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Purpose: Ultrasound biofeedback therapy (UBT) is a relatively new type of technology-assisted speech-language therapy and has shown promise in remediating speech sound disorders. However, there is a current lack of understanding of the barriers and benefits that may influence the usage behavior and clinical decision making for the implementation of UBT from a clinician perspective. In this qualitative study, we explore the perspectives of speech-language pathologists (SLPs) who have used ultrasound biofeedback in programs of speech sound therapy using the unified theory of acceptance and use of technology (UTAUT) model. Method: Seven SLPs who had clinical experience treating speech sound disorders with UBT participated. Semistructured in-depth interviews were conducted and video-recorded. Two coders coded and categorized the transcribed data, with consensus established with a third coder. Using thematic analysis, the data were exploratorily grouped into themes along components of the UTAUT model. Results: The highest number of codes was sorted into the “effort expectancy” theme, followed by “performance expectancy,” “social influence,” and “facilitating conditions” themes of the UTAUT model. Clinicians identified multiple perceived barriers and benefits to the use of ultrasound technology. The top identified barrier was limited accessibility, and the top benefit was the ability to visualize a client's articulatory response to cues on a display. Conclusions: Clinicians prioritized “effort expectancy” and “performance expectancy” when reflecting on the use of ultrasound biofeedback for speech sound disorders. Clinicians spoke favorably about using UBT for speech sound disorder treatment but acknowledged institutional barriers and limitations at organizational and social levels.

Zusammenfassung Hintergrund Die Hüftdysplasie ist eine komplexe statisch-dynamische Pathologie, welche zu chronischer Gelenkinstabilität und Arthrose führt. Das Verständnis der zugrundeliegenden Pathomorphologie hat sich weiterentwickelt, sodass eine Aktualisierung der Definition erforderlich ist. Fragestellung Wie lautet die Definition der Hüftdysplasie im Jahr 2023? Methoden Durch Zusammenfassung und Aufarbeitung der relevanten Literatur wird eine aktuelle Definition der Hüftdysplasie mit konkreten Angaben zur Diagnostik bereitgestellt. Ergebnisse Neben pathognomonischen sind supportive und deskriptive Parameter, sowie sekundäre Veränderungen von zentraler Bedeutung zur Diagnose der Hüftinstabilität. Die diagnostische Basis ist die konventionelle Beckenübersichtsaufnahme, welche bei Bedarf durch Zusatzuntersuchungen (Arthro-MRT der Hüfte; CT) ergänzt wird. Schlussfolgerung Die Komplexität, Subtilität und Vielfalt der Pathomorphologie residueller Hüftdysplasien erfordert eine sorgfältige, mehrstufige Diagnostik und Therapieplanung in spezialisierten Zentren.

OBJECTIVE Degenerative cervical myelopathy (DCM) is routinely treated with surgical decompression, but disparate postoperative outcomes are frequently observed, ranging from complete neurological recovery to persistent decline. Although numerous clinical and radiological factors have been independently associated with failure to improve, the relative impact of these proposed risk factors remains obscure. In this study, the authors assess the combined role of clinical and radiographic parameters in contributing to failure to attain neurological improvement after surgery. METHODS A consecutive series of patients who underwent surgery for DCM between July 2013 and August 2018 at a single institution was identified from a prospectively maintained database. Retrospective chart review was undertaken to record perioperative clinical and radiographic parameters. Failure to improve on the last follow-up evaluation after surgery, defined as a change in modified Japanese Orthopaedic Association (mJOA) score less than 2, was the primary outcome in univariate and multivariate analyses. RESULTS The authors included 183 patients in the final cohort. In total, 109 (59.6%) patients improved (i.e., responders with ΔmJOA score ≥ 2) after surgery and 74 (40.4%) were nonresponders with ΔmJOA score < 2. Baseline demographic variables and comorbidity rates were similar, whereas baseline Nurick score was the only clinical variable that differed between responders and nonresponders (2.7 vs 3.0, p = 0.02). In contrast, several preoperative radiographic variables differed between the groups, including presence and degree of cervical kyphosis, number of levels with bidirectional cord compression, presence and number of levels with T2-weighted signal change, intramedullary lesion (IML) length, Torg ratio, and both narrowest spinal canal and cord diameter. On multivariate analysis, preoperative degree of kyphosis at C2–7 (OR 1.19, p = 0.004), number of levels with bidirectional compression (OR 1.83, p = 0.003), and IML length (OR 1.14, p < 0.001) demonstrated the highest predictive power for nonresponse (area under the receiver operating characteristic curve 0.818). A risk factor point system that predicted failure of improvement was derived by incorporating these 3 variables. CONCLUSIONS When a large spectrum of both clinical and radiographic variables is considered, the degree of cervical kyphosis, number of levels with bidirectional compression, and IML length are the most predictive of nonresponse after surgery for DCM. Assessment of these radiographic factors can help guide surgical decision-making and more appropriately stratify patients in clinical trials.

A gap exists regarding how to design gender-specific interventions for women charged with opioid use disorder (OUD)-related crimes. National recent efforts include opioid courts. Treatment courts present opportunities for earlier intervention for women under judicial supervision. We interviewed 31 female participants in the first known opioid court so they could inform cross-sector integrated approaches to address their needs. Data reveal the complexity of participants' involvement with myriad cross-sector organizations, given the duality of their roles as simultaneous lifetime victims and as OUD-related perpetrators. Participants have difficulty trusting systems intended to help them due to systematic failures to prevent or address abuse and neglect over their lifetimes. The opioid crisis cannot be solved without an understanding of early missed intervention opportunities and a cross-sector approach.

