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This study addresses the potential to reverse age-associated morbidity by establishing methods to restore the aged hematopoietic system. Parabiotic animal models indicated that young secretome could restore aged tissues, leading us to establish a heterochronic transwell system with aged mobilized peripheral blood (MPB), co-cultured with young MPB or umbilical cord blood (UCB) cells. Functional studies and omics approaches indicate that the miRNA cargo of microvesicles (MVs) restores the aged hematopoietic system. The in vitro findings were validated in immune deficient (NSG) mice carrying an aged hematopoietic system, improving aged hallmarks such as increased lymphoid:myeloid ratio, decreased inflammation and cellular senescence. Elevated MYC and E2F pathways, and decreased p53 were key to hematopoietic restoration. These processes require four restorative miRs that target the genes for transcription/differentiation, namely PAX and phosphatase PPMIF. These miRs when introduced in aged cells were sufficient to restore the aged hematopoietic system in NSG mice. The aged MPBs were the drivers of their own restoration, as evidenced by the changes from distinct baseline miR profiles in MPBs and UCB to comparable expressions after exposure to aged MPBs. Restorative natural killer cells eliminated dormant breast cancer cells in vivo, indicating the broad relevance of this cellular paradigm - preventing and reversing age-associated disorders such as clearance of early malignancies and enhanced responses to vaccine and infection.

Knee abduction/adduction moment and knee internal rotation moment are known surrogate measures of anterior cruciate ligament (ACL) load during tasks like sidestepping and single-leg landing. Previous experimental literature has shown that a variety of kinematic strategies are associated or correlated with ACL injury risk; however, the optimal kinematic strategies needed to reduce peak knee moments and ACL injury are not well understood. To understand the complex, multifaceted kinematic factors underpinning ACL injury risk and to optimize kinematics to prevent the ACL injury, a musculoskeletal modeling and simulation experimental design was used. A 14-segment, 37-degree-of-freedom, dynamically consistent skeletal model driven by force/torque actuators was used to simulate whole-body single-leg jump landing kinematics. Using the residual reduction algorithm in OpenSim, whole-body kinematics were optimized to reduce the peak knee abduction/adduction and internal/external rotation moments simultaneously. This optimization was repeated across 30 single-leg jump landing trials from 10 participants. The general optimal kinematic strategy was to bring the knee to a more neutral alignment in the transverse plane and frontal plane (featured by reduced hip adduction angle and increased knee adduction angle). This optimized whole-body kinematic strategy significantly reduced the peak knee abduction/adduction and internal rotation moments, transferring most of the knee load to the hip.

Background Coronavirus Disease 2019 (COVID-19) has caused over 1 200 000 deaths worldwide as of November 2020. However, little is known about the clinical outcomes among hospitalized patients with active COVID-19 after in-hospital cardiac arrest (IHCA). Aim We aimed to characterize outcomes from IHCA in patients with COVID-19 and to identify patient- and hospital-level variables associated with 30-day survival. Methods We conducted a multicentre retrospective cohort study across 11 academic medical centres in the U.S. Adult patients who received cardiopulmonary resuscitation and/or defibrillation for IHCA between March 1, 2020 and May 31, 2020 who had a documented positive test for Severe Acute Respiratory Syndrome Coronavirus 2 were included. The primary outcome was 30-day survival after IHCA. Results There were 260 IHCAs among COVID-19 patients during the study period. The median age was 69 years (interquartile range 60–77), 71.5% were male, 49.6% were White, 16.9% were Black, and 16.2% were Hispanic. The most common presenting rhythms were pulseless electrical activity (45.0%) and asystole (44.6%). ROSC occurred in 58 patients (22.3%), 31 (11.9%) survived to hospital discharge, and 32 (12.3%) survived to 30 days. Rates of ROSC and 30-day survival in the two hospitals with the highest volume of IHCA over the study period compared to the remaining hospitals were considerably lower (10.8% vs. 64.3% and 5.9% vs. 35.7% respectively, p Conclusions We found rates of ROSC and 30-day survival of 22.3% and 12.3% respectively. There were large variations in centre-level outcomes, which may explain the poor survival in prior studies.

Objectives Investigate how prescribing participant-specific joint co-ordinates during model preparation influences the measurement agreement of inverse kinematic (IK) derived unplanned sidestepping (UnSS) lower limb kinematics in OpenSim in comparison to an established direct kinematic (DK) model. Design Parallel forms repeatability. Methods The lower limb UnSS kinematics of 20 elite female athletes were calculated using: 1) an established DK model (criterion) and, 2) two IK models; one with (IKPC) and one without (IK0) participant-specific joint co-ordinates prescribed during the marker registration phase of model preparation in OpenSim. Time-varying kinematic analyses were performed using one dimensional (1D) statistical parametric mapping (α = 0.05), where zero dimensional (0D) Root Mean Squared Error (RMSE) estimates were calculated and used as a surrogate effect size estimates. Results Statistical differences were observed between the IKPC and DK derived kinematics as well as the IK0 and DK derived kinematics. For the IKPC and DK models, mean kinematic differences over stance for the three dimensional (3D) hip joint, 3D knee joint and ankle flexion/extension (F/E) degrees of freedom (DoF) were 46 ± 40% (RMSE = 5 ± 5°), 56 ± 31% (RMSE = 7 ± 4°) and 3% (RMSE = 2°) respectively. For the IK0 and DK models, mean kinematics differences over stance for the 3D hip joint, 3D knee joint and ankle F/E DoF were 70 ± 53% (RMSE = 14 ± 11°), 46 ± 48% (RMSE = 8 ± 7°) and 100% (RMSE = 11°) respectively. Conclusions Prescribing participant-specific joint co-ordinates during model preparation improves the agreement of IK derived lower limb UnSS kinematics in OpenSim with an established DK model, as well as previously published in-vivo knee kinematic estimates.

