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Jaden R Kohn,1 Nora M Haney,2 Paige E Nichols,3 Katherine M Rodriguez,2 Taylor P Kohn2 1Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Department of Urology, Mayo Clinic, Rochester, MN, USACorrespondence: Taylor P KohnThe James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Marburg 134, Baltimore, MD 21287, USAEmail tpkohn@jhmi.eduAbstract: Clinical varicoceles are one of the most commonly identified physical exam abnormalities in men presenting with infertility. Clinical varicoceles can cause impaired spermatogenesis and surgical correction can improve semen parameters in select men. Increasingly, andrologists are performing varicocele repairs prior to intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) to boost male fertility potential. In this review, we evaluated the available literature 1) to determine if varicocelectomy prior to IUI or assisted reproductive technologies proved to improve sperm production or pregnancy outcomes; and 2) to identify who may be the ideal candidate for pre-IUI/ART varicocelectomy. Overall, few studies have explored this topic and little can be concluded about the impact of varicocelectomy prior to IUI. The evidence, however, does support that correcting a clinical varicocele can increase pregnancy outcomes in couples who plan to pursue IVF or ICSI. When selecting patients for varicocelectomy prior to IUI or ART, clinicians should evaluate female age as improvement in semen parameters can take 6 months after varicocelectomy and this duration of time may be deleterious in cases of advanced maternal age when each cycle becomes increasingly important. Overall, the currently limited literature regarding clinical varicoceles correction demonstrates that pregnancy rates can be increased when comparing patients who have undergone varicocelectomy prior to ART with those who had clinical varicocele but did not undergo surgery.Keywords: varicocele, varicocelectomy, sperm, intrauterine insemination, in vitro fertilization, intracytoplasmic sperm injection

Language is an important marker of identity. Guided by social identity theory and using a grounded theory approach, this study examined how languages are chosen and shape experiences in the workplace. Results suggest that language use is influenced by both external (norms, business needs) and internal (identity, language comfort) processes. Furthermore, speaking Spanish in the workplace has both positive (inclusion, camaraderie) and negative effects (exclusion, harassment, discrimination), with many more negative effects reported by our participants. Speaking Spanish appears to mark the speaker as an outsider. Together, our results indicate that language use is an important choice, personally and professionally, for employees and plays an important role in the way individuals are treated in the workplace. [ABSTRACT FROM AUTHOR]

Background: Diagnostic delays in Bipolar Disorder (BD) are common and may contribute to worse outcomes. While most studies focus on depression as a primary precursor, both anxiety and attention deficit disorders are also frequent initial diagnoses. In the current study, we utilized a large, diverse electronic health record (EHR) dataset to quantify the rates and correlates of conversion to BD from these major precursor diagnoses., Methods: Our study analyzed a comprehensive ten-year EHR dataset from Johns Hopkins Medicine, a diverse urban medical center, to assess and compare the rates and correlates of conversion to BD from Major Depressive Disorder (MDD), anxiety disorders, and ADHD. Risk factors for transition were assessed as time-varying variables in proportional hazards models., Results: Of the 21,341 patients initially included, 1232 later transitioned to a diagnosis of BD. Adjusted-one-year conversion rates for patients with MDD, anxiety disorders, and ADHD were 4.2 %, 3.4 %, and 4.0 %, respectively, with ten-year rates at 11.4 %, 9.4 %, and 10.9 %, respectively. Age (19-29 years), treatment setting (emergency and inpatient), and psychotropic medications were associated with conversion to BD across all precursor diagnoses. Severe and psychotic forms of MDD were among the strongest risk factors for transitioning to BD. Although risk factors for convertion were similar, transition rates were lower in children, particularly in indivudals with ADHD, who showed a higher rate of BD conversion in adults., Conclusions: The highest risk of transitioning to BD was observed in patients initially diagnosed with MDD, though significant risk was also noted in those with initial diagnoses of anxiety disorders and adult ADHD., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pediatric pneumonia can be severe and result in empyema. Next-generation sequencing (NGS) may broadly detect pathogens though, optimal timing and impact of sample type on diagnostic yield is unknown. This is a prospective, single-center pilot study of children aged 3 months through 17 years admitted to the PICU with a primary diagnosis of complicated pneumonia. Plasma, endotracheal, nasopharyngeal, and pleural fluid samples were collected at three time points during hospitalization. After nucleic acid extraction, combined libraries were enriched with an NGS enrichment panel kit (RPIP, Illumina), sequenced and quantitative organism detections were analyzed. NGS identified the same bacterial pathogen as traditional testing in all samples, regardless of antibiotic pre-treatment or time collected. Conventional culture methods only identified the pathogen reliably in invasively obtained pleural fluid or endotracheal aspirates. Future application of NGS may allow for non-invasive pathogen detection at a broader range of time points and more targeted antibiotic coverage., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicole Coufal reports financial support was provided by Illumina Inc. Rita Czako Stinnett reports a relationship with Illumina Inc that includes: employment. Nidhi Shah reports a relationship with Illumina Inc that includes: employment. Marta Mangifesta reports a relationship with Illumina Inc that includes: employment. Robert Schlaberg reports a relationship with Illumina Inc that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The primary purpose of this randomized, cross-sectional study was to determine whether operant conditioning of motor evoked torque (MEP TORQUE ) in individuals with total knee arthroplasty (TKA) increases quadriceps MEP TORQUE responses within a single session and induces acute corticospinal adaptations by producing sustained increases in MEP TORQUE after training. A secondary purpose was to determine if these changes were affected by the stimulus intensity and number of training trials., Methods: Thirty participants were block-randomized into one of three groups based on the participant's active motor threshold (100%, 120%, and 140%) to evaluate the effect of stimulus intensity. Participants received three blocks of conditioning trials (COND), where they trained to increase their MEP TORQUE . Control (CTRL) transcranial magnetic stimulation pulses were provided before and after each COND block to establish baseline corticospinal excitability and to evaluate the effect of the number of training trials. Two MEP TORQUE recruitment curves were collected to evaluate the effect of up-conditioning on acute corticospinal adaptations., Results: TKA participants were able to successfully increase their MEP TORQUE in a single session (F 3,81  = 10.719, p < 0.001) and induce acute corticospinal adaptations (F 1,27  = 20.029, p < 0.001), indicating sustained increases in quadriceps corticospinal excitability due to operant conditioning. While the stimulus intensity used during training did not affect the ability to increase MEP TORQUE (F 2,26  = 0.021, n.s.) or its associated acute adaptations (F 2,27  = 0.935, n.s.), the number of training trials significantly influenced these outcomes (F 3,81  = 10.719, p < 0.001; F 3,81  = 4.379, p = 0.007, respectively)., Conclusion: Operant conditioning is a feasible approach for improving quadriceps corticospinal excitability following TKA. While any of the three stimulus intensities evaluated in this study may be used in future operant conditioning interventions, using a low or moderate stimulus intensity and 150 training trials are recommended to improve treatment efficiency and patient adherence., Level of Evidence: Level II., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Restoration of limb function for individuals with unilateral weakness typically requires volitional muscle control, which is often not present for individuals with severe impairment. Mirror therapy-interventions using a mirror box to reflect the less-impaired limb onto the more-impaired limb-can facilitate corticospinal excitability, leading to enhanced recovery in severely impaired clinical populations. However, the mirror box applies limitations on mirror therapy, namely that all movements appear bilateral and are confined to a small area, impeding integration of complex activities and multisensory feedback (e.g., visuo-tactile stimulation). These limitations can be addressed with virtual reality, but the resulting effect on corticospinal excitability is unclear., Objective: Examine how virtual reality-based unilateral mirroring, complex activities during mirroring, and visuo-tactile stimulation prior to mirroring affect corticospinal excitability., Materials and Methods: Participants with no known neurological conditions (n = 17) donned a virtual reality system (NeuRRoVR) that displayed a first-person perspective of a virtual avatar that matched their motions. Transcranial magnetic stimulation-induced motor evoked potentials in the nondominant hand muscles were used to evaluate corticospinal excitability in four conditions: resting, mirroring, mirroring with prior visuo-tactile stimulation (mirroring + TACT), and control. During mirroring, the movements of each participant's dominant limb were reflected onto the nondominant limb of the virtual avatar, and the avatar's dominant limb was kept immobile (i.e., unilateral mirroring). The mirroring + TACT condition was the same as the mirroring condition, except that mirroring was preceded by visuo-tactile stimulation of the nondominant limb. During the control condition, unilateral mirroring was disabled. During all conditions, participants performed simple (flex/extend fingers) and complex (stack virtual blocks) activities., Results: We found that unilateral mirroring increased corticospinal excitability compared to no mirroring (p < 0.001), complex activities increased excitability compared to simple activities during mirroring (p < 0.001), and visuo-tactile stimulation prior to mirroring decreased excitability (p = 0.032). We also found that these features did not interact with each other., Discussions: The findings of this study shed light onto the neurological mechanisms of mirror therapy and demonstrate the unique ways in which virtual reality can augment mirror therapy. The findings have important implications for rehabilitation for design of virtual reality systems for clinical populations., (© 2024. The Author(s).)