To (1) describe the prevalence of cardiometabolic disease (CMD) at spinal cord injury (SCI) rehabilitation discharge; (2) compare this with controls without SCI; and (3) identify factors associated with increased CMD.Multicenter, prospective observational study.Five National Institute on Disability, Independent Living, and Rehabilitation Research Model SCI Rehabilitation Centers.SCI (n=95): patients aged 18-70 years, with SCI (neurologic levels of injury C2-L2, American Spinal Injury Association Impairment Scale grades A-D), and enrolled within 2 months of initial rehabilitation discharge. Control group (n=1609): age/sex/body mass index-matched entries in the National Health and Nutrition Examination Education Survey (2016-2019) (N=1704).None MAIN OUTCOME MEASURES: Percentage of participants with SCI with CMD diagnosis, prevalence of CMD determinants within 2 months of rehabilitation discharge, and other significant early risk associations were analyzed using age, sex, body mass index, insulin resistance (IR) by fasting glucose and Homeostasis Model Assessment (v.2), fasting triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, total cholesterol, and resting blood pressure (systolic and diastolic).Participants with SCI had significantly higher diastolic blood pressure and triglycerides than those without SCI, with lower fasting glucose and HDL-C. A total of 74.0% of participants with SCI vs 38.5% of those without SCI were obese when applying population-specific criteria (P.05). Low HDL-C was measured in 54.2% of participants with SCI vs 15.4% of those without (P.05). IR was not significantly different between groups. A total of 31.6% of participants with SCI had ≥3 CMD determinants, which was 40.7% higher than those without SCI (P.05). Interplay of lipids and lipoproteins (ie, total cholesterol:HDL-C ratio and triglyceride:HDL-C ratio) were associated with elevated risk in participants with SCI for myocardial infarction and stroke. The only significant variable associated with CMD was age (P.05).Individuals with SCI have an increased CMD risk compared with the general population; obesity, IR, and low HDL-C are the most common CMD risk determinants; age is significantly associated with early CMD.

The corticospinal tract (CST) is the preeminent voluntary motor pathway that controls human movements. Consequently, long-standing interest has focused on CST location and function in order to understand both loss and recovery of neurological function after incomplete cervical spinal cord injury, such as traumatic central cord syndrome. The hallmark clinical finding is paresis of the hands and upper-extremity function with retention of lower-extremity movements, which has been attributed to injury and the sparing of specific CST fibers. In contrast to historical concepts that proposed somatotopic (laminar) CST organization, the current narrative summarizes the accumulated evidence that 1) there is no somatotopic organization of the corticospinal tract within the spinal cord in humans and 2) the CST is critically important for hand function. The evidence includes data from 1) tract-tracing studies of the central nervous system and in vivo MRI studies of both humans and nonhuman primates, 2) selective ablative studies of the CST in primates, 3) evolutionary assessments of the CST in mammals, and 4) neuropathological examinations of patients after incomplete cervical spinal cord injury involving the CST and prominent arm and hand dysfunction. Acute traumatic central cord syndrome is characterized by prominent upper-extremity dysfunction, which has been falsely predicated on pinpoint injury to an assumed CST layer that specifically innervates the hand muscles. Given the evidence surveyed herein, the pathophysiological mechanism is most likely related to diffuse injury to the CST that plays a critically important role in hand function.

Recently, it has been observed that early infections after spinal cord injury (SCI) are associated with decreased long-term motor and sensory recovery. We investigate the effects of early infection after SCI on long-term bladder function.We assessed data for the years 1995 to 2006 using the National Spinal Cord Injury Database. Postoperative wound infections and pneumonia were used to classify infections during the acute inpatient and rehabilitation periods. The effect of early infections on volitional voiding status at 1-year followup was assessed. Age, gender and neurological status at rehabilitation discharge (level of injury, American Spinal Injury Association Impairment Scale [AIS] and bilateral lower extremity motor scores) were included in multivariate logistic regression modeling to control for confounding.Of the 3,561 persons studied, 1,233 (34.6%) had an early infection. Those with an infection during early recovery were less likely to void than their noninfected counterparts if in the AIS A (0.3% vs 1.9%, p=0.010), AIS B (3.8% vs 10.5%, p=0.018) and AIS C (29.1% vs 37.3%, p=0.071) classification, while those with less complete injuries (AIS D) did not appear to be affected (62.6% vs 65.4%, p=0.456). Similar findings were found when stratifying by lower extremity motor scores and persisted on multivariate analysis, where early infection decreased the odds of volitional voiding at 1-year followup (OR=0.79, p=0.042).Infections during the early recovery period may modify volitional voiding at 1-year followup by 20% or more. Future investigations to confirm our findings and potentially evaluate mitigation strategies are warranted.

BackgroundLocomotor high-intensity interval training (HIIT) has been shown to improve walking capacity more than moderate-intensity aerobic training (MAT) after stroke, but it is unclear which training parameter(s) should be prioritized (e.g. speed, heart rate, blood lactate, step count) and to what extent walking capacity gains are the result of neuromotor versus cardiorespiratory adaptations.ObjectiveAssess which training parameters and longitudinal adaptations most strongly mediate 6-minute walk distance (6MWD) gains from post-stroke HIIT.MethodsThe HIT-Stroke Trial randomized 55 persons with chronic stroke and persistent walking limitations to HIIT or MAT and collected detailed training data. Blinded outcomes included 6MWD, plus measures of neuromotor gait function (e.g. fastest 10-meter gait speed) and aerobic capacity (e.g. ventilatory threshold). This ancillary analysis used structural equation models to compare mediating effects of different training parameters and longitudinal adaptations on 6MWD.ResultsNet gains in 6MWD from HIIT versus MAT were primarily mediated by faster training speeds and longitudinal adaptations in neuromotor gait function. Training step count was also positively associated with 6MWD gains, but was lower with HIIT versus MAT, which decreased the net 6MWD gain. HIIT generated higher training heart rate and lactate than MAT, but aerobic capacity gains were similar between groups, and 6MWD changes were not associated with training heart rate, training lactate, or aerobic adaptations.ConclusionsTo increase walking capacity with post-stroke HIIT, training speed and step count appear to be the most important parameters to prioritize.