In the bone marrow (BM), breast cancer cells (BCC) can survive in dormancy for decades as cancer stem cells (CSC), resurging as tertiary metastasis. The endosteal region where BCCs exist as CSCs poses a challenge to target them, mostly due to the coexistence of endogenous hematopoietic stem cells. This study addresses the early period of dormancy when BCCs enter BM at the perivascular region to begin the transition into CSCs, which we propose as the final step in dormancy. A two-step process comprises the Wnt-β-catenin pathway mediating BCC dedifferentiation into CSCs at the BM perivascular niche. At this site, BCCs responded to two types of mesenchymal stem cell (MSC)–released extracellular vesicles (EV) that may include exosomes. Early released EVs began the transition into cycling quiescence, DNA repair, and reorganization into distinct BCC subsets. After contact with breast cancer, the content of EVs changed (primed) to complete dedifferentiation into a more homogeneous population with CSC properties. BCC progenitors (Oct4alo), which are distant from CSCs in a hierarchical stratification, were sensitive to MSC EVs. Despite CSC function, Oct4alo BCCs expressed multipotent pathways similar to CSCs. Oct4alo BCCs dedifferentiated and colocalized with MSCs (murine and human BM) in vivo. Overall, these findings elucidate a mechanism of early dormancy at the BM perivascular region and provide evidence of epigenome reorganization as a potential new therapy for breast cancer. Significance: These findings describe how the initial process of dormancy and dedifferentiation of breast cancer cells at the bone marrow perivascular niche requires mesenchymal stem cell–derived exosomes, indicating a potential target for therapeutic intervention.

Embaràs i malaltia cardíaca; Resultats de l’embaràs; Transposició de les grans artèries Embarazo y enfermedad cardíaca; Resultados del embarazo; Transposición de las grandes arterias Pregnancy and cardiac disease; Pregnancy outcomes, Transposition of the great arteries Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate. Funding from “Zabawas Foundation” and “De Hoop Foundation” in addition to the support from EURObservational Research Programme (EORP) is greatly acknowledged. Since the start of EORP, the following companies have supported the program: Abbott Vascular Int (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014–2017), Edwards (2016–2019), Gedeon Richter Plc (2014–2016), Menarini Int Op (2009–2012), MSD‐Merck & Co (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2009–2021), and Vifor (2019–2022).

Much research has investigated whole-body postures and associated knee joint loading during unanticipated sidestepping (UnSS). However, no research has considered sport-specific postures in field hockey. The purpose of this study was to investigate differences in trunk and lower limb angle and lower extremity joint moment waveforms during UnSS while holding a hockey stick in a flexed posture (HS-UnSS) and traditional UnSS. Additionally, we aimed to determine if differences in posture during HS-UnSS were associated with changes in knee joint moments. Twelve elite female field hockey athletes underwent 3D motion analysis during UnSS and HS-UnSS. Athletes increased trunk (0-100% of stance phase, hip (0-15%), knee (12-29%; 39-59%; 78-100%) and ankle (41-57%) flexion angles, and increased hip flexion (19-24%; 42-45%; 75-84%) and external rotation moments (75-80%) during HS-UnSS compared with UnSS (

Summary Background Long-lasting insecticidal nets (LLINs) are the primary malaria prevention tool, but their effectiveness is threatened by pyrethroid resistance. We embedded a pragmatic cluster-randomised trial into Uganda's national LLIN campaign to compare conventional LLINs with those containing piperonyl butoxide (PBO), a synergist that can partially restore pyrethroid susceptibility in mosquito vectors. Methods 104 health sub-districts, from 48 districts in Uganda, were randomly assigned to LLINs with PBO (PermaNet 3.0 and Olyset Plus) and conventional LLINs (PermaNet 2.0 and Olyset Net) by proportionate randomisation using an iterative process. At baseline 6, 12, and 18 months after LLIN distribution, cross-sectional surveys were done in 50 randomly selected households per cluster (5200 per survey); a subset of ten households per cluster (1040 per survey) were randomly selected for entomological surveys. The primary outcome was parasite prevalence by microscopy in children aged 2–10 years, assessed in the as-treated population at 6, 12, and 18 months. This trial is registered with ISRCTN, ISRCTN17516395. Findings LLINs were delivered to households from March 25, 2017, to March 18, 2018, 32 clusters were randomly assigned to PermaNet 3.0, 20 to Olyset Plus, 37 to PermaNet 2.0, and 15 to Olyset Net. In the as-treated analysis, three clusters were excluded because no dominant LLIN was received, and four clusters were reassigned, resulting in 49 PBO LLIN clusters (31 received PermaNet 3.0 and 18 received Olyset Plus) and 52 non-PBO LLIN clusters (39 received PermaNet 2.0 and 13 received Olyset Net). At 6 months, parasite prevalence was 11% (386/3614) in the PBO group compared with 15% (556/3844) in the non-PBO group (prevalence ratio [PR] adjusted for baseline values 0·74, 95% CI 0·62–0·87; p=0·0003). Parasite prevalence was similar at month 12 (11% vs 13%; PR 0·73, 95% CI 0·63–0·85; p=0·0001) and month 18 (12% vs 14%; PR 0·84, 95% CI 0·72–0·98; p=0·029). Interpretation In Uganda, where pyrethroid resistance is high, PBO LLINs reduced parasite prevalence more effectively than did conventional LLINs for up to 18 months. This study provides evidence needed to support WHO's final recommendation on use of PBO LLINs. Funding The Against Malaria Foundation, UK Department for International Development, Innovative Vector Control Consortium, and Bill and Melinda Gates Foundation.

