1) that promotes revascularization. Herein, we report the effects of protein coacervates incorporating both vRAGE-ELP and SDF1-ELP on wound healing in an in vitro diabetes-mimicking cell culture system, and in in vivo in full-thickness wounds on diabetic mice. Results The combination of vRAGE-ELP and SDF1-ELP increased cell metabolic activity in AGE-stimulated endothelial cells, promoted in vitro tube formation and accelerated healing in an in vitro cell migration assay. When used in a single topical application on full-thickness excisional skin wounds in diabetic mice, wound closure in the combination groups reached almost 100% on post-wounding day 35, compared to 62% and 85% on the same days in animals treated with fibrin gel control and vehicle control consisting of ELP alone. Innovation To our knowledge, this is the first study that attempts to reverse the AGE-RAGE-mediated signaling as well as to promote cell proliferation and vascularization in one single treatment. Conclusion The co-delivery of vRAGE-ELP and SDF1-ELP has potential for the treatment of diabetic wounds.

Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

Introduction Headache is a frequent cause of consultation; it is important to detect patients with secondary headache, particularly high-risk secondary headache. Such systems as the Manchester Triage System (MTS) are used for this purpose. This study aims to evaluate the frequency of sub-triage in patients attending the Emergency Department due to headache. Material and methods We studied a series of consecutive patients who came to the Emergency Department with headache and presenting some warning sign, defined as the presence of signs leading the physician to request an emergency neuroimaging study and/or assessment by the on-call neurologist. The reference diagnosis was established by neurologists. We evaluated the MTS triage level assigned and the presence of warning signs that may imply a higher level than that assigned. Results We registered a total of 1,120 emergency department visits due to headache, and 248 patients (22.8%) were eligible for study inclusion. Secondary headache was diagnosed in 126 cases (50.8% of the sample; 11.2% of the total), with 60 cases presenting high-risk secondary headache (24.2%; 5.4%). According to the MTS, two patients were classified as immediate (0.8%), 26 as very urgent (10.5%), 147 as urgent (59.3%), 68 as normal (27.4%), and five as not urgent (2%). The percentage of patients under-triaged was 85.1% in the very urgent classification level and 23.3% in the urgent level. Conclusion During the study period, at least one in 10 patients attending the Emergency Department due to headache had secondary headache; one in 20 had high-risk secondary headache. The MTS under-triaged most patients with warning signs suggesting a potential emergency.

In inverse reinforcement learning (RL), there are two agents. An expert target agent has a performance cost function and exhibits control and state behaviors to a learner. The learner agent does not know the expert's performance cost function but seeks to reconstruct it by observing the expert's behaviors and tries to imitate these behaviors optimally by its own response. In this article, we formulate an imitation problem where the optimal performance intent of a discrete-time (DT) expert target agent is unknown to a DT Learner agent. Using only the observed expert's behavior trajectory, the learner seeks to determine a cost function that yields the same optimal feedback gain as the expert's, and thus, imitates the optimal response of the expert. We develop an inverse RL approach with a new scheme to solve the behavior imitation problem. The approach consists of a cost function update based on an extension of RL policy iteration and inverse optimal control, and a control policy update based on optimal control. Then, under this scheme, we develop an inverse reinforcement Q-learning algorithm, which is an extension of RL Q-learning. This algorithm does not require any knowledge of agent dynamics. Proofs of stability, convergence, and optimality are given. A key property about the nonunique solution is also shown. Finally, simulation experiments are presented to show the effectiveness of the new approach.

Gills, JL, Spliker, B, Glenn, JM, Szymanski, D, Romer, B, Lu, H-C, and Gray, M. Acute citrulline-malate supplementation increases total work in short lower-body isokinetic tasks for recreationally active females during menstruation. J Strength Cond Res XX(X): 000-000, 2021-Citrulline-Malate (CM) exhibits acute ergogenic benefits through nitric oxide production (NO) and augmentation of vasodilatory properties. Nitric oxide is upregulated by estrogen and may influence CM's ergogenic efficacy in women. Therefore, the objective of this study was to evaluate the acute effects of CM supplementation on lower-body isokinetic performance in recreationally active women. Nineteen women (23.5 ± 3.1 years; 164.8 ± 7.0 cm; 61.9 ± 27.4 kg; 28.8 ± 8.1% body fat) completed 2 randomized, double-blind, crossover trials consuming CM (8 g CM + 12 g dextrose) or placebo (12 g dextrose). For testing trials, subjects were in the menstruating portion of the follicular phase of their menstrual cycle. Subjects performed a 5-repetition isokinetic leg extension protocol (5RP) followed by a 50-repetition isokinetic leg extension protocol (50RP), 60 minutes after supplement consumption. Repeated measures analysis of variance analysis showed that CM significantly increased total work completed, relative total work, and total work during maximum repetition compared with placebo (p < 0.05); but no significant performance differences existed between trials for peak torque production (p = 0.14) for the 5RP. No significant differences were identified between trials for peak torque production (p = 0.69) or total work (p = 0.33) completed during the 50RP. CM increased total work completed during the 5RP, but provided no ergogenic benefit during the 50RP in recreationally active menstruating women. Citrulline-Malate amplifies power-based resistance exercise performance in women during the follicular phase of the menstrual cycle, potentially because of depressed estrogen levels. Additional research is needed to identify timing efficacy of CM to increase sport performance during each phase of the menstrual cycle.