No test medical abortion - a review of the evidence on selective use of preabortion testing.

PURPOSE OF REVIEW: The last decade has seen a cascade of different telemedicine models for medical abortion (MA) being tested and implemented. Among these service delivery models is the 'no-test' MA model, in which care is provided remotely and eligibility for the MA is based on history alone. The purpose of this review is to provide an overview of the existing evidence for no-test MA. RECENT FINDINGS: The evidence base for no-test MA relies heavily on cohort and noncomparative studies predominantly from high resource settings. Recent findings indicate that no-test MA is safe, effective, and highly acceptable. Diagnoses of ectopic pregnancy and underestimation of gestational age were rare. Identified advantages included shortening time to access MA and mitigating access barriers such as cost, and geographical barriers. Abortion seekers valued omitting the ultrasound citing reasons such as privacy concerns, costs, more flexibility, and control. Due to lack of evidence, the impacts of no-test MA on unscheduled postabortion contacts and visits and on contraceptive use were unclear due to limited evidence. SUMMARY: No-test MA can be provided to complement other care pathways including those with some or no in-person care. Further research is needed to allow for widespread adoption of no-test MA and scale-up in a variety of contexts, including low-resource settings.

The Success of Mifepristone and Misoprostol in the Management of Early Pregnancy Loss at a Community Hospital: A Prospective Study.

OBJECTIVES: This prospective single-arm study was conducted to understand the expulsion rate of the gestational sac in the management of early pregnancy loss (EPL). METHODS: We recruited 441 participants; 188 met the eligibility criteria. Participants were 18 years of age and older who experienced a confirmed EPL (<12 weeks gestational age) defined by an intrauterine pregnancy with a non-viable embryonic or anembryonic gestational sac with no fetal heart activity. Participants were given 200 mg of mifepristone pre-treatment orally followed by 2 doses of misoprostol 800 µg vaginally after 24 and 48 hours. Participants were seen in follow-up on day 14 to confirm the absence of a gestational sac, classified as treatment success. For failed treatment (defined by retained gestational sac), we offered expectant management or a third dose of misoprostol and/or dilatation and curettage. We followed all participants for 30 days. We collected data on overtreatment for retained products of conception and hospital admissions for adverse events. RESULTS: Overall, 181 participants followed the protocol and 169 (93.3%) participants had a complete expulsion of the gestational sac by the second visit (day 14). Twelve (6.6%) failed the treatment and 1 had an adverse event of heavy vaginal bleeding requiring dilatation and curettage. Despite the expulsion of the gestational sac, 29 cases (17.1%) at subsequent follow-up were diagnosed as retained products of conception based on ultrasound assessment of thickened endometrium. CONCLUSIONS: Pretreatment with mifepristone followed by 2 doses of misoprostol with a 14-day follow-up resulted in a high expulsion rate and is a safe management option for EPL.

From molecules to behavior: Implications for perineuronal net remodeling in learning and memory.

Perineuronal nets (PNNs) are condensed extracellular matrix (ECM) structures found throughout the central nervous system that regulate plasticity. They consist of a heterogeneous mix of ECM components that form lattice-like structures enwrapping the cell body and proximal dendrites of particular neurons. During development, accumulating research has shown that the closure of various critical periods of plasticity is strongly linked to experience-driven PNN formation and maturation. PNNs provide an interface for synaptic contacts within the holes of the structure, generally promoting synaptic stabilization and restricting the formation of new synaptic connections in the adult brain. In this way, they impact both synaptic structure and function, ultimately influencing higher cognitive processes. PNNs are highly plastic structures, changing their composition and distribution throughout life and in response to various experiences and memory disorders, thus serving as a substrate for experience- and disease-dependent cognitive function. In this review, we delve into the proposed mechanisms by which PNNs shape plasticity and memory function, highlighting the potential impact of their structural components, overall architecture, and dynamic remodeling on functional outcomes in health and disease.

Non-linear properties of the Achilles tendon determine ankle impedance over a broad range of activations in humans.