Purpose This study estimated risk of incident mental disorders in adulthood associated with both transient and persistent adolescent psychotic experiences (PEs). Methods A nested case-control design was used within the Avon Longitudinal Study of Parents and Children (ALSPAC), a birth cohort study which recruited expectant mothers from 1991-1992. Participants consisted of 8822 offspring of ALSPAC mothers who completed the Psychosis-like Symptoms Interview Questionnaire (PLIKSi-Q). PEs were assessed using the PLIKSi-Q. Depressive disorders were assessed using the Short Mood and Feelings Questionnaire (SMFQ), anxiety disorders using the General Anxiety Disorder Assessment and the Clinical Interview Schedule-Revised, and psychotic disorder using the PLIKSi. Risk of incident depressive disorder, GAD, psychotic disorder, and past-year suicide attempts were compared amongst participants who had ever versus never reported a PE and those who reported persistent versus transient PEs. Results Adolescent PEs were associated with increased risk for incident depressive disorder (adjusted hazard ratio (aHR) = 1.62, 95% CI = 1.42, 1.84), GAD (aHR 1.23, 95% CI = 1.03, 1.47), psychotic disorder (adjusted odds ratio (aOR) = 5.08, 95% CI = 2.02, 12.79), and past-year suicide attempts (aHR = 2.56, 95% CI = 1.97, 3.25). Persistent PEs were associated with increased risk for depressive disorder (aHR = 1.81, 95% CI = 1.55, 2.12), generalized anxiety disorder (aHR = 1.34, 95% CI = 1.07, 1.68), and psychotic disorder (aOR = 7.39, 95% CI = 2.43, 22.19) but not past-year suicide attempts. Conclusion Adolescent PEs are a risk factor for multiple mental disorders and suicide attempts, with persistent PEs conferring greater risk. Identifying interventions for adolescents who report PEs, particularly persistent PEs, could lessen the burden of multiple mental health disorders and suicide attempts.

Objectives: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions., Design: Ambidirectional multisite cohort study., Setting: Four tertiary children's hospitals., Patients: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023., Interventions: None., Measurements and Main Results: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication ( p < 0.0001) and contributed to a decision to consult palliative care ( p < 0.02)., Conclusions: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management., Competing Interests: Drs. Rodriguez and Coufal’s institution received funding from the National Institutes of Health (NIH). Drs. Rodriguez, Kingsmore (grants U19HD077693, UL1TR002550, and 1UM1TR004407), and Coufal received support for article research from the NIH. Dr. Kingsmore received funding from Ultragenyx, Amgen, Horizon, Sanofi, Takeda, Alexion, Sarepta, Ionis, Inozyme, Travere, and Orchard. Dr. Coufal received funding from Rady Children’s Hospital. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Operant conditioning of motor evoked torque (MEP TORQUE ) can directly target the corticospinal pathway in patients with anterior cruciate ligament (ACL) reconstruction. However, it remains unclear whether operant conditioning can elicit short-term improvements in corticospinal excitability and whether these improvements are influenced by stimulus intensity., Hypothesis: Quadriceps MEP TORQUE responses can be upconditioned in a single session and will elicit short-term adaptations in corticospinal excitability, with higher stimulus intensities eliciting greater effects., Study Design: Randomized controlled laboratory study., Level of Evidence: Level 2., Methods: Thirty-six participants were assessed during a single session of an operant conditioning protocol. Participants were randomized into 1 of 3 groups for stimulus intensity used during operant conditioning based on the participant's active motor threshold (AMT: 100%, 120%, and 140%). Quadriceps MEP TORQUE amplitude was evaluated during a block of control transcranial magnetic stimulation trials (CTRL) to establish baseline corticospinal excitability, and 3 blocks of conditioning trials (COND) during which participants trained to upcondition their MEP TORQUE . MEP TORQUE recruitment curves were collected to evaluate the effect of operant conditioning on acute corticospinal adaptations., Results: Participants with ACL reconstruction could upcondition their MEP TORQUE in a single session ( P < 0.01; CTRL, 17.27 ± 1.28; COND, 21.35 ± 1.28 [mean ± standard error [SE] in N·m]), but this ability was not influenced by the stimulus intensity used during training ( P = 0.84). Furthermore, significant improvements in corticospinal excitability were observed ( P = 0.05; PRE, 687.91 ± 50.15; POST, 761.08 ± 50.15 [mean ± SE in N·m %AMT]), but stimulus intensity did not influence corticospinal adaptations ( P = 0.67)., Conclusion: Operant conditioning can elicit short-term neural adaptations in ACL-reconstructed patients. Future operant conditioning paradigms may effectively use any of the 3 stimulus intensities studied herein., Clinical Relevance: Operant conditioning may be a feasible approach to improve corticospinal excitability after ACL reconstruction., Competing Interests: The following author declared potential conflicts of interest: R.P.-S. is the Associate Editor for Athletic Training, Sports Health.