BackgroundMotivation is critically important for rehabilitation, exercise, and motor performance, but its neural basis is poorly understood. Recent correlational research suggests that superior frontal gyrus medial area 9 (SFG9m) may be involved in motivation for walking activity. This study experimentally evaluated brain activity changes in periods of additional motivation during walking exercise, and tested how these brain activity changes relate to self-reported exercise motivation and walking speed.MethodsNon-disabled adults (N=26; 65% female; 25 ± 5 years old) performed a vigorous exercise experiment involving 20 trials of maximal speed overground walking. Half of the trials were randomized to include ‘extra motivation’ stimuli (lap timer, tracked best lap time and verbal encouragement). Wearable nearinfrared spectroscopy measured oxygenated hemoglobin responses (ΔHbO2) from frontal lobe regions, including the SFG9m, primary motor, dorsolateral prefrontal, anterior prefrontal, supplementary motor and dorsal premotor cortices.ResultsCompared with standard trials, participants walked faster during ‘extra-motivation’ trials (2.67 vs. 2.43 m/s; p2in all tested brain regions. This extra motivation effect on ΔHbO2was greatest for SFG9m (+703 µM) compared with other regions (+45 to +354 µM; p≤0.04). Greater SFG9m activity was correlated with more self-determined motivation for exercise and faster walking speed.ConclusionsSimple motivational stimuli during walking exercise seem to upregulate widespread brain regions, especially SFG9m. This could help explain the positive effects of motivational feedback on gait outcomes observed in prior rehabilitation research. Thus, these findings provide a potential biologic basis for the benefits of motivational stimuli, elicited with clinically-feasible methods during walking exercise. Future clinical studies could build on this information to develop prognostic biomarkers and test novel brain stimulation targets for enhancing exercise motivation (e.g. SFG9m).

Many studies use GAAP effective tax rates (ETRs) as a proxy for tax avoidance and assume that very low (high) ETRs represent the greatest (least) tax avoidance, yet ETRs can be affected by items unrelated to tax avoidance. Despite awareness of the potential limitations of ETRs as a measure of tax avoidance, the literature lacks consistent evidence on the extent to which ETRs capture tax avoidance versus other factors. We take a step toward filling this void using income tax footnote disclosures from 2008 through 2016 to investigate how well ETRs capture cross-sectional differences in tax avoidance versus other factors. We document that ETRs below 5% and above 40% are significantly influenced by items largely unrelated to tax avoidance, such as valuation allowances and goodwill impairments. Truncating ETRs at zero and one, controlling for standard determinants of tax avoidance, and using industry-size-adjusted ETRs or multiyear GAAP ETRs do not eliminate the clustering of factors largely unrelated to tax avoidance in the tails of the ETR distribution. Cash ETRs attenuate but do not eliminate this clustering. Researchers can use ETR rate reconciliation data to construct an adjusted ETR that removes the influence of factors largely unrelated to tax avoidance. Our findings inform researchers about factors largely unrelated to tax avoidance that drive significant deviations in ETRs from the statutory tax rate. This is of increasing importance as the number of studies examining the consequences of very high and very low ETRs grows.

Purpose of review To date, prognostication of patients after acute traumatic spinal cord injury (SCI) mostly relies on the neurological assessment of residual function attributed to lesion characteristics. With emerging treatment candidates awaiting to be tested in early clinical trials, there is a need for wholistic high-yield prognostic biomarkers that integrate both neurogenic and nonneurogenic SCI pathophysiology as well as premorbid patient characteristics. Recent findings It is becoming clearer that effective prognostication after acute SCI would benefit from integrating an assessment of pathophysiological changes on a systemic level, and with that, extend from a lesion-centric approach. Immunological markers mirror tissue injury as well as host immune function and are easily accessible through routine blood sampling. New studies have highlighted the value of circulating white blood cells, neutrophils and lymphocytes in particular, as prognostic systemic indicators of SCI severity and outcomes. Summary We survey recent advances in methods and approaches that may allow for a more refined diagnosis and better prognostication after acute SCI, discuss how these may help deepen our understanding of SCI pathophysiology, and be of use in clinical trials.

Background Community paramedicine programs (i.e., physician-directed preventive care by emergency medical services personnel embedded in communities) offer a novel approach to community-based health care. Project Swaddle, a community paramedicine program for mothers and their infants, seeks to address (directly or through referrals) the physical, mental, social, and economic needs of its participants. The objective of this process evaluation was to describe women’s experiences in Project Swaddle. By understanding their experiences, our work begins to build the foundation for similar programs and future examinations of the efficacy and effectiveness of these approaches. Methods We completed 21 interviews with women living in Indiana (July 2019–February 2020) who were currently participating in or had graduated from Project Swaddle. Interviews were audio-recorded, transcribed, and analyzed using a six-phase approach to thematic analysis. Results Program enrollment was influenced by the community paramedics’ experience and connections, as well as information received in the community from related clinics or organizations. Participants viewed the community paramedic as a trusted provider who supplied necessary health information and support and served as their advocate. In their role as physician extenders, the community paramedics enhanced patient care through monitoring critical situations, facilitating communication with other providers, and supporting routine healthcare. Women noted how community paramedics connected them to outside resources (i.e., other experts, tangible goods), which aimed to support their holistic health and wellbeing. Conclusions Results demonstrate Project Swaddle helped women connect with other healthcare providers, including increased access to mental health services. The community paramedics were able to help women establish care with primary care providers and pediatricians, then facilitate communication with these providers. Women were supported through their early motherhood experience, received education on parenting and taking control of their health, and gained access to resources that met their diverse needs.