Regulating ankle mechanics is essential for controlled interactions with the environment and rejecting unexpected disturbances. Ankle mechanics can be quantified by impedance, the dynamic relationship between an imposed displacement and the torque generated in response. Ankle impedance in the sagittal plane depends strongly on the triceps surae and Achilles tendon, but their relative contributions remain unknown. It is commonly assumed that ankle impedance is controlled by changing muscle activation and, thereby, muscle impedance, but this ignores that tendon impedance also changes with activation-induced loading. Thus, we sought to determine the relative contributions from the triceps surae and Achilles tendon during conditions relevant to postural control. We used a novel technique that combines B-mode ultrasound imaging with joint-level perturbations to quantify ankle, muscle and tendon impedance simultaneously across activation levels from 0% to 30% of maximum voluntary contraction. We found that muscle and tendon stiffness, the static component of impedance, increased with voluntary plantarflexion contractions, but that muscle stiffness exceeded tendon stiffness at very low loads (21±7 N). Above these loads, corresponding to 1.3% of maximal strength for an average participant in our study, ankle stiffness was determined predominately by Achilles tendon stiffness. At approximately 20% MVC for an average participant, ankle stiffness was 4 times more sensitive to changes in tendon stiffness than to changes in muscle stiffness. We provide the first empirical evidence demonstrating that the nervous system, through changes in muscle activations, leverages the non-linear properties of the Achilles tendon to increase ankle stiffness during postural conditions.

Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study.

INTRODUCTION: Envarsus XR® (LCPT), a once daily dosage formulation of tacrolimus, is an FDA-approved medication in adult renal transplant recipients (RTRs). There are limited data on its pharmacokinetics (PK) in adolescent RTRs. We report here the PK profile of LCPT in adolescent RTRs. METHODS: The dose of LCPT was determined using a dose conversion ratio targeting 0.7 relative to the total daily immediate-release tacrolimus (IR-Tac) dose. On day 7 after converting to LCPT, patients had an abbreviated PK assessment with sampling at: 0 h (pre-dose), 8-, and 12-h post-dose. The PK data analysis was performed using Bayesian estimators. Our results were compared to those of published adult PK data for LCPT and pediatric PK data for IR-Tac and extended release tacrolimus (ER-Tac) formulation (Advagraf). RESULTS: PK data from three adolescent patients on LCPT were evaluated. The mean (±SD) area under the time-concentration curve (AUC) was 240 (±20.22) h*ng/mL. The mean Tmax was 9.01 ± 2.12 h, and the % fluctuation was 77.71 ± 3.96%. The AUC, Tmax , and % fluctuation were similar to reported results in adult patients taking LCPT. The AUC was higher and the Tmax was longer than what has been reported in pediatric patients taking IR-Tac and ER-Tac. In addition, the LCPT group showed a lower % fluctuation than patients receiving ER-Tac. CONCLUSION: The PK evaluation of LCPT in adolescent RTRs showed similar results to adults. Adolescents taking LCPT had a higher AUC, a more attenuated Tmax , and a lower fluctuation than that seen with ER-Tac in pediatrics.

Emergency contraception subsidy in Canada: a comparative policy analysis.

BACKGROUND: In Canada, cost prohibits access to emergency contraception (EC) which may assist to prevent unintended pregnancy. The drug, ulipristal acetate (UPA-EC), is more clinically effective and cost-effective than the prior standard levonorgestrel (LNG-EC). We analyzed provincial EC subsidization policies and examined underlying decision-making processes. METHODS: We undertook documentary analysis of provincial EC subsidization policies in publicly available drug formularies. We conducted semi-structured interviews with key informants to explore the processes underlying current policies. RESULTS: Quebec is the only province to subsidize UPA-EC, whilst all ten provinces subsidize LNG-EC. As such, provincial EC subsidization policies do not align with the latest UPA-EC evidence. Interviews revealed that evidence was valued in the policymaking process and formulary decisions were made through interdisciplinary consensus. CONCLUSIONS: We identify a gap between EC subsidization policies and the latest evidence. Institutional structures affect policies reflecting evolving evidence. Increasing interdisciplinary mechanisms may encourage evidence-based policies.