Histone deacetylases (HDACs) play a crucial role in transcriptional regulation and are implicated in various diseases, including cancer. They are involved in histone tail deacetylation and canonically linked to transcriptional repression. Previous studies suggested that HDAC recruitment to cell-cycle gene promoters via the retinoblastoma (RB) protein or the DREAM complex through SIN3B is essential for G1/S and G2/M gene repression during cell-cycle arrest and exit. Here we investigate the interplay among DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression. Knockout of SIN3B does not globally derepress cell-cycle genes in non-proliferating HCT116 and C2C12 cells. Loss of SIN3A/B moderately upregulates several cell-cycle genes in HCT116 cells but does so independently of DREAM/RB. HDAC inhibition does not induce general upregulation of RB/DREAM target genes in arrested transformed or non-transformed cells. Our findings suggest that E2F:RB and DREAM complexes can repress cell-cycle genes without relying on HDAC activity., (© 2024. The Author(s).)

Objectives: The purpose of this project was to longitudinally examine quadriceps torque complexity in a group of individuals who tore their ACL and underwent ACL reconstruction., Design: Cohort analysis., Methods: Thirty-four individuals completed maximal effort bilateral isometric strength testing after ACL injury but pre-surgery, five months' post-surgery (mid-point of rehabilitation), and when cleared to return to activity. Sample entropy, a nonlinear analysis of quadriceps torque control (complexity), was calculated from maximal isometric contractions. Two 3 × 2 repeated measures analysis of variance were used to examine changes over time and between limbs for quadriceps torque complexity and peak torque., Results: Quadriceps peak torque was lower in the involved limb when compared to the uninvolved limb at every time point (p < 0.001). Peak torque of the involved limb was decreased at mid-point of rehabilitation compared to before surgery (p = 0.023) and at mid-point compared to return to activity (p = 0.041). Quadriceps sample entropy was higher in the involved limb compared to the uninvolved limb at the mid-point of rehabilitation (p < 0.001) and return to activity (p < 0.001), indicating greater complexity. The involved limb also demonstrated increased torque sample entropy from pre-surgery to mid-point of rehabilitation (p = 0.023), but not from pre-surgery to return to activity (p = 0.169) or from mid-point to return to activity (p = 0.541)., Conclusions: Not only does quadriceps strength decline with ACL reconstruction, but quality of the quadriceps muscle contraction is also compromised. Increased torque complexity experienced in the ACL limb after reconstruction may contribute to impaired physical function in individuals following ACL reconstruction., Competing Interests: Declaration of Interest Statement Alexa K. Johnson, Kazandra Rodriguez, Adam Lepley, and Riann Palmieri-Smith all report no competing interests, conflicts of interest, or other kinds of associations., (Copyright © 2023 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Controlled protein synthesis is required to regulate gene expression and is often carried out in a cell type-specific manner. Protein synthesis is commonly measured by labeling the nascent proteome with amino acid analogs or isotope-containing amino acids. These methods have been difficult to implement in vivo as they require lengthy amino acid replacement procedures. O-propargyl-puromycin (OPP) is a puromycin analog that incorporates into nascent polypeptide chains. Through its terminal alkyne, OPP can be conjugated to a fluorophore-azide for directly visualizing nascent protein synthesis, or to a biotin-azide for capture and identification of newly-synthesized proteins. To achieve cell type-specific OPP incorporation, we developed phenylacetyl-OPP (PhAc-OPP), a puromycin analog harboring an enzyme-labile blocking group that can be removed by penicillin G acylase (PGA). Here, we show that cell type-specific PGA expression in Drosophila can be used to achieve OPP labeling of newly-synthesized proteins in targeted cell populations within the brain. Following a brief 2 hr incubation of intact brains with PhAc-OPP, we observe robust imaging and affinity purification of OPP-labeled nascent proteins in PGA-targeted cell populations. We apply this method to show a pronounced age-related decline in neuronal protein synthesis in the fly brain, demonstrating the capability of PhAc-OPP to quantitatively capture in vivo protein synthesis states. This method, which we call POPPi ( P GA-dependent OPP i ncorporation), should be applicable for rapidly visualizing protein synthesis and identifying nascent proteins synthesized under diverse physiological and pathological conditions with cellular specificity in vivo., Competing Interests: SV, RB, AC, AA, KR, MC, IM No competing interests declared, (© 2023, Villalobos-Cantor et al.)

Introduction: Parkinson's disease (PD) is characterized by high-rates of depression with limited evidence-based treatment options to improve mood. Objective: To expand therapeutic options, we evaluated the feasibility and effect of a telehealth mindfulness-based cognitive therapy intervention adapted for PD (MBCT-PD) in a sample of participants with DSM-5 depressive disorders. Methods: Fifteen participants with PD and clinically-significant depression completed 9 sessions of MBCT-PD. Depression, anxiety, and quality of life were evaluated at baseline, endpoint, and 1-month follow-up. Results: Telehealth MBCT-PD was feasible and beneficial. Completion rates exceeded 85% and treatment satisfaction rates were high. Notable improvements were observed for depression, anxiety, and quality of life over the course of the trial. Conclusion: Telehealth MBCT-PD shows promise and warrants further evaluation via randomized clinical trial with more diverse participants. Such research holds the potential to expand the range of therapeutic options for depression in PD, thereby setting the stage for personalized care.

Objective: The present study aims to determine if psychotic experiences in a general population sample are a risk factor for depressive disorders at a 15-year follow-up visit., Method: A longitudinal population cohort of adults over age 18 from East Baltimore were followed from 1981 to 1996 with 1409 participants included in analyses. Delusions and hallucinations and depressive disorders were assessed using DSM-III criteria. Odds ratios were obtained using logistic regression with psychotic experiences modeled both dichotomously and as count variables as predictors of major and minor depressive disorders at wave three. Age, race, and sex were included as covariates in the model., Results: Both delusions and hallucinations were associated with an increased odds of incident depressive disorders. Delusions, but not hallucinations, were associated with increased odds of major depressive disorder (adjusted odds ratio, 3.04 [95% CI = 1.29-7.13]) and both delusions and hallucinations were associated with increased odds of minor depressive disorder (adjusted odds ratios, 4.6 [95% CI = 2.11-10.04] and 3.93 [95% CI = 2.11-7.32]). There was a dose-response relationship in number of psychotic experiences reported and odds of depressive disorders., Conclusions: Lifetime psychotic experiences, particularly delusions, in the absence of mental disorders, are associated with later depressive disorders. Results persist in a dose-response manner. Future research should determine whether transitory versus persistent psychotic experiences have a differential effect on later depression., (© 2023 The Authors. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