Aim There has been a significant reduction in unicompartmental knee arthroplasty (UKA) procedures recorded in Australia. This follows several national joint registry studies documenting high UKA revision rates when compared to total knee arthroplasty (TKA). With the recent introduction of robotically assisted UKA procedures, it is hoped that outcomes improve. This study examines the cumulative revision rate of UKA procedures implanted with a newly introduced robotic system and compares the results to one of the best performing non-robotically assisted UKA prostheses, as well as all other non-robotically assisted UKA procedures. Methods Data from the Australian Orthopaedic Association National Joint Arthroplasty Registry (AOANJRR) for all UKA procedures performed for osteoarthritis (OA) between 2015 and 2018 were analyzed. Procedures using the Restoris MCK UKA prosthesis implanted using the Mako Robotic-Arm Assisted System were compared to non-robotically assisted Zimmer Unicompartmental High Flex Knee System (ZUK) UKA, a commonly used UKA with previously reported good outcomes and to all other non-robotically assisted UKA procedures using Cox proportional hazard ratios (HRs) and Kaplan-Meier estimates of survivorship. Results There was no difference in the rate of revision when the Mako-assisted Restoris UKA was compared to the ZUK UKA (zero to nine months: HR 1.14 (95% CI 0.71 to 1.83; p = 0.596) vs nine months and over: HR 0.66 (95% CI 0.42 to 1.02; p = 0.058)). The Mako-assisted Restoris had a significantly lower overall revision rate compared to the other types of non-robotically assisted procedures (HR 0.58 (95% confidence interval (CI) 0.42 to 0.79); p < 0.001) at three years. Revision for aseptic loosening was lower for the Mako-assisted Restoris compared to all other non-robotically assisted UKA (entire period: HR 0.34 (95% CI 0.17 to 0.65); p = 0.001), but not the ZUK prosthesis. However, revision for infection was significantly higher for the Mako-assisted Restoris compared to the two comparator groups (ZUK: entire period: HR 2.91 (95% CI 1.22 to 6.98; p = 0.016); other non-robotically assisted UKA: zero to three months: HR 5.57 (95% CI 2.17 to 14.31; p < 0.001)). Conclusion This study reports comparable short-term survivorship for the Mako robotically assisted UKA compared to the ZUK UKA and improved survivorship compared to all other non-robotic UKA. These results justify the continued use and investigation of this procedure. However, the higher rate of early revision for infection for robotically assisted UKA requires further investigation. Cite this article: Bone Joint J 2020;102-B(3):319–328

Isolating tumor exosomes (TEX) secreted by cancer cells can provide valuable information about the state of a tumor. Here, we present a method to rapidly isolate TEX using magnetic nanowires (MNWs)...

There is strong evidence linking an athlete's movement technique during sidestepping with anterior cruciate ligament (ACL) injury risk. However, it is unclear how these injurious postures are influenced by prior movement. We aim to describe preparatory trunk and thigh kinematics at toe-off of the penultimate-step and flight-phase angular momenta, and explore their associations with frontal-plane risk factors during unplanned sidestepping maneuvers. We analyzed kinematic and kinetic data of 33 male Australian Football players performing unplanned sidestepping tasks (103 trials). Linear mixed models tested for reliable associations between ACL injury risk during weight acceptance of the execution-step, with preparatory kinematics and angular momenta of the trunk and thigh during the penultimate-step. Multi-planar flight-phase trunk momenta along with hip abduction angle at penultimate-step toe-off were significantly associated with peak knee valgus moments during the execution-step (R2 = .21, P

OBJECTIVE: Assess clinician perceptions of a machine learning-based early warning system to predict severe sepsis and septic shock (EWS 2.0) DESIGN: Prospective observational study SETTING: Tertiary teaching hospital in Philadelphia, PA PATIENTS: Non-ICU admissions November-December 2016 INTERVENTIONS: During a six-week study period conducted five months after EWS 2.0 alert implementation, nurses and providers were surveyed twice about their perceptions of the alert’s helpfulness and impact on care, first within 6 hours of the alert, and again 48 hours post-alert. MEASUREMENTS AND MAIN RESULTS: For the 362 alerts triggered, 180 nurses (50% response rate) and 107 providers (30% response rate) completed the First Survey. Of these, 43 nurses (24% response rate) and 44 providers (41% response rate) completed a Second Survey. Few (24% nurses, 13% providers) identified new clinical findings after responding to the alert. Perceptions of the presence of sepsis at the time of alert were discrepant between nurses (13%) and providers (40%). The majority of clinicians reported no change in perception of the patient’s risk for sepsis (55% nurses, 62% providers). A third of nurses (30%) but few providers (9%) reported the alert changed management. Almost half of nurses (42%) but less than a fifth of providers (16%) found the alert helpful at 6 hours. CONCLUSIONS: In general, clinical perceptions of EWS 2.0 were poor. Nurses and providers differed in their perceptions of sepsis and alert benefits. These findings highlight the challenges of achieving acceptance of predictive and machine learning-based sepsis alerts.

Objectives:Develop and implement a machine learning algorithm to predict severe sepsis and septic shock and evaluate the impact on clinical practice and patient outcomes.Design:Retrospective cohort for algorithm derivation and validation, pre-post impact evaluation.Setting:Tertiary teaching hospital

Background Electromyography (EMG) is frequently used as a guide for exercise rehabilitation progression following rotator cuff repair. Knowledge of EMG activity during passive and active-assisted exercises may help guide clinicians when considering exercise prescription in the early post-operative period. # Purpose The purpose of this study was to investigate EMG activity of the rotator cuff and deltoid musculature during passive and active-assisted shoulder range of motion (ROM) exercises commonly performed in post-operative rehabilitation. # Study Design Descriptive cohort laboratory study using healthy subjects. # Methods In sixteen active healthy volunteers, surface and fine-wire EMG activity was measured in the supraspinatus, infraspinatus, subscapularis, and anterior, middle and posterior deltoid muscles during eight common ROM exercises. Mean %MVIC values and 95% confidence intervals were used to rank exercises from the least to the most amount of muscular activity generated during the exercises. # Results Standard pendulum exercises generated low levels of EMG activity in the supraspinatus and infraspinatus (≤15% MVIC), while active-assisted table slides, and the upright wall slide generated low levels of EMG activity in only the supraspinatus. No exercises were found to generate low levels of muscular activation (≤15% MVIC) in the subscapularis. # Conclusion This study found no clear distinctions between the EMG activity of the supraspinatus or the infraspinatus occurring during common passive and active-assisted ROM exercises. Subdividing ROM exercises based on muscle activity, may not be necessary to guide progression of exercises prior to commencing active motion after rotator cuff repair. # Level of Evidence Level 3b

Ibrutinib is a first-generation Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in autoimmune diseases and has consequently been developed as a positron emission tomography (PET) radiotracer. Herein, we report the automated radiosynthesis of [11C]ibrutinib through 11C-carbonylation of the acrylamide functional group, by reaction of the secondary amine precursor with [11C]CO, iodoethylene, and palladium–NiXantphos. [11C]Ibrutinib was reliably formulated in radiochemical yields of 5.4% ± 2.5% (non-decay corrected; n = 9, relative to starting [11C]CO2), radiochemical purity >99%, and molar activity of 58.8 ± 30.8 GBq/μmol (1.55 ± 0.83 Ci/μmol). Preliminary PET/magnetic resonance imaging with [11C]ibrutinib in experimental autoimmune encephalomyelitis (EAE) mice showed a 49% higher radioactivity accumulation in the spinal cord of mice with EAE scores of 2.5 vs. sham mice.