A Retrospective Study of Clinical Encounters for Pelvic Inflammatory Disease: Missed Opportunities to Screen for Syphilis and HIV?

OBJECTIVE: Missed screening opportunities may contribute to the rising rates of sexually transmitted and blood borne infections (STBBIs) in Manitoba. This study sought to determine the proportion of women who are screened for syphilis and human immunodeficiency virus (HIV) when admitted with pelvic inflammatory disease (PID). METHODS: We performed a retrospective analysis of all inpatient admissions for PID over 3 discrete years (fiscal years 2007, 2012, 2017) at a single tertiary care centre. Data extracted from medical records included STBBI screening performed, clinical signs at presentation, and history of PID or STBBI. To improve the accuracy of our estimates, we complemented the records data with population data from Manitoba. We evaluated predictive factors influencing any or concurrent STBBI screening using bivariate analysis for significance (P < 0.05). RESULTS: One hundred and five admissions met inclusion criteria. Syphilis and HIV screening was ordered concurrently with chlamydia and gonorrhoea screening in 6 (6%) of encounters and was ordered at any point during admission for PID in 28 (27%). A history of substance abuse (odds ratio [OR] 4.94 [95% CI 1.62-15.05] for syphilis screening and OR 6.94 [95% CI 2.38-20.23] for HIV screening) and a positive gonorrhea result while admitted (OR 3.40 [95% CI 1.06-10.88] for syphilis screening) were strongly associated with receiving any screening. Reporting multiple sexual partners was also strongly associated with receiving any STBBI screening while admitted (OR 19.44 [95% CI 2.01-187.92] and OR 15.00 [95% CI 1.58-142.70] for syphilis and HIV screening, respectively). CONCLUSION: A minority of patients were screened for syphilis and HIV while admitted for PID. This study highlights a missed opportunity to screen for STBBI among sexually active women.

Impact of Minimally Invasive Gynaecology Fellowship Training on Quality Performance Metrics for Hysterectomy.

OBJECTIVE: To evaluate differences in quality metrics between hysterectomies performed by fellowship-trained surgeons and those performed by generalists. METHODS: Retrospective review of 2845 consecutive hysterectomies by 75 surgeons (23 fellowship-trained, 52 generalists) at 7 hospitals in Ontario, Canada. The primary outcome was a composite of any complication or return to the emergency department (ED) within 30 days of hysterectomy. Secondary outcomes were 2 quality outcome measures (grade of complication and return to ED within 30 days) and 4 quality process measures (minimally invasive hysterectomy rate, rate of preoperative anemia, same-day discharge for laparoscopic hysterectomy [LH], and performing cystoscopy at LH). RESULTS: Fellowship-trained surgeons were more likely to perform concurrent resection of endometriosis, bilateral ureterolysis, lysis of adhesions, uterine/internal iliac artery ligation, and morcellation (all P < 0.001). Generalists performed more vaginal procedures, including vaginal repair, vault suspension, and insertion of mid-urethral sling (all P < 0.001). After controlling for patient and surgical factors, there was no difference in the primary outcome (adjusted odds ratio [aOR] 1.07; 95% CI 0.79-1.45, P = 0.667). Fellowship-trained surgeons were more likely to perform minimally invasive hysterectomy (aOR 2.38; 95% CI 1.15-4.93, P = 0.020), had higher rates of same-day discharge for LH (aOR 2.23; 95% CI 1.31-3.81, P = 0.003), and were more likely to perform cystoscopy (unadjusted OR 2.94; 95% CI 2.30-3.85, P < 0.001). There were no differences in the rates of preoperative anemia, surgical complications, and ED visits. CONCLUSION: Differences exist between fellowship-trained surgeons and generalists regarding case mix and process quality metrics. Postoperative complications and readmissions were comparable for both groups of surgeons.

Influence of limb position on assessment of nerve mechanical properties by using shear wave ultrasound elastography.