The mono-ADP-ribosyltransferase PARP7 has emerged as a key negative regulator of cytosolic NA-sensors of the innate immune system. We apply a rational design strategy for converting a pan-PARP inhibitor into a potent selective PARP7 inhibitor (KMR-206). Consistent with studies using the structurally distinct PARP7 inhibitor RBN-2397, co-treatment of mouse embryonic fibroblasts with KMR-206 and NA-sensor ligands synergistically induced the expression of the type I interferon, IFN-β. In mouse colon carcinoma (CT-26) cells, KMR-206 alone induced IFN-β. Both KMR-206 and RBN-2397 increased PARP7 protein levels in CT-26 cells, demonstrating that PARP7's catalytic activity regulates its own protein levels. Curiously, treatment with saturating doses of KMR-206 and RBN-2397 achieved different levels of PARP7 protein, which correlated with the magnitude of type I interferon gene expression. These latter results have important implications for the mechanism of action of PARP7 inhibitors and highlights the usefulness of having structurally distinct chemical probes for the same target., Competing Interests: Declaration of interests M.S.C, D.J.S, K.M.R, and S.S are co-inventors on a provisional patent describing the inhibitors in this study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Complement factor I deficiency (CFID; OMIM #610984) is a rare immunodeficiency caused by deficiencies in the serine protease complement factor I (CFI). CFID is characterized by predisposition to severe pneumococcal infection, often in infancy. We report a previously healthy adolescent male who presented with respiratory failure secondary to pneumococcal pneumonia and severe systemic inflammatory response. Rapid genome sequencing (rGS) identified compound heterozygous variants in CFI in the proband, with a novel maternally inherited likely pathogenic variant, a single nucleotide deletion resulting in premature stop (c.1646del; p.Asn549ThrfsTer25) and a paternally inherited novel likely pathogenic deletion (Chr 4:110685580-110692197del)., (© 2022 Rodriguez et al.; Published by Cold Spring Harbor Laboratory Press.)

This study comprehensively evaluated the test-retest reliability of raw and normalized quadriceps motor evoked responses elicited by transcranial magnetic stimulation (TMS) in individuals with anterior cruciate ligament (ACL) reconstruction. Fifteen participants were tested on three different days that were separated at least by 24 h. Motor evoked responses were collected during a small background contraction on the reconstructed leg across a range of TMS intensities using torque (MEP TORQUE ) and electromyographic (MEP EMG ) responses. MEP TORQUE and MEP EMG were evaluated using different normalization procedures (raw, normalized to maximum voluntary isometric contraction [MVIC], peak MEP, and background contraction). MEP TORQUE was also normalized to the magnetically-evoked peripheral resting twitch torque. The area under the recruitment curve was computed for both raw and normalized MEPs. Intraclass correlation coefficients (ICCs) were determined to assess test-retest reliability. Results indicated that MEP TORQUE generally showed greater reliability than MEP EMG for all normalization procedures. Vastus medialis MEP EMG generally showed greater reliability than rectus femoris MEP EMG . Finally, both MEP TORQUE and MEP EMG exhibited good reliability, even when not normalized. These findings indicate that MEP TORQUE and MEP EMG offer reliable measures of corticospinal function and suggest that MEP TORQUE is a suitable alternative to MEP EMG for measuring quadriceps corticospinal excitability in individuals with ACL reconstruction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The negative relationship between schizophrenia (SCZ) and rheumatoid arthritis (RA) has been observed for 85 years, but the mechanisms driving this association are unknown. This study analyzed differences in profiles of cytokines (IL-1β, IL-Ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα), selected genes (HLA-DRB1, IL1RN, HP2), and antibodies related to gluten sensitivity (AGA-IgG, AGA-IgA), celiac disease (tTG), and systemic autoimmunity (ANA, anti-CCP, RF) in 40 subjects with SCZ, 40 with RA, and 40 healthy controls (HC). HLA-DRB1*04:01 alleles were enriched in persons with SCZ and RA compared with HC, and the HP2/HP2 genotype was 2-fold more prevalent in AGA/tTG-positive versus negative SCZ patients. Patients with SCZ demonstrated 52.5% positivity for any of the antibodies tested, compared to 90% of RA patients and 30% of HC. Cluster analysis of the cytokines revealed three clusters: one associated with SCZ marked by high levels of IL-1Ra, one associated with HC, and one associated with both SCZ and RA marked by elevated levels of IFNγ, TNFα, and IL-6. These analyses suggest that stratification of SCZ patients by cytokine profile may identify unique SCZ subgroups and enable the use of currently available cytokine-targeted treatment strategies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Caregiver distress is prevalent in Parkinson's disease (PD) and predictive of negative health outcomes for both people with PD and caregivers. To identify future intervention targets, it is important to better elucidate the specific processes, such as criticism, that perpetuate burden., Objective: Evaluate the frequency and impact of criticism and reactivity to criticism in PD caregiving dyads., Methods: Eighty-three people with PD and their caregivers independently completed measures of criticism and physical and emotional health., Results: Criticism in the caregiving relationship was reported by 71.1% (n = 59) of people with PD and 80.7% (n = 67) of caregivers. Both perceived criticism and emotional reactivity to criticism were significant predictors of caregiver distress, adjusting for PD motor and non-motor symptom severity. In contrast, criticism was not related to PD depression., Conclusion: Criticism in the PD caregiving relationship is a clear target for psychotherapeutic intervention and may improve caregiver health and quality of life.

Bacillus Calmette-Guérin (BCG) vaccine is an attenuated strain of Mycobacterium bovis that provides weak protection against tuberculosis (TB). Mast cells (MCs) are tissue-resident immune cells strategically that serve as the first line of defence against pathogenic threats. In this study, we investigated the response of human MCs (hMCs) to BCG. We found that naïve hMCs exposed to BCG did not secrete cytokines, degranulate, or support the uptake and intracellular growth of bacteria. Since we could show that in hMCs IL-33 promotes the transcription of host-pathogen interaction, cell adhesion and activation genes, we used IL-33 for cell priming. The treatment of hMCs with IL-33, but not IFN- γ , before BCG stimulation increased IL-8, MCP-1 and IL-13 secretion, and induced an enhanced expression of the mycobacteria-binding receptor CD48. These effects were comparable to those caused by the recombinant Mycobacterium tuberculosis ( Mtb ) 19-KDa lipoprotein. Finally, stimulation of hMCs with IL-33 incremented MC-BCG interactions. Thus, we propose that IL-33 may improve the immunogenicity of BCG vaccine by sensitising hMCs.

Cutaneous melanoma is one of the most aggressive human malignancies and shows increasing incidence. Mast cells (MCs), long-lived tissue-resident cells that are particularly abundant in human skin where they regulate both innate and adaptive immunity, are associated with melanoma stroma (MAMCs). Thus, MAMCs could impact melanoma development, progression, and metastasis by secreting proteases, pro-angiogenic factors, and both pro-inflammatory and immuno-inhibitory mediators. To interrogate the as-yet poorly characterized role of human MAMCs, we have purified MCs from melanoma skin biopsies and performed RNA-seq analysis. Here, we demonstrate that MAMCs display a unique transcriptome signature defined by the downregulation of the FcεRI signaling pathway, a distinct expression pattern of proteases and pro-angiogenic factors, and a profound upregulation of complement component C3. Furthermore, in melanoma tissue, we observe a significantly increased number of C3 + MCs in stage IV melanoma. Moreover, in patients, C3 expression significantly correlates with the MC-specific marker TPSAB1 , and the high expression of both markers is linked with poorer melanoma survival. In vitro , we show that melanoma cell supernatants and tumor microenvironment (TME) mediators such as TGF-β, IL-33, and IL-1β induce some of the changes found in MAMCs and significantly modulate C3 expression and activity in MCs. Taken together, these data suggest that melanoma-secreted cytokines such as TGF-β and IL-1β contribute to the melanoma microenvironment by upregulating C3 expression in MAMCs, thus inducing an MC phenotype switch that negatively impacts melanoma prognosis., Competing Interests: RD has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaxiVAX SA, and touchIME outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bahri, Kiss, Prise, Garcia-Rodriguez, Atmoko, Martínez-Gómez, Levesque, Dummer, Smith, Wellbrock and Bulfone-Paus.)