Resistance in malaria vectors to pyrethroids, the most widely used class of insecticides for malaria vector control, threatens the continued efficacy of vector control tools. Target-site resistance is an important genetic resistance mechanism caused by mutations in the voltage-gated sodium channel (Vgsc) gene that encodes the pyrethroid target-site. Understanding the geographic distribution of target-site resistance, and temporal trends across different vector species, can inform strategic deployment of vector control tools. Here we develop a Bayesian statistical spatiotemporal model to interpret species-specific trends in the frequency of the most common resistance mutations, Vgsc-995S and Vgsc-995F, in three major malaria vector species Anopheles gambiae, An. coluzzii, and An. arabiensis. For nine selected countries, we develop annual predictive maps which reveal geographically-structured patterns of spread of each mutation at regional and continental scales. The results show associations, as well as stark differences, in spread dynamics of the two mutations across the three vector species. The coverage of ITNs was an influential predictor of Vgsc allele frequencies in our models. Our mapped Vgsc allele frequencies are a significant partial predictor of phenotypic resistance to the pyrethroid deltamethrin in An. gambiae complex populations, highlighting the importance of molecular surveillance of resistance mechanisms.

Insecticide resistance in Anopheles mosquitoes is a major obstacle in maintaining the momentum in reducing the malaria burden; mitigating strategies require improved understanding of the underlying mechanisms. Mutations in the target site of insecticides (the voltage gated sodium channel for the most widely used pyrethroid class) and over-expression of detoxification enzymes are commonly reported, but their relative contribution to phenotypic resistance remain poorly understood. Here we present a genome editing pipeline to introduce single nucleotide polymorphisms in An. gambiae which we have used to study the effect of the classical kdr mutation L1014F (L995F based on An. gambiae numbering), one of the most widely distributed resistance alleles. Introduction of 1014F in an otherwise fully susceptible genetic background increased levels of resistance to all tested pyrethroids and DDT ranging from 9.9-fold for permethrin to >24-fold for DDT. The introduction of the 1014F allele was sufficient to reduce mortality of mosquitoes after exposure to deltamethrin treated bednets, even as the only resistance mechanism present. When 1014F was combined with over-expression of glutathione transferase Gste2, resistance to permethrin increased further demonstrating the critical combined effect between target site resistance and detoxification enzymes in vivo. We also show that mosquitoes carrying the 1014F allele in homozygosity showed fitness disadvantages including increased mortality at the larval stage and a reduction in fecundity and adult longevity, which can have consequences for the strength of selection that will apply to this allele in the field., Author summary Escalation of pyrethroid resistance in Anopheles mosquitoes threatens to reduce the effectiveness of our most important tools in malaria control. Studying the mechanisms underlying insecticide resistance is critical to design mitigation strategies. Here, using genome modified mosquitoes, we functionally characterize the most prevalent mutation in resistant mosquitoes, showing that it confers substantial levels of resistance to all tested pyrethroids and undermines the performance of pyrethroid-treated nets. Furthermore, we show that combining this mutation with elevated levels of a detoxification enzyme further increases resistance. The pipeline we have developed provides a robust approach to quantifying the contribution of different combinations of resistance mechanisms to the overall phenotype, providing the missing link between resistance monitoring and predictions of resistance impact.

Performance enhancement and injury prevention are often perceived as opposite sides of a coin, where focusing on improvements of one leads to detriment of the other. In this study, we used physics-based simulations with novel optimization methods to find participant-specific, whole-body mechanics of volleyball spiking that enhances performance (the peak height of the hitting hand and its forward velocity) while minimizing injury risk. For the volleyball spiking motion, the shoulder is the most common injury site because of the high mechanical loads that are most pronounced during the follow-through phase of the movement. We analyzed 104 and 209 spiking trials across 13 participants for the power and follow-through phases, respectively. During the power phase, simulations increased (p &lt, 0.025) the peak height of the hitting wrist by 1% and increased (p &lt, 0.025) the forward wrist velocity by 25%, without increasing peak shoulder joint torques, by increasing the lower-limb forward swing (i.e., hip flexion, knee extension). During the follow-through phase, simulations decreased (p &lt, 0.025) peak shoulder joint torques by 75% elicited by synergistic rotation of the trunk along the pathway of the hitting arm. Our results show that performance enhancement and injury prevention are not mutually exclusive and may both be improved simultaneously, potentially leading to better-performing and injury-free athletes.

Traumatic brain injury (TBI) is a predisposing factor for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). Although defects in nucleocytoplasmic transport (NCT) is reported ALS and other neurodegenerative diseases, whether defects in NCT occur in TBI remains unknown. We performed proteomic analysis on Drosophila exposed to repeated TBI and identified resultant alterations in several novel molecular pathways. TBI upregulated nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) proteins as well as alter nucleoporin stability. Traumatic injury disrupted RanGAP1 and NPC protein distribution in flies and a rat model and led to coaggregation of NPC components and TDP-43. In addition, trauma-mediated NCT defects and lethality are rescued by nuclear export inhibitors. Importantly, genetic upregulation of nucleoporins in vivo and in vitro triggered TDP-43 cytoplasmic mislocalization, aggregation, and altered solubility and reduced motor function and lifespan of animals. We also found NUP62 pathology and elevated NUP62 concentrations in postmortem brain tissues of patients with mild or severe CTE as well as co-localization of NUP62 and TDP-43 in CTE. These findings indicate that TBI leads to NCT defects, which potentially mediate the TDP-43 pathology in CTE.