INTRODUCTION: Evaluation of nerve mechanical properties has the potential to improve assessment of nerve impairment. Shear wave velocity, as measured by using shear wave (SW) ultrasound elastography, is a promising indicator of nerve mechanical properties such as stiffness. However, elucidation of external factors that influence SW velocity, particularly nerve tension, is required for accurate interpretations. METHODS: Median and ulnar nerve SW velocities were measured at proximal and distal locations with limb positions that indirectly altered nerve tension. RESULTS: Shear wave velocity was greater at proximal and distal locations for limb positions that induced greater tension in the median (mean increase proximal 89.3%, distal 64%) and ulnar (mean increase proximal 91.1%, distal 37.4%) nerves. DISCUSSION: Due to the influence of nerve tension when SW ultrasound elastography is used, careful consideration must be given to limb positioning.

Conference report on contractures in musculoskeletal and neurological conditions.

Limb contractures are debilitating complications associated with various muscle and nervous system disorders. This report summarizes presentations at a conference at the Shirley Ryan AbilityLab in Chicago, Illinois, on April 19-20, 2018, involving researchers and physicians from diverse disciplines who convened to discuss current clinical and preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, cerebral palsy, and other conditions. Presenters described changes in muscle architecture, activation, extracellular matrix, satellite cells, and muscle fiber sarcomeric structure that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint, and neuronal tissues during contracture development with imaging, molecular, and physiologic approaches. Participants identified the requirement for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development.

How does multimorbidity affect middle-aged adults? A cross-sectional survey in the Singapore primary healthcare setting.

BACKGROUND: Multimorbidity is of increasing prevalence and importance. It has been associated with poorer health-related quality of life (HrQoL) especially in the elderly population. Despite substantial multimorbidity in the middle-aged population, defined as those aged between 40-64 years old, there is a paucity of research investigating the impact of multimorbidity in this population. This study aimed to investigate the association between multimorbidity and HrQoL in the middle-aged primary care population in Singapore. METHODS: A cross-sectional study was conducted at a primary care centre in Singapore. Interviewer-administered questionnaires were used to collect data regarding the participants' sociodemographic characteristics, chronic conditions, and HrQoL, as measured by the EuroQol five dimensions 3-levels questionnaire (EQ5D). We defined multimorbidity as the presence of three or more conditions, out of a list of 14 chronic conditions. The associations between multimorbidity and the components of the EQ5D were assessed using multivariable regression analyses. RESULTS: The study included 297 participants, aged 40-64 years, of which 124 (41.7%) had multimorbidity. After adjusting for sociodemographic factors, participants with multimorbidity had significantly lower EQ5D UI, (ß-coefficient - 0.064 (C.I -0.125, - 0.003), p = 0.04), but not significantly lower EQ5D VAS, (ß-coefficient - 0.045 (C.I 0.102, 0.012), p = 0.12). Additionally, participants with multimorbidity had higher odds (OR = 2.41, p = 0.01) of reporting problems due to pain/discomfort. CONCLUSION: Multimorbidity was not significantly associated with the overall health state, as measured by the EQ5D VAS, in middle-aged primary care patients. However, it was associated with the EQ5D UI which is a composite measure of five specific domains of HrQoL. Specifically, there was a statistically significant association between multimorbidity and the pain domain. Further studies are required to understand the relationship between multimorbidity and pain to enable physicians to better manage pain and HrQoL in this population.

A Multicenter Study Evaluating the Effect of Ulipristal Acetate during Myomectomy.