Poly-ADP-ribose-polymerases (PARPs) are a family of 17 enzymes that regulate a diverse range of cellular processes in mammalian cells. PARPs catalyze the transfer of ADP-ribose from NAD + to target molecules, most prominently amino acids on protein substrates, in a process known as ADP-ribosylation. Identifying the direct protein substrates of individual PARP family members is an essential first step for elucidating the mechanism by which PARPs regulate a particular pathway in cells. Two distinct chemical genetic (CG) strategies have been developed for identifying the direct protein substrates of individual PARP family members. In this review, we discuss the design principles behind these two strategies and how target identification has provided novel insight into the cellular function of individual PARPs and PARP-mediated ADP-ribosylation., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Context: Serum biomarkers may allow for the early identification of posttraumatic osteoarthritis after anterior cruciate ligament (ACL) injury and reconstruction. Homeostasis of matrix-metalloproteinase-3 (MMP-3) and type II collagen turnover biomarkers (C2C:CPII ratio) is believed to be compromised in individuals with ACL injury, yet the influence of sex, body mass index (BMI), and age on these biomarkers before and after ACL reconstruction remains unknown., Objective: To determine the relationship of sex, BMI, and age with serum levels of MMP-3 and C2C:CPII before and after ACL reconstruction., Design: Descriptive laboratory study., Setting: Laboratory., Patients or Other Participants: Thirty-two (females = 18, males = 14) individuals with ACL injuries., Main Outcome Measure(s): Demographic variables and blood samples were collected before surgery and at return to activity. Serum was extracted from the blood and assays were used to quantify MMP-3 and C2C:CPII. Generalized linear mixed-effects regression models were used to assess the relationships between sex, BMI, age, time, and participant on the outcome variables., Results: A significant time × sex interaction was identified for MMP-3 levels (P = .021), whereby MMP-3 levels were higher in males at return to activity (males, 2.71 ± 0.59 ng/mL; females, 1.92 ± 0.60 ng/mL; P = .017). Males also had higher MMP-3 levels at return to activity when compared with presurgery levels (P = .009). A main effect for age demonstrated that older age was associated with higher MMP-3 levels. No significant main or interaction effects were noted for C2C:CPII levels., Conclusions: Upregulation of MMP-3 serum levels may occur after ACL reconstruction, particularly in males, which may have deleterious consequences for the cartilage matrix. Sex, BMI, and time did not influence C2C:CPII ratios, but further research with larger sample sizes is needed to confirm these findings., (© by the National Athletic Trainers' Association, Inc.)

Abstract: We report process outcomes of the pilot randomized controlled trial of Texting 4 Relapse Prevention (T4RP), a text messaging-based relapse prevention program for people with schizophrenia or schizoaffective disorder (SAD). Forty people were randomized to either the intervention or treatment as usual control group at a 2:1 ratio. Process indicators were collected at 6 months post enrollment.Over 90% of patients agreed or strongly agreed that the text messages were easy to understand, easy to answer, positive, and helped them feel supported. Patient acceptability was positively associated with recovery (β = 0.29, p = <0.001) and patient-provider communication scores (β = 1.04, p < 0.001), and negatively associated with symptoms of the disorder (β = -0.27, p = 0.07). Acceptability was similar by diagnosis (β, SAD diagnosis = 0.40, p = 0.90) and age (β = 0.05, p = 0.67). Findings suggest that a text messaging intervention aimed at preventing relapse is feasible and perceived as beneficial in individuals with schizophrenia and SAD. Future research might include a targeted study of T4RP within the context of hospital discharge when people with schizophrenia/SAD are at highest risk of relapse., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Accurate quantification of voluntary activation is important for understanding the extent of quadriceps dysfunction in individuals with anterior cruciate ligament reconstruction (ACLR). Voluntary activation has been quantified using both percent activation derived from the interpolated twitch technique and central activation ratio (CAR) derived from the burst superimposition technique, as well as by using different types of electrical stimulators and pulse train conditions. However, it is unclear how these parameters affect voluntary activation estimates in individuals with ACLR. This study was performed to fill this important knowledge gap in the anterior cruciate ligament literature., Methods: Quadriceps strength and voluntary activation were examined in 18 ACLR participants (12 quadriceps/patellar tendon graft, 6 hamstring tendon graft; time since ACLR: 1.06 ± 0.82 years, mean ±  SD) at 90° of knee flexion using 2 stimulators (Digitimer and Grass) and pulse train conditions (3-pulse and 10-pulse). Voluntary activation was quantified by calculating both CAR and percent activation., Results: Results indicated that voluntary activation was significantly overestimated by CAR when compared with percent activation (p < 0.001). Voluntary activation estimates were not affected by pulse train conditions when using percent activation; however, 3-pulse stimuli resulted in greater overestimation than 10-pulse stimuli when using CAR (p = 0.003). Voluntary activation did not differ between stimulators (p > 0.05); however, the Digitimer evoked greater torque at rest than the Grass (p < 0.001)., Conclusion: These results indicate that percent activation derived from the interpolated twitch technique provides superior estimates of voluntary activation than CAR derived from burst superimposition and is less affected by pulse train conditions or stimulators in individuals with ACLR., (Copyright © 2020. Production and hosting by Elsevier B.V.)

Electrically evoked torque at rest (i.e., the torque produced from supramaximal stimul applied to a resting muscle) has been shown to be related to muscle size in healthy adults, but this relationship has not been evaluated in pathological populations where atrophy is present. This study aimed to evaluate the relationship between the electrically evoked torque at rest and vastus lateralis cross-sectional area (CSA) in individuals with anterior cruciate ligament (ACL) reconstruction. Eighteen individuals with ACL reconstruction participated. Quadriceps electrically evoked torque at rest was elicited bilaterally via sex-specific, standardized supramaximal triplet stimulations. Vastus lateralis CSA was measured at 50% of thigh length using ultrasound. Pearson's r and partial correlations were used to evaluate associations between outcomes. Evoked torque at rest was positively associated with vastus lateralis CSA in the ACL reconstructed limb ( r =0.865, partial r=0.816, P<0.01), non-reconstructed limb ( r =0.628, partial r=0.575, P<0.05), and side-to-side ratios ( r =0.670, partial r=0.659, P<0.01). These results indicate that electrically evoked torque at rest may indirectly assess side-to-side differences in quadriceps muscle size after ACL reconstruction.

