Relationship Between Perioperative Regional Anesthesia and the Risk of Missing Acute Compartment Syndrome Following Tibia Fractures.

BACKGROUND: The aim of this study was to determine the incidence of missed compartment syndrome in tibia fractures treated with and without regional anesthesia. METHODS: A retrospective chart review was performed of patients with operative tibial shaft or plateau fractures at a single level-one trauma hospital between January 2015 and April 2022 with a minimum of 3-month follow-up. Patients under 18 years of age, an ipsilateral knee dislocation, known neurologic injury at presentation, or prophylactic fasciotomy were excluded. We defined missed acute compartment syndrome (ACS) as a postinjury motor deficit still present at the 3-month postoperative appointment. For patients that received a peripheral nerve block, we recorded whether a continuous perineural catheter or one-time single-shot injection was performed, and the number of nerves blocked. Incidence rates for ACS were calculated with exact binomial 95% confidence intervals (CIs). Morphine milligram equivalents (MMEs) consumed 24 hours after surgery, use of nerve block, nerve block timing, and type of block were compared using Mann-Whitney and Kruskal-Wallis nonparametric tests. Statistical significance was defined as P < .05. RESULTS: The incidence of compartment syndrome diagnosed and treated during index hospitalization was 2.2% (17/791, 95% CI, 1.3%-3.4%). The incidence of missed ACS was 0.9% (7/791, 95% CI, 0.4%-1.8%). The incidence of missed ACS was not different between those who received nerve block 0.7% (4/610, 95% CI, 0.2%-1.7%), and those who did not (1.7% (3/176, 95% CI, 0.4%-4.8%) P = .19). Within patients receiving a nerve block, all patients with missed ACS (n = 4) received a perineural catheter. Similar missed ACS rates were observed between tibial shaft and plateau fractures. Patients receiving a nerve block had lower MME compared to those who did not receive a nerve block (P < .001). CONCLUSIONS: The results do not provide evidence that perioperative regional anesthesia increases the incidence of missed ACS in patients with operative tibial shaft or plateau injuries. but does decrease postoperative opioid requirements.

Comparable outcomes with intramedullary nail and plate constructs for Schatzker VI tibial plateau fractures.

BACKGROUND: Outcomes data of intramedullary nail fixation (IMN) constructs for complex Schatzker VI tibial plateau fractures are scant in the literature. This study compares the clinical and radiographic outcomes of IMN, dual plate, and single plate constructs for Schatzker IV tibial plateau fractures. METHODS: Retrospective cohort study of sixty-two patients at a University-based Level 1 trauma center who underwent open reduction internal fixation for Schatzker VI tibial plateau fracture. Constructs evaluated were IMN (with or without raft screws), dual plating, and single plating. Demographic, clinical, and radiographic outcomes were recorded. All fractures were additionally classified based on the OTA classification for sub analyses. Mean follow-up was 13.2 (SD 13.3) months. Predictors of construct selection and outcomes were evaluated with bivariate logistic regression. Outcomes were compared between groups with independent samples t-tests and Chi Square tests. RESULTS: No significant demographic differences were found between IMN, dual plate or single plate construct cohorts. There was a higher proportion of open fractures within the IMN construct group versus the dual plate cohort (21.1% vs 3.6%). No statistically significant differences in radiographic outcomes were observed between cohort groups except for small but statistically significant differences in condylar width (CW) ratio change and tibial slope; when fracture cohorts were sub analyzed by specific OTA classification, there were no significant differences in any radiographic outcomes. There was a significant difference between the ratio of OTA 41C1, C2 and C3 fractures regarding treatment allocation (p = 0.004), favoring dual plate fixation for OTA 41C3 fractures. There were no significant differences found between treatment cohorts in terms of all cause complications (p > 0.05). IMN and single plate constructs were utilized when posteromedial condyle fractures were nondisplaced or minimally displaced. CONCLUSION: Intramedullary nail fixation with or without supplemental raft screws produced similar short-term clinical and radiographic results compared to dual and single plate constructs among patients with Schatzker VI fracture types, regardless of OTA classification. Level of Evidence Level III retrospective cohort.

Introducing mobile apps to promote the well-being of German and Italian university students. A cross-national application of the Technology Acceptance Model.