STUDY OBJECTIVE: To compare surgical experience at myomectomy between patients with myomas pretreated with ulipristal acetate versus no pretreatment. DESIGN: A prospective, observational, multicenter study of myomectomy procedures by any route (hysteroscopic, laparoscopic, or laparotomy) (Canadian Task Force classification II-2). SETTING: Five university-affiliated hospitals including tertiary care and community sites. PATIENTS: Any patient who underwent hysteroscopic, laparotomic, or laparoscopic myomectomy regardless of medical pretreatment. INTERVENTIONS: Surgeons completed a Web-based questionnaire after each myomectomy procedure. Surgeons evaluated visualization, the myoma-myometrium relationship, extrusion, fluid deficit, blood loss, and overall ease of hysteroscopic myomectomies. For laparotomic/laparoscopic myomectomies, plane delineation, myoma separation, blood loss, and overall ease were assessed. The total surgical experience score was calculated by summing the values for each subscale. MEASUREMENTS AND MAIN RESULTS: A total of 309 myomectomies were evaluated by 52 surgeons (response rate = 83%) at 5 institutions. Of 140 hysteroscopic myomectomies, 84 (60%) were performed without pretreatment, 29 (21%) after ulipristal acetate pretreatment, and 27 (19%) after pretreatment with gonadotropin-releasing hormone agonist/other. Of 169 laparotomic/laparoscopic myomectomies, 104 (62%) were performed without pretreatment, 46 (27%) after ulipristal acetate, and 19 (11%) after gonadotropin-releasing hormone agonist/other. The mean surgical experience score (±standard deviation) was comparable between the no pretreatment and ulipristal acetate groups for hysteroscopic myomectomies (13.8 ± 2.2 vs 13.3 ± 2.2, p = .35) and laparotomic/laparoscopic myomectomies (12.9 ± 4.1 vs 12.1 ± 4.2, p = .30). Compared with no pretreatment, more laparotomic/laparoscopic myomectomies after ulipristal acetate pretreatment were associated with difficult delineation of surgical planes (22 [47.8%] vs 23 [22.1%], p = .002) and difficult myoma separation (20 [43.5%] vs 21 [20.2%], p = .003). More myomas were described as soft with ulipristal acetate pretreatment (14 [30.4%] vs 17 [16.4%], p = .049). The rates of profuse/abundant endometrium during hysteroscopy were similar between the no pretreatment (21 [25.0%]) and ulipristal acetate (7 [24.1%], p = .93) groups. CONCLUSION: Despite differences in surgical nuances, the overall myomectomy experience was not negatively affected by ulipristal acetate pretreatment.

Interaction of ARC and Daxx: A Novel Endogenous Target to Preserve Motor Function and Cell Loss after Focal Brain Ischemia in Mice.

UNLABELLED: The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenous ARC protein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD). TAT.ARC protein delivery led to a dose-dependent better survival after OGD. Infarct sizes 72 h after 60 min middle cerebral artery occlusion (MCAo) were on average 30 ± 8% (mean ± SD; p = 0.005; T2-weighted MRI) smaller in TAT.ARC-treated mice (1 µg intraventricularly during MCAo) compared with controls. TAT.ARC-treated mice showed better performance in the pole test compared with TAT.ß-Gal-treated controls. Importantly, post-stroke treatment (3 h after MCAo) was still effective in affording reduced lesion volume by 20 ± 7% (mean ± SD; p < 0.05) and better functional outcome compared with controls. Delayed treatment in mice subjected to 30 min MCAo led to sustained neuroprotection and functional behavior benefits for at least 28 d. Functionally, TAT.ARC treatment inhibited DAXX-ASK1-JNK signaling in the ischemic brain. ARC interacts with DAXX in a CARD-dependent manner to block DAXX trafficking and ASK1-JNK activation. Our work identifies for the first time ARC-DAXX binding to block ASK1-JNK activation as an ARC-specific endogenous mechanism that interferes with neuronal cell death and ischemic brain injury. Delayed delivery of TAT.ARC may present a promising target for stroke therapy. SIGNIFICANCE STATEMENT: Up to now, the only successful pharmacological target of human ischemic stroke is thrombolysis. Neuroprotective pharmacological strategies are needed to accompany therapies aiming to achieve reperfusion. We describe that apoptosis repressor with CARD (ARC) interacts and inhibits DAXX and proximal signals of cell death. In a murine stroke model mimicking human malignant infarction in the territory of the middle cerebral artery, TAT.ARC salvages brain tissue when given during occlusion or 3 h delayed with sustained functional benefits (28 d). This is a promising novel therapeutic approach because it appears to be effective in a model producing severe injury by interfering with an array of proximal signals and effectors of the ischemic cascade, upstream of JNK, caspases, and BIM and BAX activation.

Skeletal muscle mechanics, energetics and plasticity.