Objective: To test whether Mindfulness-Based Cognitive Therapy to Prevent Suicide (MBCT-S) is associated with improvement in attentional control, an objective marker of suicide attempt., Method: In the context of a randomized clinical trial targeting suicide risk in Veterans, computerized Stroop and emotion Stroop (E-Stroop) tasks were administered 3 times over 6-months follow-up to 135 high suicide risk Veterans. Seventy were randomized to receive MBCT-S in addition to enhanced treatment as usual (eTAU), and 65 were randomized to eTAU only. E-Stroop word types included positively- and negatively-valenced emotion, suicide, and combat-related words. Interference scores and mixed effects linear regression analyses were used., Results: Veterans receiving MBCT-S showed a more favorable trajectory of attentional control over time, as indicated by performance on two E-Stroop tasks. Combat-stress interference scores improved over time among Veterans in MBCT-S. Interference processing time for negative affective words deteriorated over time among Veterans receiving eTAU only., Conclusions: MBCT-S may effectively target attentional control, and in particular reduce processing time during affective interference, in high suicide risk Veterans. Future studies to replicate these findings are warranted., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: This study examined demographic and diagnostic characteristics associated with self-reported recovery in patients with serious mental illness., Methods: Patient demographics and diagnoses were obtained from a retrospective review of charts from 981 patients attending a community psychiatry outpatient program between January 2015 and December 2016. All patients completed the Recovery Assessment Scale-Revised (RAS-R), a self-report recovery questionnaire consisting of 5 subscales, approximately every 6 months. Generalized estimating equation models were used to assess change in RAS-R scores over time and to test for associations with demographic characteristics, clinical diagnoses, and appointment adherence., Results: RAS-R scores increased among all demographic and diagnostic groups during the study period. A primary diagnosis of a psychotic disorder (including schizophrenia) was associated with higher 2-year average RAS-R total scores and scores on the Personal Confidence and Hope, Goal and Success Orientation, and Not Dominated by Symptoms subscales. African American race was associated with higher 2-year average scores on the Personal Confidence and Hope subscale. Increasing age was associated with higher total RAS-R scores and multiple subscale scores. No significant associations were found between sex or appointment adherence and RAS-R total scores or any of the subscale scores., Conclusions: While certain demographic and diagnostic groups were associated with higher RAS-R scores, study results suggest that time in treatment is itself associated with higher self-reported recovery among all demographic groups. Age, race, and diagnosis were all associated with higher scores on the Personal Confidence and Hope subscale, highlighting the need for individualized treatment that takes multiple patient characteristics into account., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: For several decades, a myriad of factors have contributed to the inadequate diagnosis and management of depression in Parkinson's disease (PD), leaving up to 60% of significantly symptomatic patients untreated. Poor access to evidence-based neuropsychiatric care is one major barrier to achieving optimal Parkinson's outcomes., Objective: The goal of this study was to compare the efficacy of individual Parkinson's-informed, video-to-home cognitive-behavioral therapy (experimental group), to clinic-based treatment as usual (control group), for depression in PD., Method: Ninety United States military veterans with clinical diagnoses of both depression and PD were computer-randomized (1:1) to either the experimental or control group; randomization was stratified by baseline antidepressant use and blind to all other baseline data. The acute treatment period spanned 10 weeks and was followed by a 6-month extension phase. The Hamilton Depression Rating Scale was the a priori primary outcome. Depression treatment response was defined as a score ≤2 on the Clinical Global Impression Improvement Scale. All statistical analyses were intent to treat., Results: Video-to-home cognitive-behavioral therapy outperformed clinic-based treatment as usual across three separate depression measures (P < 0.001). Effects were observed at the end of acute treatment and maintained through 6-month follow-up. Number needed to treat (based on treatment response classification) was 2.5 with an absolute risk reduction of 40%., Conclusion: Video-to-home cognitive-behavioral therapy may be an effective intervention to bypass access barriers to specialized, evidence-based depression care in PD and to address the unmet neuropsychiatric treatment needs of the Parkinson's community. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Anurans (frogs and toads) are among the most globally threatened taxonomic groups. Successful conservation of anurans will rely on improved data on the status and changes in local populations, particularly for rare and threatened species. Automated sensors, such as acoustic recorders, have the potential to provide such data by massively increasing the spatial and temporal scale of population sampling efforts. Analyzing such data sets will require robust and efficient tools that can automatically identify the presence of a species in audio recordings. Like bats and birds, many anuran species produce distinct vocalizations that can be captured by autonomous acoustic recorders and represent excellent candidates for automated recognition. However, in contrast to birds and bats, effective automated acoustic recognition tools for anurans are not yet widely available. An effective automated call-recognition method for anurans must be robust to the challenges of real-world field data and should not require extensive labeled data sets. We devised a vocalization identification tool that classifies anuran vocalizations in audio recordings based on their periodic structure: the repeat interval-based bioacoustic identification tool (RIBBIT). We applied RIBBIT to field recordings to study the boreal chorus frog (Pseudacris maculata) of temperate North American grasslands and the critically endangered variable harlequin frog (Atelopus varius) of tropical Central American rainforests. The tool accurately identified boreal chorus frogs, even when they vocalized in heavily overlapping choruses and identified variable harlequin frog vocalizations at a field site where it had been very rarely encountered in visual surveys. Using a few simple parameters, RIBBIT can detect any vocalization with a periodic structure, including those of many anurans, insects, birds, and mammals. We provide open-source implementations of RIBBIT in Python and R to support its use for other taxa and communities., (© 2021 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Background: The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis., Methods: We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection., Results: We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1 + HLA (human leukocyte antigen)-DR + endothelial cells and CD8 + T cells (slope, -18.3 [95% CI, -35.3 to -1.3]; P =0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2 Cre pdl1 fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls., Conclusions: Loss of graft endothelial PD-L1 expression may play a role in regulating CD8 + T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.