Stress represents a significant risk factor for several psychophysical diseases among college students, such as depression and anxiety, which may undermine their academic functioning, resulting in high drop rates from college. Nevertheless, university services for mental health promotion are typically underutilized. As a result, professionals and authorities strive to find new ways to address students' mental health needs. In this view, mobile apps seem appropriate for well-being promotion interventions. Drawing on the Technology Acceptance Model (TAM), which is the most widely used theory on users' intention to use technologies, we assumed that perceived usefulness (PU) and perceived ease of use (PEOU) would be positively related to intention to use (INT), and PEOU would be positively related to PU among both Italian and German university students. To test our hypotheses, we replicated the same cross-sectional study in Italy (n = 255) and Germany (n = 228) with university students. Although we found partial scalar invariance of the TAM dimensions across the two nations, our predictions were only partially confirmed: PEOU was positively related to PU in the Italian sample only. Overall, this study is one of the first empirical attempts to compare TAM cross-nationally within the European context and it contributes to the small but increasing body of research investigating students' acceptance of smartphone-based interventions for stress management and well-being promotion. Understanding mobile health acceptance could help universities increase students' chances of adopting the proposed services, considering the factors influencing this choice.

Acceptance and Commitment Therapy for Major Depressive Disorder: Insights into a New Generation of Face-to-Face Treatment and Digital Self-Help Approaches.

Major depressive disorder (MDD) represents a key contributor to the global burden of mental illness given its relatively high lifetime prevalence, frequent comorbidity, and disability rates. Evidence-based treatment options for depression include pharmacotherapy and psychotherapy, such as cognitive behavioral therapy (CBT). Beyond traditional CBT, over 15 years ago, Hayes proclaimed a new generation of contextualistic and process-orientated so-called third wave of CBT interventions, including acceptance and commitment therapy (ACT). Using mindfulness and acceptance as well as commitment and behavior change processes, the transdiagnostic ACT approach aims to increase psychological flexibility as universal mechanism of behavior change and to build a value-driven orientation in life. ACT for MDD can be provided as either stand-alone individual, group, or self-help formats (e.g., apps) or combined with other approaches like behavioral activation. To date, a steadily growing empirical support from outcome and process research suggests the efficacy of ACT, which appears to work specifically through the six proposed core processes involved in psychological flexibility, such as defusion. In view of an ongoing interest of clinicians in "third-wave" CBTs and the important role of clients' preferences in providing therapy choices that work, the purpose of this chapter is to give a brief overview on the application of ACT in the treatment of MDD in adults.

[Awareness and Use of Digital Health Services in Germany: A Cross-sectional Study Representative of the Population]. / Bekanntheit und Nutzung von digitalen Gesundheitsangeboten in Deutschland: eine bevölkerungsrepräsentative Querschnittsuntersuchung.

OBJECTIVES: In light of the current efforts of health policy to implement eHealth, the question arises which sections of the population already use online self-help in order to tailor them to users' needs. The present study aims to determine the differences in the use of health information and psychological online counseling based on socio-demographic variables, health status and previous illnesses. METHODS: The basis for the cross-sectional data analyses using logistic regression analysis was the innovation sample of the German socio-economic panel. Data were collected from September 2016 to February 2017, with 4802 participants aged between 17-95 years. RESULTS: Fifty-five percent of the sample searched for health information on the Internet, while 1.1% had experience with online counseling. Logistic regression analyses showed that online search for information was significantly determined by age (Odds Ratio (OR)=0.96; 95-%-CI=0.96-0.97), gender (OR=1.20; 95-%-CI=1.05-1.36), awareness of Internet therapy (OR=2.57; 95-%-CI=2.20-3.00), experience with psychotherapy (OR=1.40; 95-%-CI=1.16-1.69) and the diagnosis of asthma (OR=1.14; 95-%-CI=1.01-1.29) or stroke (OR=0.66; 95-%-CI=0.52-0.84). Regarding the use of online counseling, awareness of Internet therapy and experience with face-to-face psychotherapy proved to be significant determinants. CONCLUSION: For the first time, a reliable picture has become available of the determinants of the awareness of internet therapy and online self-help utilization among the German public that should enable target-group-specific strategies to improve the care situation.

Impact of Injury Severity on the Inflammatory State and Severe Anemia.

BACKGROUND: Severe traumatic injury is a major cause of morbidity and mortality. Our goal was to analyze blunt traumatic injury by injury severity score (ISS) and compare with elective hip repair, as a transient injury, and healthy control with the hypothesis that more severe injury would lead to an increase in neuroendocrine activation, systemic inflammation, and worse anemia. MATERIALS AND METHODS: A prospective observational cohort study was performed at a level 1 trauma center, comparing blunt trauma patients (n = 37), elective hip replacement patients (n = 26), and healthy controls (n = 8). Bone marrow and plasma were assessed for hyperadrenergic state, erythropoiesis, and systemic inflammation. Trauma patient's ISS ranged from 4 to 41 and were broken down into quartiles for analysis. The ISS quartiles were 4-13, 14-20, 21-26, and 27-41. RESULTS: Plasma norepinephrine, interleukin-6, tumor necrosis factor-alpha, and hepcidin increased progressively as ISS increased. Hemoglobin significantly decreased as ISS increased and packed red blood cell (pRBC) transfusion increased as ISS increased. Elective hip replacement patients had an appropriate increase in the bone marrow expression of erythropoietin and the erythropoietin receptor, which was absent in all trauma patient groups. CONCLUSIONS: Increased neuroendocrine activation, systemic inflammation, and anemia correlated with worsening injury severity, lower age, and increased pRBC transfusions. Elective hip replacement patients have only minimal systemic inflammation with an appropriate bone marrow response to anemia. This study demonstrates a link between injury severity, neuroendocrine activation, systemic inflammation, and the bone marrow response to anemia.