Multi-planar forces and moments are known to injure the anterior cruciate ligament (ACL). In ACL injury risk studies, however, the uni-planar frontal plane external knee abduction moment is frequently studied in isolation. This study aimed to determine if the frontal plane knee moment (KM-Y) could classify all individuals crossing a risk threshold compared to those classified by a multi-planar non-sagittal knee moment vector (KM-YZ). Recreationally active females completed three sports tasks-drop vertical jumps, single-leg drop vertical jumps and planned sidesteps. Peak knee abduction moments and peak non-sagittal resultant knee moments were obtained for each task, and a risk threshold of the sample mean plus 1.6 standard deviations was used for classification. A sensitivity analysis of the threshold from 1-2 standard deviations was also conducted. KM-Y did not identify all participants who crossed the risk threshold as the non-sagittal moment identified unique individuals. This result was consistent across tasks and threshold sensitivities. Analysing the peak uni-planar knee abduction moment alone is therefore likely overly reductionist, as this study demonstrates that a KM-YZ threshold identifies 'at risk' individuals that a KM-Y threshold does not. Multi-planar moment metrics such as KM-YZ may help facilitate the development of screening protocols across multiple tasks. ispartof: SPORTS BIOMECHANICS vol:22 issue:1 pages:80-90 ispartof: location:England status: published

Background Maternal congenital heart disease (CHD) is the most common cardiac condition to complicate pregnancy and women now become pregnant even with complex CHD. The Registry Of Pregnancy And Cardiac disease (ROPAC) examines the relationship between maternal heart disease and pregnancy outcome. Methods The ESC EORP ROPAC is a worldwide prospective registry of pregnancies in women with structural heart disease (n=5739, recruiting between 2007-2018), including CHD. Maternal and fetal outcomes were examined in all women with CHD. Multivariable regression was used to identify associations with a composite endpoint of maternal mortality and/or heart failure. Results In CHD pregnancies (n=3295, mean age 29 years), maternal mortality was 0.3% and heart failure occurred in 6.6%. Preterm births (16%) and Caesarean section (46.3%) were higher than global averages, but otherwise cardiac, obstetric and fetal outcomes were good. The composite endpoint was highest in complex CHD: Eisenmenger syndrome (58.1%), congenitally corrected transposition of the great arteries (12.8%), Fontan circulation (11.2%), double outlet right ventricle (11.1%). Pre-pregnancy signs of heart failure (OR 10.6, 95% CI 7.1-16), multiple gestation (4.6, 2-10.8), pulmonary hypertension (2.5, 1.5-4), estimated LVEF Conclusion Overall pregnancy outcomes for women with CHD are good but women with complex CHD are at increased risk of complications. Pre-pregnancy assessment can identify women at increased risk of an adverse outcome and should be used to counsel women appropriately.

Insecticide resistance in Anopheles mosquitoes is a major obstacle in maintaining the momentum in reducing the malaria burden; mitigating strategies require improved understanding of the underlying mechanisms. Mutations in the target site of insecticides (the voltage gated sodium channel for the most widely used pyrethroid class) and over-expression of detoxification enzymes are commonly reported, but their relative contribution to phenotypic resistance remain poorly understood. Here we present a genome editing pipeline to introduce single nucleotide polymorphisms in An. gambiae which we have used to study the effect of the classical kdr mutation L1014F (L995F based on An. gambiae numbering), one of the most widely distributed resistance alleles. Introduction of 1014F in an otherwise fully susceptible genetic background increased levels of resistance to all tested pyrethroids and DDT ranging from 9.9-fold for permethrin to >24-fold for DDT. The introduction of the 1014F allele was sufficient to reduce mortality of mosquitoes after exposure to deltamethrin treated bednets, even as the only resistance mechanism present. When 1014F was combined with over-expression of glutathione transferase Gste2, resistance to permethrin increased further demonstrating the critical combined effect between target site resistance and detoxification enzymes in vivo. We also show that mosquitoes carrying the 1014F allele in homozygosity showed fitness disadvantages including increased mortality at the larval stage and a reduction in fecundity and adult longevity, which can have consequences for the strength of selection that will apply to this allele in the field.Author SummaryEscalation of pyrethroid resistance in Anopheles mosquitoes threatens to reduce the effectiveness of our most important tools in malaria control. Studying the mechanisms underlying insecticide resistance is critical to design mitigation strategies. Here, using genome modified mosquitoes, we functionally characterize the most prevalent mutation in resistant mosquitoes, showing that it confers substantial levels of resistance to all tested pyrethroids and undermines the performance of pyrethroid-treated nets. Furthermore, we show that combining this mutation with elevated levels of a detoxification enzyme further increases resistance. The pipeline we have developed provides a robust approach to quantifying the contribution of different combinations of resistance mechanisms to the overall phenotype, providing the missing link between resistance monitoring and predictions of resistance impact.

Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration. We observed the expression levels of DEAD-Box Helicase 17 (DDX17) to be significantly downregulated in response to mutant FUS in Drosophila and human cell lines. Mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and physically interacts with DDX17 through the RGG1 domain of FUS. Ectopic expression of DDX17 reduces cytoplasmic mislocalization and sequestration of mutant FUS into cytoplasmic stress granules. We identified DDX17 as a novel regulator of the DNA damage response pathway whose upregulation repairs defective DNA damage repair machinery caused by mutant neuronal FUS ALS. In addition, we show DDX17 is a novel modifier of FUS-mediated neurodegeneration in vivo. Our findings indicate DDX17 is downregulated in response to mutant FUS, and restoration of DDX17 levels suppresses FUS-mediated neuropathogenesis and toxicity in vivo.