Objective: This study evaluated whether Mindfulness-Based Cognitive Therapy for Preventing Suicide Behavior (MBCT-S) effectively augmented treatment-as-usual enhanced for suicide prevention (eTAU)., Methods: From December 2013 through March 2018, veterans (N = 140) at high risk for suicide were recruited mostly (88.6%) during a suicide-related inpatient admission and randomly assigned to either (1) eTAU augmented with MBCT-S or (2) eTAU only. MBCT-S began during inpatient treatment (2 individual sessions emphasizing safety planning) and continued post-discharge (8 group sessions emphasizing mindfulness skills and elaborated safety planning). Four follow-up evaluations occurred over 12 months, and primary outcomes were (1) time to suicide event and (2) number of suicide events. Secondary outcomes were time to and number of suicide attempts, proportion with acute psychiatric hospitalization, and change in suicide-related factors (eg, depression, hopelessness, suicidal ideation)., Results: Relative to eTAU, MBCT-S did not significantly delay time to suicide event (hazard ratio = 0.86; 95% CI, 0.52-1.41; P  = .54), but did reduce total number of suicide events (MBCT-S: 56 events; eTAU: 92 events; incident rate ratio = 0.59; 95% CI, 0.36-0.99; P  < .05). There were no significant differences in time to or number of suicide attempts. In a post hoc analysis, however, MBCT-S significantly reduced the proportion of participants attempting suicide ( P  < .05). MBCT-S also reduced the proportion with a psychiatric hospitalization. No significant between-group differences emerged on any suicide-related factors., Conclusions: Adding MBCT-S to system-wide suicide prevention efforts produced mixed findings on the primary outcome (suicide events) and promising findings on other important outcomes (suicide attempts, psychiatric hospitalizations). MBCT-S should continue to be examined in future research., Trial Registration: ClinicalTrials.gov identifier: NCT01872338., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Tuberculosis (TB) is still a major worldwide health threat and primarily a lung disease. The innate immune response against Mycobacterium tuberculosis (Mtb) is orchestrated by dendritic cells, macrophages, neutrophils, natural killer cells and apparently mast cells (MCs). MCs are located at mucosal sites including the lungs and contribute in host-defence against pathogens, but little is known about their role during Mtb infection. This study investigates the location and characteristics of MCs in TB lesions to assess their contribution to TB pathology. To this purpose, number, location and phenotype of MCs was studied in 11 necropsies of pulmonary TB and 3 necropsies of non-TB infected lungs that were used as controls. MCs were localised at pneumonic areas, in the granuloma periphery and particularly abundant in fibrotic tissue. Furthermore, MCs displayed intracellular Mtb and IL-17A and TGF-β immunostaining. These findings were validated by analysing, post-mortem lung tissue microarrays from 44 individuals with pulmonary TB and 25 control subjects. In affected lungs, increased numbers of MCs expressing intracellularly both tryptase and chymase were found at fibrotic sites. Altogether, our data suggest that MCs are recruited at the inflammatory site and that actively produce immune mediators such as proteases and TGF-β that may be contributing to late fibrosis in TB lesions.

Background: Cancer recurrence is a serious problem in breast cancer (BC) patients, and immunogenic cell death (ICD) has been proposed as a strategy to overcome this recurrence. IMMUNEPOTENT CRP (ICRP) acts as an immunomodulator and can be cytotoxic to cancer cells. Thus, we evaluated if ICRP induces ICD in BC cells., Methods: Immunogenicity of ICRP-induced cell death was evaluated in vitro, analysing the principal biochemical characteristics of ICD in MCF-7, MDA-MB-231 and 4T1 cells. Ex vivo, we assessed the ability of killed cancer cells (KCC) obtained from ICRP-treated 4T1 cells (ICRP-KCC) to induce DC maturation, T-cell priming and T-cell-mediated cancer cytotoxicity. In vivo, we evaluated tumour establishment and antitumour immune memory after prophylactic ICRP-KCC vaccination in BALB/c mice., Results: ICRP induced caspase-independent, ROS-dependent cell death, autophagosome formation, P-eIF2α, chaperone protein exposure, CD47 loss, ATP and HMBG1 release in BC cells. Additionally, ICRP-KCC promoted DC maturation, which triggered T-cell priming and cancer cytotoxicity. Prophylactic vaccination with ICRP-KCC prevented tumour establishment and induced long-term antitumour memory in BALB/c mice, involving DC maturation in lymph nodes, CD8+ T-cell augmentation in lymph nodes, peripheral blood and tumour site and ex vivo tumour-specific cytotoxicity by splenocytes., Conclusions: ICRP induces ICD in BC cells, leading to long-term antitumour memory.

Objective: To examine the effect of anterior cruciate ligament (ACL) reconstruction on spinal-reflex and corticospinal excitability of the quadriceps muscle., Methods: A comprehensive electronic database search was performed to identify studies that objectively measured Hoffmann reflex to muscle response ratio, motor threshold, and motor evoked potentials after ACL reconstruction. Pooled standardized mean differences (SMDs) were computed using a random effects meta-analysis model., Results: A total of 13 studies were eligible for analysis. The Hoffmann reflex to muscle response ratio was significantly higher on both the reconstructed and non-reconstructed legs when compared with the healthy control leg (SMD = 0.28, 95% confidence interval (95%CI): 0.08-0.49, p = 0.006 and SMD = 0.22, 95%CI: 0.04-0.40, p = 0.016, respectively) but did not differ between legs (SMD = 0.10, 95%CI: -0.01 to 0.21, p = 0.078). The motor threshold was significantly higher on both the reconstructed (SMD = 0.76, 95%CI: 0.40-1.12, p < 0.001) and non-reconstructed legs (SMD = 0.47, 95%CI: 0.00-0.95, p = 0.049) when compared with the legs of healthy controls. The reconstructed leg also had a higher motor threshold when compared with the non-reconstructed leg (SMD = 0.20, 95%CI: 0.06-0.34, p = 0.005). These changes were paralleled by bilateral reductions in quadriceps strength (ACL reconstructed: SMD = -0.78, 95%CI: -1.07 to -0.49, p < 0.001; non-reconstructed: SMD = -0.32, 95%CI: -0.63 to -0.01, p = 0.042) and quadriceps voluntary activation (ACL reconstructed: SMD = -0.73, 95%CI: -0.97 to -0.50, p < 0.001; non-reconstructed: SMD = -0.55, 95%CI: -0.82 to -0.27, p < 0.001) when compared with healthy controls., Conclusion: There is increased excitability of the spinal-reflex pathways and reduced excitability of the corticospinal pathways following ACL reconstruction. These changes are paralleled by reductions in quadriceps strength and voluntary activation, suggesting that rehabilitation interventions should focus on normalizing the excitability of neural pathways to effectively address quadriceps dysfunction after ACL reconstruction., (Copyright © 2020. Production and hosting by Elsevier B.V.)

Both, aberrant mast cell responses and complement activation contribute to allergic diseases. Since mast cells are highly responsive to C3a and C5a, while Interleukin-33 (IL-33) is a potent mast cell activator, we hypothesized that IL-33 critically regulates mast cell responses to complement anaphylatoxins. We sought to understand whether C3a and C5a differentially activate primary human mast cells, and probe whether IL-33 regulates C3a/C5a-induced mast cell activities. Primary human mast cells were generated from peripheral blood precursors or isolated from healthy human lung tissue, and mast cell complement receptor expression, degranulation, mediator release, phosphorylation patterns, and calcium flux were assessed. Human mast cells of distinct origin express constitutively higher levels of C3aR1 than C5aR1, and both receptors are downregulated by anaphylatoxins. While C3a is a potent mast cell degranulation inducer, C5a is a weaker secretagogue with more delayed effects. Importantly, IL-33 potently enhances the human mast cell reactivity to C3a and C5a (degranulation, cytokine and chemokine release), independent of changes in C3a or C5a receptor expression or the level of Ca 2+ influx. Instead, this reflects differential dynamics of intracellular signaling such as ERK1/2 phosphorylation. Since primary human mast cells respond differentially to anaphylatoxin stimulation, and that IL-33 is a key regulator of mast cell responses to complement anaphylatoxins, this is likely to aggravate Th2 immune responses. This newly identified cross-regulation may be important for controlling exacerbated complement- and mast cell-dependent Th2 responses and thus provides an additional rationale for targeting anti-IL33 therapeutically in allergic diseases., Competing Interests: LR is an employee at GSK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 West, Bahri, Garcia-Rodriguez, Sweetland, Wileman, Shah, Montero, Rapley and Bulfone-Paus.)