Geospatial Analyses of Pain Intensity and Opioid Unit Doses Prescribed on the Day of Discharge Following Orthopedic Surgery.

OBJECTIVE: Inappropriate opioid prescribing after surgery contributes to opioid use disorder and risk of opioid overdose. In this cross-sectional analysis of orthopedic surgical patients, we examined the role of patient location on postoperative pain intensity and opioids prescribed on hospital discharge. METHODS: We used geospatial analyses to characterize spatial patterns of mean pain intensity on the day of discharge (PiDoD) and opioid units prescribed on the day of discharge (OuPoD), as well as the effect of regional social deprivation on these outcomes. RESULTS: At a 500-km radius from the surgery site, the Global Moran's I for PiDoD (2.71 × 10-3, variance = 1.67 × 10-6, P = 0.012) and OuPoD (2.19 × 10-3, SD = 1.87, variance = 1.66 × 10-6, P = 0.03) suggested significant spatial autocorrelation within each outcome. Local indicators of spatial autocorrelation, including local Moran's I, Local Indicator of Spatial Autocorrelation cluster maps, and Getis-Ord Gi* statistics, further demonstrated significant, specific regions of clustering both OuPoD and PiDoD. These spatial patterns were associated with spatial regions of area deprivation. CONCLUSIONS: Our results suggest that the outcomes of pain intensity and opioid doses prescribed exhibit varying degrees of clustering of patient locations of residence, at both global and local levels. This indicates that a given patient's pain intensity on discharge is related to the pain intensity of nearby individuals. Similar interpretations exist for OuPoD, although the relative locations of hot spots of opioids dispensed in a geographic area appear to differ from those of hot spots of pain intensity on discharge.

Cognitive Behavioral Therapy, Mindfulness-Based Cognitive Therapy and Acceptance Commitment Therapy for Anxiety Disorders: Integrating Traditional with Digital Treatment Approaches.

Anxiety disorders are an enormous societal burden given their high lifetime prevalence among adult populations worldwide. A variety of anxiety disorders can be successfully treated with psychological treatments such as cognitive behavioral therapy (CBT), mindfulness-based cognitive therapy (MBCT), and acceptance and commitment therapy (ACT), either as stand-alone individual or group treatment or as adjunctive treatment to pharmacotherapy. Furthermore, a growing body of evidence suggests that therapist-guided Internet-delivered CBT (iCBT) and, to some degree, digitalized mindfulness- and acceptance-based interventions may be an efficacious complement to traditional face-to-face therapy. In view of the current advances regarding the integration of traditional and innovative treatment approaches, this chapter provides an overview on the theory and evidence base for different delivery modes of CBT-related interventions for specific phobia, panic disorder, agoraphobia, social anxiety disorder, and generalized anxiety disorder in adults. Finally, implications for clinical practice and research will be derived, and future directions for the psychological treatment of anxiety disorders will be outlined.

Can an Integrative Care Approach Improve Physical Function Trajectories after Orthopaedic Trauma? A Randomized Controlled Trial.