Purpose To investigate the association of age with delay in spine surgery and the effects on neurological outcome after traumatic spinal cord injury (SCI). Methods Ambispective cohort study (2011–2017) in n = 213 patients consecutively enrolled in a Level I trauma center with SCI care in a metropolitan region in Germany. Age-related differences in the injury to surgery interval and conditions associated with its delay (> 12 h after SCI) were explored using age categories or continuous variables and natural cubic splines. Effects of delayed surgery or age with outcome were analyzed using multiple logistic regression. Results The median age of the study population was 58.8 years (42.0–74.6 IQR). Older age (≥ 75y) was associated with a prolonged injury to surgery interval of 22.8 h (7.2–121.3) compared to 6.6 h (4.4–47.9) in younger patients (≤ 44y). Main reasons for delayed surgery in older individuals were secondary referrals and multimorbidity. Shorter time span to surgery (≤ 12 h) was associated with higher rates of ASIA impairment scale (AIS) conversion (OR 4.22, 95%CI 1.85–9.65), as mirrored by adjusted spline curves ( 60 h Conclusion Older patient age complexifies surgical SCI care and research. Tackling secondary referral to Level I trauma centers and delayed spine surgery imposes as tangible opportunity to improve the outcome of older SCI patients.

Caregiver support is an important contextual factor in the daily functioning of children with cerebral palsy (CP), but few studies have examined child-caregiver interactions during collaborative motor tasks to identify characteristics of effective support that should be promoted in clinical interventions. The aims of this exploratory study were to (1) describe the interaction dynamics of children with CP and typically developing (TD) children with their respective caregivers during a collaborative motor task and (2) develop clinically relevant hypotheses regarding features of child-caregiver interactions that relate to effective caregiver support. Twelve child-caregiver dyads (6 including children with CP, 6 including TD children) participated. Each dyad attempted to construct the tallest tower structure in 10 min using marshmallows and raw spaghetti. Time-series of upper extremity positions were obtained through motion capture and used to examine child-caregiver movement coordination. Videos were coded for language structure and number of building materials used. Five TD dyads and one CP dyad successfully constructed a free-standing tower. During periods of increased tower breakage, TD dyads demonstrated increased movement coordination compared to CP dyads. Unsuccessful dyads (most of whom were CP dyads) demonstrated interaction dynamics characterized by the child leading in movement during periods of increased tower breakage. Overall, in TD dyads, caregivers used more interrogatives than imperatives, and children used more imperatives than interrogatives. This pattern was reversed for CP dyads. From these results we identified future hypotheses about aspects of interactions that may facilitate collaborative motor performance (and thus caregiver support) between children with CP and their caregivers.

In this study, we examine the incidence, valuation and management of tax-related reputational costs during the window surrounding the Occupy Wall Street (OWS) movement, a period characterized by heightened awareness and scrutiny of corporate tax avoidance. We report four main results. First, consistent with firms incurring tax-related reputational costs, we find that tax avoidance is positively associated with negative news media sentiment during the period surrounding the Occupy Wall Street (OWS) movement. Second, consistent with tax-related reputational costs resulting in negative valuation consequences, we find that (1) firm value, measured using Tobin’s q, is negatively associated with tax avoidance during the OWS period and (2) a hedge portfolio long (short) in firms exhibiting low (high) levels of tax avoidance generates significant positive abnormal returns during the OWS window. Third, consistent with firms taking actions to manage potential tax-related reputational damage, we find that firms experiencing the largest reputational costs during the OWS window exhibit higher tax rates in the following year. Fourth, to provide assurance that our results are due to reputational costs and not political costs, we re-estimate our analyses after excluding firms operating in politically-sensitive industries and find that all inferences hold. We provide some of the first large sample evidence of tax-related reputational costs and how these costs vary with public perception of tax avoidance.

Induced myeloid leukemia cell differentiation protein (MCL1) is a member of the B-cell lymphoma-2 (BCL2) family of apoptosis regulators, which plays a critical role in maintaining cellular homeostasis and promoting cancer cell survival. Increased expression of MCL1 in various cancers has been associated with poor prognosis and resistance to chemotherapeutic and targeted agents. We previously described PRT1419, a novel, potent, selective MCL1 inhibitor that demonstrates anti-tumor efficacy in various preclinical models of solid and hematologic malignancies. PRT1419 is currently under evaluation in Phase I clinical trials in patients with relapsed/refractory hematologic malignancies and advanced solid tumors. To identify novel biomarkers that might predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using publicly available human cancer cell line gene dependency data generated from genome-wide CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with deleterious alterations in PBRM1 (Polybromo 1) displayed a strong dependency on MCL1. PBRM1, also known as BAF180, is a chromatin-targeting subunit of mammalian pBAF (SWI/SNF-B) complexes. PBRM1 is frequently altered in various human cancers but it has a particularly high alteration rate in ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We had previously described alterations in other mammalian SWI/SNF factors as biomarkers of MCL1 inhibitor sensitivity.We observed potent inhibition of tumor growth as well as induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not in PBRM1-WT tumor models. Depletion of PBRM1 via RNAi in PBRM1-WT ccRCC induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming PBRM1-loss cells for caspase-mediated cell death following MCL1 inhibition. Increased MCL1 activity has previously been described as a resistance mechanism to Sunitinib and Everolimus, two approved targeted agents for ccRCC. To investigate if MCL1 inhibition could potentiate the anti-tumor effects of these agents, we evaluated PRT1419 in combination with Sunitinib or Everolimus in PBRM1-loss ccRCC. PRT1419 synergized with both Sunitinib and Everolimus in inhibiting tumor growth in various models. Taken together, these findings suggest PBRM1 loss is associated with sensitivity to MCL1 inhibition in ccRCC and provide rationale for the evaluation of PRT1419 for the treatment for PBRM1-deficient ccRCC Citation Format: Norman Fultang, Brian Vidal, Ashley M. Schwab, Alexander Grego, Diane Heiser, Kris Vaddi, Neha Bhagwat, Peggy Scherle. MCL1 inhibitor PRT1419 demonstrates anti-tumor activity in PBRM1-altered clear cell renal cancer and synergizes with standard of care agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6147.