The following papers by Richard Lieber (Skeletal Muscle as an Actuator), Thomas Roberts (Elastic Mechanisms and Muscle Function), Silvia Blemker (Skeletal Muscle has a Mind of its Own: a Computational Framework to Model the Complex Process of Muscle Adaptation) and Sabrina Lee (Muscle Properties of Spastic Muscle (Stroke and CP) are summaries of their representative contributions for the session on skeletal muscle mechanics, energetics and plasticity at the 2016 Biomechanics and Neural Control of Movement Conference (BANCOM 2016). Dr. Lieber revisits the topic of sarcomere length as a fundamental property of skeletal muscle contraction. Specifically, problems associated with sarcomere length non-uniformity and the role of sarcomerogenesis in diseases such as cerebral palsy are critically discussed. Dr. Roberts then makes us aware of the (often neglected) role of the passive tissues in muscles and discusses the properties of parallel elasticity and series elasticity, and their role in muscle function. Specifically, he identifies the merits of analyzing muscle deformations in three dimensions (rather than just two), because of the potential decoupling of the parallel elastic element length from the contractile element length, and reviews the associated implications for the architectural gear ratio of skeletal muscle contraction. Dr. Blemker then tackles muscle adaptation using a novel way of looking at adaptive processes and what might drive adaptation. She argues that cells do not have pre-programmed behaviors that are controlled by the nervous system. Rather, the adaptive responses of muscle fibers are determined by sub-cellular signaling pathways that are affected by mechanical and biochemical stimuli; an exciting framework with lots of potential. Finally, Dr. Lee takes on the challenging task of determining human muscle properties in vivo. She identifies the dilemma of how we can demonstrate the effectiveness of a treatment, specifically in cases of muscle spasticity following stroke or in children with cerebral palsy. She then discusses the merits of ultrasound based elastography, and the clinical possibilities this technique might hold. Overall, we are treated to a vast array of basic and clinical problems in skeletal muscle mechanics and physiology, with some solutions, and many suggestions for future research.

E-Learning with virtual teammates: A novel approach to interprofessional education.

The Institute of Medicine identified interprofessional education (IPE) as a key innovation for achieving the triple aim of better care, better outcomes, and reduced healthcare costs. Yet, a shortage of qualified faculty and difficulty with aligning learners' schedules often prevent sustainable and scalable IPE. A virtual IPE intervention was developed to circumvent these barriers and compared to a blended-learning IPE intervention. We used a pre-test and post-test design with two comparison interventions to test the effects of these IPE interventions on changes in teamwork knowledge, skills, and attitudes. The interventions were delivered to pre-licensure learners at a large, metropolitan medical and a nursing school. We used one-sample and independent-sample t-tests to analyze data from 220 learners who received the blended-learning intervention in 2011 and 540 learners who received the virtual learning intervention in 2012. The students in the blended-learning intervention did not significantly (p < 0.05) outperform the students in the virtual learning intervention for any of the measured outcomes, except for medical students' attitudes around team value. Virtual IPE learning is an effective, scalable, and sustainable solution for imparting foundational teamwork knowledge in health profession students.

Aging Does Not Alter Ankle, Muscle, and Tendon Stiffness at Low Loads Relevant to Stance.

Older adults have difficulty maintaining balance when faced with postural disturbances, a task that is influenced by the stiffness of the triceps surae and Achilles tendon. Age-related changes in Achilles tendon stiffness have been reported at matched levels of effort, but measures typically have not been made at matched loads, which is important due to age-dependent changes in strength. Moreover, there has been limited investigation into age-dependent changes in muscle stiffness. Here, we investigate how age alters muscle and tendon stiffness and their influence on ankle stiffness. We hypothesized that age-related changes in muscle and tendon contribute to reduced ankle stiffness in older adults and evaluated this hypothesis when either load or effort were matched. We used B-mode ultrasound with joint-level perturbations to quantify ankle, muscle, and tendon stiffness across a range of loads and efforts in seventeen healthy younger and older adults. At matched loads relevant to standing and the stance phase of walking, there was no significant difference in ankle, muscle, or tendon stiffness between groups (all p > 0.13). However, at matched effort, older adults exhibited a significant decrease in ankle (27%; p = 0.008), muscle (37%; p = 0.02), and tendon stiffness (22%; p = 0.03) at 30% of maximum effort. This is consistent with our finding that older adults were 36% weaker than younger adults in plantarflexion (p = 0.004). Together, these results indicate that, at the loads tested in this study, there are no age-dependent changes in the mechanical properties of muscle or tendon, only differences in strength that result in altered ankle, muscle, and tendon stiffness at matched levels of effort.

ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis.

BACKGROUND & AIMS: Acetaminophen (AAP) overdose is the most frequent cause of drug-induced liver failure. c-Jun N-terminal kinase (JNK) is thought to play a central role in AAP-induced hepatocellular necrosis. The apoptosis repressor with caspase recruitment domain (ARC) is a death repressor that inhibits death receptor and mitochondrial apoptotic signaling. Here, we investigated ARC's therapeutic effect and molecular mechanisms on AAP-induced hepatocellular necrosis. METHODS: We tested the in vivo and in vitro effects of ARC fused with the transduction domain of HIV-1 (TAT-ARC) on murine AAP hepatotoxicity. RESULTS: Treatment with TAT-ARC protein completely abrogated otherwise lethal liver failure induced by AAP overdose in C57BL/6 mice. AAP triggered caspase-independent necrosis, as evidenced by liver histology, elevated serum transaminases, and secreted HMGB1 that was inhibited by ARC. ARC-mediated hepatoprotection was not caused by an alteration of AAP metabolism, but resulted in reduced oxidative stress. AAP overdose led to induction of RIP-dependent signaling with subsequent JNK activation. Ectopic ARC inhibited JNK activation by specific interactions between ARC and JNK1 and JNK2. Importantly, survival of mice was even preserved when ARC therapy was initiated in a delayed manner after AAP administration. CONCLUSIONS: This work identifies for the first time ARC-JNK-binding with subsequent inhibition of JNK signaling as a specific mechanism of ARC to interfere with AAP-dependent necrosis. Our data suggests that AAP-mediated induction of RIP signaling serves as a critical switch for hepatocellular necrosis. The efficacy of TAT-ARC protein transduction in murine AAP hepatotoxicity suggests its therapeutic potential for reversing AAP intoxication also in humans.

Recruitment of faster motor units is associated with greater rates of fascicle strain and rapid changes in muscle force during locomotion.

Animals modulate the power output needed for different locomotor tasks by changing muscle forces and fascicle strain rates. To generate the necessary forces, appropriate motor units must be recruited. Faster motor units have faster activation-deactivation rates than slower motor units, and they contract at higher strain rates; therefore, recruitment of faster motor units may be advantageous for tasks that involve rapid movements or high rates of work. This study identified motor unit recruitment patterns in the gastrocnemii muscles of goats and examined whether faster motor units are recruited when locomotor speed is increased. The study also examined whether locomotor tasks that elicit faster (or slower) motor units are associated with increased (or decreased) in vivo tendon forces, force rise and relaxation rates, fascicle strains and/or strain rates. Electromyography (EMG), sonomicrometry and muscle-tendon force data were collected from the lateral and medial gastrocnemius muscles of goats during level walking, trotting and galloping and during inclined walking and trotting. EMG signals were analyzed using wavelet and principal component analyses to quantify changes in the EMG frequency spectra across the different locomotor conditions. Fascicle strain and strain rate were calculated from the sonomicrometric data, and force rise and relaxation rates were determined from the tendon force data. The results of this study showed that faster motor units were recruited as goats increased their locomotor speeds from level walking to galloping. Slow inclined walking elicited EMG intensities similar to those of fast level galloping but different EMG frequency spectra, indicating that recruitment of the different motor unit types depended, in part, on characteristics of the task. For the locomotor tasks and muscles analyzed here, recruitment patterns were generally associated with in vivo fascicle strain rates, EMG intensity and tendon force. Together, these data provide new evidence that changes in motor unit recruitment have an underlying mechanical basis, at least for certain locomotor tasks.

Approximating the influence of external factors on the technical efficiency score of hospital care: evidence from the federal states of Germany.