Poly(ADP-ribose) polymerase 7 (PARP-7) has emerged as a critically important member of a large enzyme family that catalyzes ADP-ribosylation in mammalian cells. PARP-7 is a critical regulator of the innate immune response. What remains unclear is the mechanism by which PARP-7 regulates this process, namely because the protein targets of PARP-7 mono-ADP-ribosylation (MARylation) are largely unknown. Here, we combine chemical genetics, proximity labeling, and proteome-wide amino acid ADP-ribosylation site profiling for identifying the direct targets and sites of PARP-7-mediated MARylation in a cellular context. We found that the inactive PARP family member, PARP-13-a critical regulator of the antiviral innate immune response-is a major target of PARP-7. PARP-13 is preferentially MARylated on cysteine residues in its RNA binding zinc finger domain. Proteome-wide ADP-ribosylation analysis reveals cysteine as a major MARylation acceptor of PARP-7. This study provides insight into PARP-7 targeting and MARylation site preference., Competing Interests: KR, SB, IK, IS, DH, MR, DG, LD, JM, MN, MC No competing interests declared, (© 2021, Rodriguez et al.)

We describe a case of croup in a 14-month-old boy caused by severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019. The patient presented with classic signs and symptoms consistent with croup. Workup was remarkable for a positive point-of-care test for severe acute respiratory syndrome coronavirus 2. This case represents recognition of a new clinical entity caused by coronavirus disease 2019., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Purpose: This study investigated associations between psychiatric symptom severity and delay in seeking general medical services among individuals with serious mental illness., Methods: The association of psychiatric symptom severity, measured by the Positive and Negative Syndrome Scale (PANSS), and general medical care delay was examined among 271 patients at two urban, outpatient psychiatric clinics., Results: Higher scores for PANSS paranoid/belligerence were associated with delays in accessing general medical care (adjusted odds ratio [AOR]=1.46, 95% confidence interval [CI]=1.04-2.01, p=.025). Higher scores on the depression symptom cluster were also associated with care delay (AOR=1.43, 95% CI=1.06-1.93, p=.018). Other symptom types showed no associations with care delay., Conclusion: Severity of specific psychiatric symptoms was associated with delays in seeking general medical care among people with serious mental illness. Increased focus on psychiatric symptom management may reduce medical care delay, thereby reducing the elevated morbidity and mortality among this population.

Understanding host immune function and ecoimmunology is increasingly important at a time when emerging infectious diseases (EIDs) threaten wildlife. One EID that has emerged and spread widely in recent years is chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), which is implicated unprecedented amphibian declines around the world. The impacts of Bd have been severe for many amphibian species, but some populations have exhibited signs of persistence, and even recovery, in some regions. Many mechanisms may underpin this pattern and amphibian immune responses are likely one key component. Although we have made great strides in understanding amphibian immunity, the complement system remains poorly understood. The complement system is a nonspecific, innate immune defense that is known to enhance other immune responses. Complement activation can occur by three different biochemical pathways and result in protective mechanisms, such as inflammation, opsonization, and pathogen lysis, thereby providing protection to the host. We currently lack an understanding of complement pathway activation for chytridiomycosis, but several studies have suggested that it may be a key part of an early and robust immune response that confers host resistance. Here, we review the available research on the complement system in general as well as amphibian complement responses to Bd infection. Additionally, we propose future research directions that will increase our understanding of the amphibian complement system and other immune responses to Bd. Finally, we suggest how a deeper understanding of amphibian immunity could enhance the conservation and management of amphibian species that are threatened by chytridiomycosis., (© 2020 The Authors. Journal of Experimental Zoology Part A: Ecological Genetics and Physiology published by Wiley Periodicals LLC.)

Purpose of Review: The purpose of this article is to highlight how sex differences in the gut-brain axis may contribute to the discrepancies in incidence of neurodevelopmental, psychiatric, and neurodegenerative disorders between females and males. We focus on autism spectrum disorder, psychotic disorders, stress and anxiety disorders, depression, Alzheimer's disease, and Parkinson's disease and additionally discuss the comorbidity between inflammatory bowel disorder and mental health disorders., Recent Findings: Human and animal studies show that sex may modify the relationship between the gut or immune system and brain and behavior. Sex also appears to modify the effect of microbial treatments such as probiotics and antibiotics on brain and behavior. There is emerging evidence that assessing the role of sex in the gut-brain axis may help elucidate the etiology of and identify effective treatments for neurodevelopmental, psychiatric, and neurodegenerative disorders.

Objective: The relative contribution of muscle size and voluntary activation (VA) on quadriceps strength after anterior cruciate ligament (ACL) reconstruction remains inconclusive. Here, we aimed to determine the contributions of muscle size and VA on quadriceps strength in ACL-reconstructed patients and determine if contributions were similar if unilateral outcomes (i.e. ACL-reconstructed limb) or the LSI was used., Design: A cross-sectional study., Setting: A university research laboratory., Participants: Sixteen individuals 6-12 months after ACL reconstruction (Age: 22.3 ± 6.0yr, Height: 1.7 ± 0.1 m, Mass: 68.7 ± 11.5 kg) were recruited., Main Outcome Measures: Quadriceps isometric strength and VA, via the interpolated triplet technique, were assessed bilaterally. Ultrasound images were acquired of the vastus lateralis to calculate cross-sectional area (CSA) in both legs. LSI's were computed for all variables by expressing values of the reconstructed leg as a percent of the non-reconstructed leg. Separate stepwise linear regressions were performed to examine the contribution of VA and CSA on quadriceps strength. Model 1 used LSI for all outcomes and model 2 used outcomes from the reconstructed leg., Results: We observed between limb deficits of 27.78% in quadriceps strength, 13.61% in vastus lateralis CSA, and 13.18% in VA (P < 0.05). Strength LSI was significantly predicted by VA LSI (R 2  = 0.45, P < 0.01), but not by CSA LSI (R 2  = 0.01, P =0.87). Reconstructed leg strength was significantly predicted by VL CSA (R 2  = 0.50, P < 0.01) but not quadriceps VA (R 2  = 0.08, P =0.11)., Conclusions: The contributions of VA and CSA on quadriceps PT differed greatly if LSI or reconstructed leg outcomes were used. Evaluation of VA and CSA in unison may be provide a more holistic understanding of the sources of muscle weakness after ACL reconstruction., Competing Interests: Declaration of competing interest None Declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)