We use data envelopment analysis (DEA) to develop a measure of effective tax planning that is theoretically aligned with the Scholes-Wolfson paradigm and captures how efficiently firms maximize after-tax returns given their operating, investing, and financing decisions. We then (1) document that the measure is associated with higher after-tax returns to provide assurance DEA achieves its objective in our setting, (2) demonstrate that the measure is incremental to cash ETRs in predicting after-tax returns, (3) validate the measure by showing its association with lower tax and non-tax costs, and (4) provide evidence that the measure captures something about taxes distinct from overall firm performance. This measure is useful to researchers given the known limitations of ETRs as a measure of tax planning. Data Availability: Tax Effectiveness values are available on the authors' websites.

In this review, we will explore the clinical and commercial focus on amniotic membranes (AMs) and their use in tissue engineering (TE). We will showcase the therapeutic potential of AM-isolated epithelial cells (hAECs) and the prospective use of their secreted factors, extracellular vesicles (EVs), in cell and non-cell therapies. The potential of the hAECs as a therapeutic source has been investigated in various preclinical models with some progressing into phase I clinical trials to evaluate their safety. Additionally, multiple animal studies showcase the therapeutic potential of EVs as non-cellular treatments. The amniotic membrane (AM) has been used as a form of regenerative medicine in wound healing for burns and ulcerated surfaces and in ophthalmology for over a century. In the last few decades, research has looked to the use of the various stem cells that can be isolated from the AM. The use of AM-isolated hAECs has proven rather promising with phase I clinical trials currently underway across life-threatening diseases in both pediatric and adult populations. However, due to limitations of using cell-based therapies (e.g., cost of production, delivery restricted to major hospitals, etc.), attention has turned to investigating EVs secreted by the cells.

The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

BACKGROUND Periacetabular osteotomy (PAO) has been shown to be a valuable option for delaying the onset of osteoarthritis in patients with hip dysplasia. Published studies at 30 years of follow-up found that postoperative anterior overcoverage and posterior undercoverage were associated with early conversion to THA. The anterior and posterior wall indices are practical tools for assessing AP coverage on standard AP radiographs of the pelvis pre-, intra-, and postoperatively. However, no study that we know of has evaluated the relationship between the postoperative anterior and posterior wall indices and survivorship free from arthroplasty. QUESTIONS/PURPOSES In a study including patients after PAO for developmental dysplasia of the hip (DDH), we evaluated whether the acetabular wall index is associated with conversion to THA in the long-term after PAO. We asked: (1) Is an abnormal postoperative anterior wall index associated with conversion to THA after PAO? (2) Is an abnormal postoperative posterior wall index associated with conversion to THA after PAO? (3) Are there other factors associated with joint replacement after PAO? METHODS This retrospective study involved pooling data of PAO for DDH from two previously published sources. The first series (1984-1987) comprised the very first 75 PAOs for symptomatic DDH performed at the inventor's institution. The second (1997-2000) comprised a series of PAOs for symptomatic DDH completed at the same institution 10 years later. No patient was lost to follow-up. Fifty hips (44 patients) were excluded for predefined reasons (previous surgery, substantial femoral pathomorphologies, poor-quality radiographs), leaving 115 hips (102 patients, mean age 29 ± 11 years, 28% male) for analysis with a mean follow-up of 22 ± 6 years. One observer not involved in patient treatment digitally measured the anterior and posterior wall indices on postoperative AP pelvic radiographs of all patients. All patients were contacted by mail or telephone to confirm any conversion to THA and the timing of that procedure relative to the index procedure. We performed univariate and multivariate Cox regression analyses using conversion to THA as our endpoint to determine whether the anterior and posterior wall indices are associated with prosthetic replacement in the long-term after PAO. Thirty-one percent (36 of 115) of hips were converted to THA within a mean of 15 ± 7 years until failure. The mean follow-up duration of the remaining patients was 22 ± 6 years. RESULTS A deficient anterior wall index was associated with conversion THA in the long-term after PAO (adjusted hazard ratio 10 [95% CI 3.6 to 27.9]; p < 0.001). Although observed in the univariate analysis, we could not find a multivariate association between the posterior wall index and a higher conversion rate to THA. Grade 0 Tonnis osteoarthritis was associated with joint preservation (adjusted HR 0.2 [95% CI 0.07 to 0.47]; p = 0.005). Tonnis osteoarthritis Grades 2 and 3 were associated with conversion to THA (adjusted HR 2.3 [95% CI 0.9 to 5.7]; p = 0.08). CONCLUSION A deficient anterior wall index is associated with a decreased survivorship of the native hip in the long-term after PAO. Intraoperatively, in addition to following established radiographical guidelines, the acetabular wall indices should be measured systematically to ascertain optimal acetabular fragment version to increase the likelihood of reconstructive survival after PAO for DDH. LEVEL OF EVIDENCE Level III, therapeutic study.