Objective: This review identified and evaluated apps intended to aid women in conception that were available across major mobile platforms; secondary objectives were to highlight additional criteria and considerations when evaluating conception-related apps. Data Sources: Apple iTunes and Google Play stores were searched using the keywords conception, fertility, and pregnant. Data Selection: Included apps were as follows: contained in the first 50 search results; presented in English; intended for layperson use; updated July 1, 2018, or after; marketed as a conception aid; and used a defined fertility tracking method. Excluded apps were intended for men only, marketed for contraception only, promoted a single fertility service or branded product, or not found in both app stores. Data Extraction: Apps were evaluated using the adapted APPLICATIONS Scoring System. Two additional criteria were assessed: inclusion of a privacy policy and inclusion of a search function, medical terminology glossary, or Frequently Asked Questions section. Data Synthesis: A total of 300 apps were screened; 7 app pairs were analyzed. Scores ranged from 9 to 13 of a possible 15 points (mean = 11; median = 11). No app reported advisement from a health professional during development. Relevance to Patient Care in Clinical Practice: Widely available apps that score highly per the adapted APPLICATIONS Scoring System may be considered for use by and recommended to women seeking apps useful for conception. Conclusion: Evaluation tools should evolve as app features change. Criteria related to privacy and search functions that promote health literacy should be considered for future app evaluation tools.

Background Long-lasting insecticidal nets (LLINs) are a key malaria control intervention, but their effectiveness is threatened by resistance to pyrethroid insecticides. Some new LLINs combine pyrethroids with piperonyl butoxide (PBO), a synergist that can overcome P450-based metabolic resistance to pyrethroids in mosquitoes. In 2017–2018, the Ugandan Ministry of Health distributed LLINs with and without PBO through a national mass-distribution campaign, providing a unique opportunity to rigorously evaluate PBO LLINs across different epidemiological settings. Methods/design Together with the Ministry of Health, we embedded a cluster-randomised trial to evaluate the impact of LLINs delivered in the 2017–2018 national campaign. A total of 104 clusters (health sub-districts) in Eastern and Western Uganda were involved, covering 48 of 121 (40%) districts. Using adaptive randomisation driven by the number of LLINs available, clusters were assigned to receive one of four types of LLINs, including two brands with PBO: 1) PermaNet 3.0 (n = 32) and 2) Olyset Plus (n = 20); and two without PBO: 3) PermaNet 2.0 (n = 37) and 4) Olyset Net (n = 15). We are conducting cross-sectional community surveys in 50 randomly selected households per cluster (5200 households per survey) and entomological surveillance for insecticide resistance in up to 10 randomly selected households enrolled in the community surveys per cluster (1040 households per survey) at baseline and 6, 12, and 18 months after LLIN distribution. Net durability and bio-efficacy will be assessed in 400 nets withdrawn from households with replacement at 12 months. The primary trial outcome is parasite prevalence as measured by microscopy in children aged 2–10 years in the follow-up surveys. Discussion PBO LLINs are a promising new tool to reduce the impact of pyrethroid resistance on malaria control. The World Health Organization has issued a preliminary endorsement of PBO LLINs, but additional epidemiological evidence of the effect of PBO LLINs is urgently needed. The results of this innovative, large-scale trial embedded within a routine national distribution campaign will make an important contribution to the malaria control policy in Uganda and throughout Africa, where pyrethroid resistance in malaria vectors has increased dramatically. This model of evaluation could be a paradigm for future assessment of malaria control interventions. Trial registration ISRCTN, ISRCTN17516395. Registered on 14 February 2017. World Health Organization Trial Registration Data Set See Additional file 1. Electronic supplementary material The online version of this article (10.1186/s13063-019-3382-8) contains supplementary material, which is available to authorized users.

The effectiveness of the plantarflexor muscle group to generate desired plantarflexion moments is modulated by the geometry of the Achilles tendon moment arm (ATMA). Children with cerebral palsy (CP) frequently have reduced plantarflexion function, which is commonly attributed to impaired muscle structure and function, however little attention has been paid to the potential contribution of ATMA geometry. The use of musculoskeletal modelling for the simulation of gait and understanding of gait mechanics, rely on accuracy of ATMA estimates. This study aimed to compare 3D in-vivo estimates of ATMA of adults, children with CP and typically developing (TD) children, as well as compare 3D in-vivo estimates to linearly scaled musculoskeletal model estimates. MRI scans for eight children with CP, 11 TD children and nine healthy adults were used to estimate in-vivo 3D ATMA using a validated method. A lower limb musculoskeletal model was linearly scaled to individual tibia length to provide a scaled ATMA estimate. Normalised in-vivo 3D ATMA for children with CP was 17.2% ± 2.0 tibia length, which was significantly larger than for TD children (15.2% ± 1.2, p = 0.013) and adults (12.5% ± 0.8, p 0.001). Scaled ATMA estimates from musculoskeletal models significantly underestimated in-vivo estimates for all groups, by up to 34.7%. The results of this study show children with CP have larger normalised 3D ATMA compared to their TD counterparts, which may have implications in understanding reduced plantarflexor function and the efficacy of surgical interventions whose aim is to modify the musculoskeletal geometry of this muscle group.

PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions., Assessment of PD-1 and PD-L1 expression can be predictive of immunotherapy response in lung cancer. Here the authors assess the clinical toxicity, safety and quality of non-invasive imaging of PD-1 and PD-L1 expression in 13 patients with advanced lung cancer prior to treatment with immunotherapy and show it correlates with response.

The practice of assigning "case level" biopsy Grade Group (GG) or Gleason Score is variable. To our knowledge, a comparison of the concordance of different biopsy "case level" GG with the prostatectomy GG has not been done in a post-2005 prostate cancer cohort. We evaluated the GG in 2527 patients who had biopsy and radical prostatectomy performed at our institution between 2005 and 2014. We compared the agreements, the upgrades, and the downgrades of 3 different "case level" biopsy GG, with the final GG: (1) Global GG (sum of most prevalent and highest Gleason grade in any biopsy part/site-specific specimen); (2) Highest GG (found in any biopsy part/site-specific specimen); and (3) Largest Volume Cancer GG (found in any biopsy part/site-specific specimen). The concordance between the biopsy and the final GG were evaluated using weighted kappa (κ) coefficient. The biopsy Global GG, Highest GG, and Largest Volume Cancer GG were the same as the final GG in 60.4%, 57.1%, and 54.3% cases, respectively (weighted κ values: 0.49, 0.48, and 0.44, respectively). When final GG contained tertiary 5, the overall GG agreement decreased: Global GG 41.5%, Highest GG 40.3%, and Largest Volume Cancer GG 37.1% (weighted κ: 0.22, 0.21, and 0.18, respectively). A subset analysis for cases in which the biopsy Global GG and Highest GG were different (n=180) showed an agreement of 62.4% (weighted κ: 0.37) and 18.8% (weighted κ: 0.16), respectively. In patients without a tertiary Gleason pattern on radical prostatectomy, the Global GG and the Highest GG were identical in 92.4% of biopsies. Assigning a biopsy "case level" Global GG versus using the Highest GG and the Largest Volume Cancer GG resulted in comparable and slightly improved agreement with the final GG in this cohort.