BACKGROUND: A good health care system and, especially, the provision of efficient hospital care are the goals of national and regional health policies. However, the scope of general hospital care in the 16 federal states in Germany varies considerably from region to region. The objectives of this paper are to evaluate the technical efficiencies of all general hospitals of the 16 federal states for the period from 2015 to 2020, to find out the relation between the exogenous factors and score of efficiency, and also the influence of the COVID-19 pandemic on the results of the technical efficiency of hospital care in the German states. METHODS: A two-step approach was used. First, an input-oriented Data Envelopment Analysis model with constant returns to scale and variable returns to scale was applied for the 6-year period from 2015 to 2020. The calculation of technical efficiency according to the input-oriented DEA model contains the three components-total technical efficiency (TTE), pure technical efficiency (PTE) and scale efficiency (SE). In the second stage, the influence of exogenous variables on the previously determined technical efficiency was evaluated by applying the tobit regression analysis. RESULTS: Although the level of average technical efficiency of about 90% is high, total technical efficiency deteriorated steadily from 2015 to 2020. Its lowest point at around 78%, was in the year 2020. The deterioration of the average technical efficiency is notably influenced by the lower results in the years 2019 and 2020. The decomposition of technical efficiency also revealed that the deterioration of overall average efficiency was influenced by both pure technical efficiency (PTE) and scale efficiency (SE). Based on the tobit regression analysis performed, it was possible to conclude that the change in the efficiency score can be explained by the influence of exogenous factors only from 6.4% for overall efficiency and from 7.1% for scale efficiency. CONCLUSIONS: The results of the analysis of the overall technical efficiency reveal that the aggregated data of all general hospitals of all 16 federal states show a steadily worsening total technical efficiency every year since 2015. Although, especially, the deterioration of the year 2020 with the occurrence of COVID-19 pandemic, contributes to a deteriorated efficiency average, the deterioration of the efficiency values, based on the analysis performed, is also observable between the years 2016 and 2019. Considering the output generated, for inefficient units and the relevant policy authorities in the hospital sector, it can be recommended that the number of beds and in particular the number of physicians, should be reduced as inputs. Based on this study, it is also recommended that decisions to increase the efficiency of general hospitals should be made with consideration of exogenous factors such as the change in the number of general hospitals or the population density in the respective state, as these had explanatory value in connection with the increase in efficiency values. Due to the wide variation in the size of the federal states, the recommendation is more appropriate for federal states with low population density.

Axial stress determines the velocity of shear wave propagation in passive but not active muscles in vivo.

Ultrasound shear wave elastography can be used to characterize mechanical properties of unstressed tissue by measuring shear wave velocity (SWV), which increases with increasing tissue stiffness. Measurements of SWV have often been assumed to be directly related to the stiffness of muscle. Some have also used measures of SWV to estimate stress, since muscle stiffness and stress covary during active contractions, but few have considered the direct influence of muscle stress on SWV. Rather, it is often assumed that stress alters the material properties of muscle, and in turn, shear wave propagation. The objective of this study was to determine how well the theoretical dependency of SWV on stress can account for measured changes of SWV in passive and active muscles. Data were collected from six isoflurane-anesthetized cats; three soleus muscles and three medial gastrocnemius muscles. Muscle stress and stiffness were measured directly along with SWV. Measurements were made across a range of passively and actively generated stresses, obtained by varying muscle length and activation, which was controlled by stimulating the sciatic nerve. Our results show that SWV depends primarily on the stress in a passively stretched muscle. In contrast, the SWV in active muscle is higher than would be predicted by considering only stress, presumably due to activation-dependent changes in muscle stiffness. Our results demonstrate that while SWV is sensitive to changes in muscle stress and activation, there is not a unique relationship between SWV and either of these quantities when considered in isolation.NEW & NOTEWORTHY Ultrasound shear wave elastography may be an inexpensive way to measure muscle stress in passive muscle. Here, using a cat model we directly measured shear wave velocity (SWV), muscle stress, and muscle stiffness. Our results show that SWV depends primarily on the stress in a passively stretched muscle. In contrast, the SWV in active muscle is higher than would be predicted by considering only stress, presumably due to activation-dependent changes in muscle stiffness.