Individuals with neuromotor disabilities demonstrate motor control patterns characterized by a decreased capacity to adapt to contextual change. Task-oriented training is one promising intervention...

The purpose of this study was to examine whether the choice of means by persons who die by suicide is associated with a prior psychiatric diagnosis. In this cross-sectional study, we analyzed suicide surveillance data from 18 states reporting to the National Violent Death Reporting System (NVDRS) between 2003 and 2014. NVDRS compiled data from multiple sources (e.g., coroner’s reports, police reports, death certificates) on every violent death within reporting jurisdictions, including information on indicated psychiatric disorders and suicide means. We assessed whether the selected suicide means were associated with diagnoses using multinomial logistic regression. Adjusted models suggested that, compared to decedents using firearms, those using poisoning were more likely to have each psychiatric disorder examined, including bipolar disorder (aOR: 2.17 [95% CI 2.03–2.32]), schizophrenia (aOR: 1.81 [1.61–2.04]), depression (aOR: 1.64 [1.58–1.70]), anxiety disorder (aOR: 1.46 [1.35–1.57]), and PTSD (aOR: 1.41 [1.22–1.64]). A far greater proportion of individuals who died from less common means (other than firearms, suffocation, or poisoning) had schizophrenia (aOR: 4.52 [4.00–5.11]). Many existing and proposed means restriction interventions have focused on firearms. Additional focus on access to potential agents of poisoning (e.g., the type and quantity of medication administered to patients) among individuals with psychiatric diagnoses may be warranted.

Study question Does complete resection of endometriosis improve embryo quality as assessed by morphokinetic parameters using time-lapse microscopy? Summary answer Complete resection of endometriosis in affected women undergoing assisted reproduction is shown to have a positive impact on embryo morphokinetic parameters represented in embryo quality. What is known already Endometriosis is one of the most common gynaecological diseases. It is characterized by the presence of cells comparable to those in the endometrium but being located outside of the uterine cavity. About 4-30% women of child-bearing age are affected by endometriosis. In vitro fertilization (IVF) studies have suggested that women with more advanced endometriosis have poor ovarian reserve, low oocyte and embryo quality and poor implantation rates. Moreover inflammatory peritoneal fluid shows a toxic effect on embryos. This might have an impact on morphokinetic timings but there is only limited data available concerning morphokinetics and endometriosis. Study design, size, duration 246 embryos (endometriosis group: n = 85; non-endometriosis control group: n = 115; complete resection of endometriosis= 46) undergoing infertility treatment at our clinics were included in this retrospective study. Inclusion criteria were female patients aged between 18 and 45 years undergoing IVF and / or ICSI treatment. The in vitro culture was performed in a closed time-lapse incubator (EmbryoScope®, Vitrolife) up to day 3 or in a prolonged culture up to day 5. Participants/materials, setting, methods Patient treatment included conventional insemination or intracytoplasmatic sperm injection. IVF inseminated or ICSI injected oocytes were culturd in the TimeLapse monitoring incubator. Embryos were cultured for 3 to 5 days without media change at 6.8% CO2 and 5% O2 at 37°C. During embryo culture morphokinetic parameters and events were constantly annotated. Analysis was performed using the EmbryoViewer software and evaluated applying KIDScoreTM D3 or KIDScoreTM D5 according to the day of embryo transfer. Main results and the role of chance The analysis revealed a median KIDScoreTM D5 of 2.3 (on a scale from 1 to 9.9) for embryos from patients suffering from endometriosis without complete resection. The control group without endometriosis achieved a score of 7.0 (p = 0.001). The median for embryos from endometriosis patients with complete resection was 7.1 which meant a significant increase compared to embryos from patients without complete resection (p = 0.002). Effect size according to Cohen showed a moderate up to strong biological effect (r = 0.4) for complete resection vs. no resection of endometriosis. For the three groups KIDScoreTM D3, pregnancy rates as well as abortion rates showed the same clinical trends. Additionally, we could describe a series of four patients undergoing IVF-cycles before and after a complete resection of their endometriosis. As expected, in three out of four cases they showed a clear increase in their embryo quality after complete resection of endometriosis. Limitations, reasons for caution The main limitation of the study is the relative small sample size of the groups, especially the number of patients with endometriosis resection. Additionally, the study is limited to its retrospective design. Wider implications of the findings Pathogenesis of endometriosis related infertility is multifactorial and not completely understood. But knowing that endometrioid lesions produce inflammatory cytokines which are toxic for oocytes and embryos, resection of the lesions in order to reduce inflammation seems to be a plausible approach. Trial registration number 20191007 01

The patient found it hard to climb stairs-and to complete a particular task when getting dressed. Difficulty with that task provided a useful diagnostic clue.

The myelin-associated inhibitor Nogo-A (Reticulon 4, RTN4) restricts axonal outgrowth, plasticity, and neural circuitry formation in experimental models of spinal cord injury (SCI) and is targeted in clinical interventions starting treatment within 4 weeks post-SCI. Specifically, Nogo-A expressed by oligodendroglia restricts compensatory neurite sprouting. To interrogate the hypothesis of an inducible, lesion reactive Nogo-A expression over time, we analyzed the spatiotemporal Nogo-A expression at the spinal lesion core (region of tissue necrosis and axonal damage/pruning) and perilesional rim (region of plasticity formation). Spinal cord specimens of SCI subjects (n = 22) were compared to neuropathologically unaltered controls (n = 9). Nogo-A expression was investigated ranging from acute (0-3 days), early subacute (4-21 days), late subacute (22-90 days) to early chronic-chronic (91 days to 1.5 years after SCI) stages after SCI. Nogo-A expression in controls is confined to motoneurons in the anterior horn and to oligodendrocytes in gray and white matter. After SCI, the number of Nogo-A

The International Classification of Functioning, Disability and Health (ICF) recognizes that disability arises from the interaction between an individual with a medical condition and the context in which they are embedded. Context in the ICF is comprised of environmental and personal factors. Personal factors, the background life and lifestyle of an individual, are poorly understood in rehabilitation. There is limited knowledge about how personal and environmental factors interact to shape the contextual conditions critical for explaining functioning and disability. In this paper, we explore how a newly proposed model of disability, the Ecological-Enactive Model of Disability, can enhance understanding of personal factors across multiple rehabilitation disciplines. We draw from a review of evidence and phenomenological interviews of individuals with Friedreich's Ataxia. We consider the practical impact of this understanding on disability and rehabilitation research and pathways for the future focusing on representative design.