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal mRNAs. The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by qRT-PCR, while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups (“healthy”, “osteosarcoma”, “other bone tumor”, or “non-neoplastic disease”). Pre-treatment samples from osteosarcoma cases were used as the training set and a validation set from post-treatment samples was used for testing, classifying as “osteosarcoma–detected” or “osteosarcoma–NOT detected”. Dogs in a validation set whose post-treatment samples were classified as “osteosarcoma–NOT detected” had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof-of-concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response.Abstract Figure

Background Minimally invasive spine surgery (MISS) has the potential to further advance with the use of robot-assisted (RA) techniques. While RA pedicle screw placement has been extensively investigated, there is a lack of literature on the use of the robot for other tasks, such as accessing Kambin's triangle in percutaneous lumbar interbody fusion (percLIF). Objective To characterize the surgical feasibility and preliminary outcomes of an initial case series of 10 patients receiving percLIF with RA cage placement via Kambin's triangle. Methods We performed a single-center, retrospective review of patients undergoing RA percLIF using robot-guided trajectory to access Kambin's triangle for cage placement. Patients undergoing RA percLIF were eligible for enrollment. Baseline health and demographic information in addition to peri- and postoperative data was collected. The dimensions of each patient's Kambin's triangle were measured. Results Ten patients and 11 levels with spondylolisthesis were retrospectively reviewed. All patients successfully underwent the planned procedure without perioperative complications. Four patients underwent their procedure with awake anesthesia. The average dimension of Kambin's triangle was 66.3 m2. With the exception of 1 patient who stayed in the hospital for 7 d, the average length of stay was 1.2 d, with 2 patients discharged the day of surgery. No patients suffered postoperative motor or sensory deficits. Spinopelvic parameters and anterior and posterior disc heights were improved with surgery. Conclusion As MISS continues to evolve, further exploration of robot-guided surgical practice, such as our technique, will lead to creative solutions to challenging anatomical variation and overall improved patient care.

Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) share clinical, neuropathological, and genetic features. This includes common genetic disease-causing mutations such as the expanded G4C2 repeat in the C9orf72 gene (C9-ALS/FTLD) and cytoplasmic and insoluble protein depositions of the TDP-43 in degenerating regions of the brain and spinal cord. Proposed mechanisms of toxicity in C9-ALS/FTLD are the production of repeat expansion transcripts and their dipeptide repeat proteins (DPRs) products which are hypothesized to drive nucleocytoplasmic transport defects. The nuclear pore complex (NPC) regulates nucleocytoplasmic trafficking by creating a selectivity and permeability barrier comprised of phenylalanine glycine nucleoporins (FG nups). However, the relationship between FG nups and TDP-43 pathology remains elusive. Here, we define two mechanisms through which TDP-43 promotes Nup62 nuclear depletion and cytoplasmic in C9-ALS/FTLD and sALS/FTLD. In C9-ALS/FTLD, poly-GR initiates the formation of TDP-43 containing stress granules (SGs) that trigger the nuclear loss and recruitment of Nup62 in vitro and in vivo. When colocalized, cytoplasmic TDP-43:Nup62 assemblies mature into insoluble inclusions through an interaction within the TDP-43 nuclear localization sequence (NLS) suggesting Nup62 promotes deleterious phase transitions. Absent of poly-GR, aberrant TDP-43 phase transitions in the cytoplasm recruits and mislocalizes Nup62 into pathological inclusions. The result of these cytoplasmic Nup62 and TDP-43 interactions are pathological and insoluble TDP-43:Nup62 assemblies that are observed in C9-ALS/FTLD and sALS/FTLD CNS tissue.

Introduction. Longitudinal monitoring of outdoor-biting malaria vector populations is becoming increasingly important in understanding the dynamics of residual malaria transmission. However, the human landing catch (HLC), the gold standard for measuring human biting rates indoors and outdoors, is costly and raises ethical concerns related to increased risk of infective bites among collectors. Consequently, routine data on outdoor-feeding mosquito populations are usually limited due to the lack of a scalable tool with similar sensitivity to outdoor HLC. Methodology. The Anopheles trapping sensitivity of four baited proxy outdoor trapping methods—Furvela tent trap (FTT), host decoy trap (HDT), mosquito electrocuting traps (MET) and outdoor CDC light traps (OLT)—was assessed relative to HLC in a 5x5 replicated Latin square conducted over 25 nights in two villages of western Kenya. Indoor CDC light trap (ILT) was run in one house in each of the compounds with outdoor traps, while additional non-Latin square indoor and outdoor HLC collections were performed in one of the study villages. Results. The MET, FTT, HDT and OLT sampled approximately 4.67, 7.58, 5.69 and 1.98 times more An. arabiensis compared to HLC, respectively, in Kakola Ombaka. Only FTT was more sensitive relative to HLC in sampling of An. funestus in Kakola Ombaka (RR=5.59, 95%CI: 2.49-12.55, P < 0.001) and Masogo (RR=4.38, 95%CI: 1.62-11.80, P = 0.004) and in sampling An. arabiensis in Masogo (RR=5.37, 95%CI: 2.17-13.24, P < 0.001). OLT sampled significantly higher numbers of An. coustani in Kakola Ombaka (RR=3.03, 95%CI: 1.65-5.56, P < 0.001) and Masogo (RR=2.88, 95%CI: 1.15-7.22, P=0.02) compared to HLC. OLT, HLC and MET sampled mostly An. coustani, FTT had similar proportions of An. funestus and An. arabiensis, while HDT sampled predominantly An. arabiensis in both villages. FTT showed close correlation with ILT in vector abundance for all three species at both collection sites. Conclusion. FTT and OLT are simple, easily scalable traps and are potential replacements for HLC in outdoor sampling of Anopheles mosquitoes. However, the FTT closely mirrored indoor CDC light trap in mosquito indices and therefore may be more of an indoor mimic than a true outdoor collection tool. HDT and MET show potential for sampling outdoor host seeking mosquitoes. However, the traps as currently designed may not be feasible for large scale, longitudinal entomological monitoring. Therefore, the baited outdoor CDC light trap may be the most appropriate tool currently available for assessment of outdoor-biting and malaria transmission risk.