Background and objectivesCognitive symptoms persisting beyond three months following COVID-19 present a considerable disease burden. We aimed to establish a domain-specific cognitive profile of post-COVID syndrome (PCS) and relationships with subjective cognitive complaints and clinical variables to provide relevant information for the understanding of cognitive dysfunction and its predictors in a clinical cohort with PCS.MethodsIn this cross-sectional study, we compared cognitive performance on the clinically viable Oxford Cognitive Screen-Plus between a large post-COVID cohort (n= 282) and a socio-demographically matched healthy control group (n= 52). We assessed group differences in terms of fatigue and depression as well as relationships between cognitive dysfunction and clinical and patient-reported outcomes.ResultsOn a group-level, patients scored significantly lower on delayed verbal memory (non-parametric effect sizer= .13), attention (r= .1), and executive functioning (r=.1) than healthy controls. In each of these domains, 10-20% of patients performed more than 1.5 SD below the healthy control mean. Delayed Memory was particularly affected and a small proportion of its variance was explained by hospitalisation (β= -.72,p< .01) and age (β= -.03,p< .05; R2adj. = .08). Attention scores were significantly predicted by hospitalisation (β= -.78,p< .01) and fatigue (β= -.04,p< .05; R2adj. = .06).DiscussionPCS is associated with long-term cognitive dysfunction, particularly in delayed verbal memory, attention, and executive functioning. Deficits in delayed memory performance seem to be of particular relevance to patients’ subjective experience of impairment. Initial disease severity, current level of fatigue, and age seem to predict cognitive performance, while time since infection, depression, and pre-existing conditions do not. Longitudinal data are needed to map long-term course of cognitive dysfunction in PCS.

Background and Objectives: Even after the ‘death’ of Lewinnek’s safe zone, the orientation of the prosthetic cup in total hip arthroplasty is crucial for success. Accurate cup placement can be achieved with surgical navigation systems. The literature lacks study cohorts with large numbers of hips because postoperative computer tomography is required for the reproducible evaluation of the acetabular component position. To overcome this limitation, we used a validated software program, HipMatch, to accurately assess the cup orientation based on an anterior-posterior pelvic X-ray. The aim of this study were to (1) determine the intraoperative ‘individual adjustment’ of the cup positioning compared to the widely suggested target values of 40° of inclination and 15° of anteversion, and evaluate the (2) ‘accuracy’, (3) ‘precision’, and (4) robustness, regarding systematic errors, of an image-free navigation system in routine clinical use. Material and Methods: We performed a retrospective, accuracy study in a single surgeon case series of 367 navigated primary total hip arthroplasties (PiGalileoTM, Smith+Nephew) through an anterolateral approach performed between January 2011 and August 2018. The individual adjustments were defined as the differences between the target cup orientation (40° of inclination, 15° of anteversion) and the intraoperative registration with the navigation software. The accuracy was the difference between the intraoperative captured cup orientation and the actual postoperative cup orientation determined by HipMatch. The precision was analyzed by the standard deviation of the difference between the intraoperative registered and the actual cup orientation. The outliers were detected using the Tukey method. Results: Compared to the target value (40° inclination, 15° anteversion), the individual adjustments showed that the cups are impacted in higher inclination (mean 3.2° ± 1.6°, range, (−2)–18°) and higher anteversion (mean 5.0° ± 7.0°, range, (−15)–23°) (p < 0.001). The accuracy of the navigated cup placement was −1.7° ± 3.0°, ((−15)–11°) for inclination, and −4.9° ± 6.2° ((−28)–18°) for anteversion (p < 0.001). Precision of the system was higher for inclination (standard deviation SD 3.0°) compared to anteversion (SD 6.2°) (p < 0.001). We found no difference in the prevalence of outliers for inclination (1.9% (7 out of 367)) compared to anteversion (1.63% (6 out of 367), p = 0.78). The Bland-Altman analysis showed that the differences between the intraoperatively captured final position and the postoperatively determined actual position were spread evenly and randomly for inclination and anteversion. Conclusion: The evaluation of an image-less navigation system in this large study cohort provides accurate and reliable intraoperative feedback. The accuracy and the precision were inferior compared to CT-based navigation systems particularly regarding the anteversion. However the assessed values are certainly within a clinically acceptable range. This use of image-less navigation offers an additional tool to address challenging hip prothesis in the context of the hip–spine relationship to achieve adequate placement of the acetabular components with a minimum of outliers.