Blocking the interaction of the immune checkpoint molecule programmed cell death protein-1 and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression PET imaging may potentially allow for a better prediction of response to programmed cell death protein-1–targeted therapies. Imaging of PD-L1 expression is feasible by PET with the adnectin protein (18)F-BMS-986192. However, radiofluorination of proteins such as BMS-986192 remains complex and labeling yields are low. The goal of this study was therefore the development and preclinical evaluation of a (68)Ga-labeled adnectin protein ((68)Ga-BMS-986192) to facilitate clinical trials. Methods: (68)Ga labeling of DOTA-conjugated adnectin (BXA-206362) was performed in NaOAc-buffer at pH 5.5 (50°C, 15 min). In vitro stability in human serum at 37°C was analyzed using radio-thin layer chromatography and radio-high-performance liquid chromatography. PD-L1 binding assays were performed using the transduced PD-L1–expressing lymphoma cell line U-698-M and wild-type U-698-M cells as a negative control. Immunohistochemical staining studies, biodistribution studies, and small-animal PET studies of (68)Ga-BMS-986192 were performed using PD-L1–positive and PD-L1–negative U-698-M–bearing NSG mice. Results: (68)Ga-BMS-986192 was obtained with quantitative radiochemical yields of more than 97% and with high radiochemical purity. In vitro stability in human serum was at least 95% after 4 h of incubation. High and specific binding of (68)Ga-BMS-986192 to human PD-L1–expressing cancer cells was confirmed, which closely correlates with the respective PD-L1 expression level determined by flow cytometry and immunohistochemistry staining. In vivo, (68)Ga-BMS-986192 uptake was high at 1 h after injection in PD-L1–positive tumors (9.0 ± 2.1 percentage injected dose [%ID]/g) and kidneys (56.9 ± 9.2 %ID/g), with negligible uptake in other tissues. PD-L1–negative tumors demonstrated only background uptake of radioactivity (0.6 ± 0.1 %ID/g). Coinjection of an excess of unlabeled adnectin reduced tumor uptake of PD-L1 by more than 80%. Conclusion: (68)Ga-BMS-986192 enables easy radiosynthesis and shows excellent in vitro and in vivo PD-L1–targeting characteristics. The high tumor uptake combined with low background accumulation at early imaging time points demonstrates the feasibility of (68)Ga-BMS-986192 for imaging of PD-L1 expression in tumors and is encouraging for further clinical applications of PD-L1 ligands.

BACKGROUNDPure arterial malformations (PAMs) are rare vascular anomalies that are commonly mistaken for other vascular malformations. Because of their purported benign natural history, PAMs are often conservatively managed. The authors report the case of a ruptured PAM leading to subarachnoid hemorrhage (SAH) with intraventricular extension that was treated endovascularly.OBSERVATIONSA 38-year-old man presented with a 1-day history of headaches and nausea. A computed tomography scan demonstrated diffuse SAH with intraventricular extension, and angiography revealed a right posterior inferior cerebellar artery–associated PAM. The PAM was treated with endovascular Onyx embolization.LESSONSTo the authors’ knowledge, only 2 other cases of SAH associated with PAM have been reported. In those 2 cases, surgical clipping was pursued for definitive treatment. Here, the authors report the first case of a ruptured PAM treated using an endovascular approach, showing its feasibility as a treatment option particularly in patients in whom open surgery is too high a risk.

While youth with autism spectrum disorder (ASD) are psychiatrically hospitalized at high rates, general psychiatric settings are not designed to meet their unique needs. Previous evaluations of an ASD-Care Pathway (ASD-CP) on a general psychiatric unit revealed sustained reductions in crisis interventions (intramuscular medication use, holds/restraints; Cervantes et al. in J Autism Dev Disord 49(8):3173–3180, https://doi.org/10.1007/s10803-019-04029-6 , 2019; Kuriakose et al. in J Autism Dev Disord 48(12):4082–4089, https://doi.org/10.1007/s10803-018-3666-y , 2018). The current study investigated staff perceptions of the ASD-CP (N = 30), and examined rates of ASD-CP implementation fidelity in relation to patient outcomes (N = 28). Staff identified visual communication aids and reward strategies as most helpful. The number of days of reward identification early in the inpatient stay was associated with fewer crisis interventions later in a patient’s stay.

The primary pain disorders of childhood are highly prevalent but have infrequently been studied collectively. Genetic influences have been suggested to be causally implicated. Surveys were sent to 3909 Australian twin families, assessing the lifetime prevalence of growing pains, migraine, headache, recurrent abdominal pain, low back pain, and persistent pain (not otherwise specified) in pediatric twins and their immediate family members. Comparisons between monozygous (MZ) and dizygous (DZ) twin pair correlations, concordances and odds ratios were performed to assess the contribution of additive genetic influences. Random-effects logistic regression modelling was used to evaluate relationships between twin individuals and their co-twins, mothers, fathers and oldest siblings with the subject conditions. Twin analyses of responses from 1016 families revealed significant influence of additive genetic effects on the presence of growing pains, migraine, and recurrent abdominal pain. The analyses for headache, low back pain, and persistent pain overall did not conclusively demonstrate that genetic influences were implicated more than shared environmental factors. Regression analyses demonstrated varying levels of significance in relationships between family members and twin individuals for the tested conditions, with strongest support for genetic influences in growing pains and migraine. These data, together with previously published association analyses, suggest common causal influences including genes.