Traumatic spinal cord injury (SCI) above the major spinal sympathetic outflow (T6 level) disinhibits sympathetic neurons from supraspinal control, causing systems-wide “dysautonomia.” We recently showed that remarkable structural remodeling and plasticity occurs within spinal sympathetic circuitry, creating abnormal sympathetic reflexes that exacerbate dysautonomia over time. As an example, thoracic VGluT2+spinal interneurons (SpINs) become structurally and functionally integrated with neurons that comprise the spinal–splenic sympathetic network and immunological dysfunction becomes progressively worse after SCI. To test whether the onset and progression of SCI-induced sympathetic plasticity is neuron activity dependent, we selectively inhibited (or excited) thoracic VGluT2+interneurons using chemogenetics. New data show that silencing VGluT2+interneurons in female and male mice with a T3 SCI, using hM4Di designer receptors exclusively activated by designer drugs (GiDREADDs), blocks structural plasticity and the development of dysautonomia. Specifically, silencing VGluT2+interneurons prevents the structural remodeling of spinal sympathetic networks that project to lymphoid and endocrine organs, reduces the frequency of spontaneous autonomic dysreflexia (AD), and reduces the severity of experimentally induced AD. Features of SCI-induced structural plasticity can be recapitulated in the intact spinal cord by activating excitatory hM3Dq-DREADDs in VGluT2+interneurons. Collectively, these data implicate VGluT2+excitatory SpINs in the onset and propagation of SCI-induced structural plasticity and dysautonomia, and reveal the potential for neuromodulation to block or reduce dysautonomia after severe high-level SCI.SIGNIFICANCE STATEMENTIn response to stress or dangerous stimuli, autonomic spinal neurons coordinate a “fight or flight” response marked by increased cardiac output and release of stress hormones. After a spinal cord injury (SCI), normally harmless stimuli like bladder filling can result in a “false” fight or flight response, causing pathological changes throughout the body. We show that progressive hypertension and immune suppression develop after SCI because thoracic excitatory VGluT2+spinal interneurons (SpINs) provoke structural remodeling in autonomic networks within below-lesion spinal levels. These pathological changes can be prevented in SCI mice or phenocopied in uninjured mice using chemogenetics to selectively manipulate activity in VGluT2+SpINs. Targeted neuromodulation of SpINs could prevent structural plasticity and subsequent autonomic dysfunction in people with SCI.

BACKGROUND Assessment of AP acetabular coverage is crucial for choosing the right surgery indication and for obtaining a good outcome after hip-preserving surgery. The quantification of anterior and posterior coverage is challenging and requires either other conventional projections, CT, MRI, or special measurement software, which is cumbersome, not widely available and implies additional radiation. We introduce the "rule of thirds" as a promising alternative to provide a more applicable and easy method to detect an excessive or deficient AP coverage. This method attributes the intersection point of the anterior (posterior) wall to thirds of the femoral head radius (diameter), the medial third suggesting deficient and the lateral third excessive coverage. QUESTION/PURPOSE What is the validity (area under the curve [AUC], sensitivity, specificity, positive/negative likelihood ratios [LR(+)/LR(-)], positive/negative predictive values [PPV, NPV]) for the rule of thirds to detect (1) excessive and (2) deficient anterior and posterior coverages compared with previously established radiographic values of under-/overcoverage using HipNorm as the gold standard? METHODS We retrospectively evaluated all consecutive patients between 2003 and 2015 from our institutional database who were referred to our hospital for hip pain and were potentially eligible for joint-preserving hip surgery. We divided the study group into six specific subgroups based on the respective acetabular pathomorphology to cover the entire range of anterior and posterior femoral coverage (dysplasia, overcoverage, severe overcoverage, excessive acetabular anteversion, acetabular retroversion, total acetabular retroversion). From this patient cohort, 161 hips were randomly selected for analysis. Anterior and posterior coverage was determined with HipNorm, a validated computer software program for evaluating acetabular morphology. The anterior and posterior wall indices were measured on standardized AP pelvis radiographs, and the rule of thirds was applied by one observer. RESULTS The detection of excessive anterior and posterior acetabular wall using the rule of thirds revealed an AUC of 0.945 and 0.933, respectively. Also the detection of a deficient anterior and posterior acetabular wall by applying the rule of thirds revealed an AUC of 0.962 and 0.876, respectively. For both excessive and deficient anterior and posterior acetabular coverage, we found high specificities and PPVs but low sensitivities and NPVs. CONCLUSION We found a high probability for an excessive (deficient) acetabular wall when this intersection point lies in the lateral (medial) third, which would qualify for surgical correction. On the other hand, if this point is not in the lateral (medial) third, an excessive (deficient) acetabular wall cannot be categorically excluded. Thus, the rule of thirds is very specific but not as sensitive as we had expected. LEVEL OF EVIDENCE Level II, diagnostic study.

Objective To determine whether screening tests of upper body, trunk region, and of whole-body function could prospectively identify community AFL players who sustain in-season shoulder/head/neck injuries. Additionally, to present screening test reference values. Design Prospective cohort; Setting Community sport; Participants 142 male community AFL players (range 15–37 years). Main outcome measures (i) isometric shoulder external and internal rotation (ER/IR) strength; (ii) upper body combined elevation functional ROM; (iii/iv) whole-body functional jump ROM; (v) static thoracic spine angle; (vi) cervical joint proprioception, and (vii) trunk muscle size and function. Results were compared among players with (n = 21) and without (n = 121) an in-season shoulder, head, or neck injury. ROC analysis and odds ratios were used to determine the predictive values. Results Two screening tests predicted an in-season shoulder, head, or neck injury; dominant and non-dominant isometric ER strength (AUC 0.629, 95%CI 0.51–0.74; optimal cut point 182 N and AUC 0.619, 95%CI 0.50–0.74; optimal cut point 184 N, respectively). The adjusted odds ratio for the strongest predictor: dominant ER muscle strength was 6.02 (95%CI 1.8–19.9). Conclusion Greater ER strength was associated with in-season shoulder/head/neck injuries in community AFL players; however, further research is required to determine the clinical significance of this finding.