BACKGROUND: Orthopaedic trauma patients frequently experience mobility impairment, fear-related issues, self-care difficulties, and work-related disability []. Recovery from trauma-related injuries is dependent upon injury severity as well as psychosocial factors []. However, traditional treatments do not integrate psychosocial and early mobilization to promote improved function, and they fail to provide a satisfying patient experience. QUESTIONS/PURPOSES: We sought to determine (1) whether an early psychosocial intervention (integrative care with movement) among patients with orthopaedic trauma improved objective physical function outcomes during recovery compared with usual care, and (2) whether an integrative care approach with orthopaedic trauma patients improved patient-reported physical function outcomes during recovery compared with usual care. METHODS: Between November 2015 and February 2017, 1133 patients were admitted to one hospital as orthopaedic trauma alerts to the care of the three orthopaedic trauma surgeons involved in the study. Patients with severe or multiple orthopaedic trauma requiring one or more surgical procedures were identified by our orthopaedic trauma surgeons and approached by study staff for enrollment in the study. Patients were between 18 years and 85 years of age. We excluded individuals outside of the age range; those with diagnosis of a traumatic brain injury []; those who were unable to communicate effectively (for example, at a level where self-report measures could not be answered completely); patients currently using psychotropic medications; or those who had psychotic, suicidal, or homicidal ideations at time of study enrollment. A total of 112 orthopaedic trauma patients were randomized to treatment groups (integrative and usual care), with 13 withdrawn (n = 99; 58% men; mean age 44 years ± 17 years). Data was collected at the following time points: baseline (acute hospitalization), 6 weeks, 3 months, 6 months, and at 1 year. By 1-year follow-up, we had a 75% loss to follow-up. Because our data showed no difference in the trajectories of these outcomes during the first few months of recovery, it is highly unlikely that any differences would appear months after 6 months. Therefore, analyses are presented for the 6-month follow-up time window. Integrative care consisted of usual trauma care plus additional resources, connections to services, as well as psychosocial and movement strategies to help patients recover. Physical function was measured objectively (handgrip strength, active joint ROM, and Lower Extremity Gain Scale) and subjectively (Patient-Reported Outcomes Measurement Information System-Physical Function [PROMIS®-PF] and Tampa Scale of Kinesiophobia). Higher values for hand grip, Lower Extremity Gain Scale (score range 0-27), and PROMIS®-PF (population norm = 50) are indicative of higher functional ability. Lower Tampa Scale of Kinesiophobia (score range 11-44) scores indicate less fear of movement. Trajectories of these measures were determined across time points. RESULTS: We found no differences at 6 months follow-up between usual care and integrative care in terms of handgrip strength (right handgrip strength ß = -0.0792 [95% confidence interval -0.292 to 0.133]; p = 0.46; left handgrip strength ß = -0.133 [95% CI -0.384 to 0.119]; p = 0.30), or Lower Extremity Gain Scale score (ß = -0.0303 [95% CI -0.191 to 0.131]; p = 0.71). The only differences between usual care and integrative care in active ROM achieved by final follow-up within the involved extremity was noted in elbow flexion, with usual care group 20° ± 10° less than integrative care (t [27] = -2.06; p = 0.05). Patients treated with usual care and integrative care showed the same Tampa Scale of Kinesiophobia score trajectories (ß = 0.0155 [95% CI -0.123 to 0.154]; p = 0.83). CONCLUSION: Our early psychosocial intervention did not change the trajectory of physical function recovery compared with usual care. Although this specific intervention did not alter recovery trajectories, these interventions should not be abandoned because the greatest gains in function occur early in recovery after trauma, which is the key time in transition to home. More work is needed to identify ways to capitalize on improvements earlier within the recovery process to facilitate functional gains and combat psychosocial barriers to recovery. LEVEL OF EVIDENCE: Level II, therapeutic study.

Human placenta-derived matrix with cancellous autograft and demineralized bone matrix for large segmental long-bone defects in two dogs with septic nonunion.

OBJECTIVE: To report the successful treatment of septic nonunion in two dogs with large segmental defects secondary to long-bone fractures by using a novel human placenta-derived matrix (hPM) as adjunct to fixation. ANIMALS: One 3-kg 9-year-old neutered male Yorkshire terrier with a distal antebrachial fracture and one 6-kg 4-year-old spayed female miniature pinscher with a distal humeral fracture. STUDY DESIGN: Short case series. METHODS: Both dogs presented for septic nonunion after internal fixation of Gustilo type II open diaphyseal fractures from dog bite injuries. During revision, debridement of nonviable bone resulted in segmental defects of 32% and 20% of the bone length for the antebrachial and humeral fractures, respectively. The antebrachial fracture was stabilized with a circular external fixator, and the humeral fracture was stabilized with biaxial bone plating. The fracture sites were not collapsed, and full length was maintained with the fixation. Autogenous cancellous bone graft and canine demineralized bone allograft were packed into the defects, and hPM was injected into the graft sites after closure. RESULTS: Radiographic union was documented at 8 weeks and 6 weeks for the antebrachial and humeral fractures, respectively. Both dogs became fully weight bearing on the affected limbs and returned to full activity. CONCLUSION: Augmenting fixation with grafts and hPM led to a relatively rapid union in both dogs reported here.

Comparison of Ligament-Repair Techniques for the Syndesmosis: A Simulated Cadaveric Weight-Bearing Computed Tomography Analysis.

Although the literature describes a variety of reconstructive techniques for the syndesmosis, only few studies offer comparative data. Therefore, the authors compared 2 different ligament repair techniques for the syndesmosis. Sixteen paired fresh-frozen human cadaveric lower limbs were embedded in polymethyl methacrylate mid-calf and placed in a custom-made weightbearing simulation frame. Computed tomography scans of each limb were obtained in a simulated foot-flat loading (75N) and single-leg stance (700N) in 5 different foot positions (previously reported data). One of each pair was then reconstructed via 1 of 2 methods: a free medial Achilles tendon autograft or a long peroneal tendon ligament repair. The specimens were rescanned, compared with their respective intact states and directly with each other. Measurements of fibular diastasis, rotation, anteroposterior translation, mediolateral translation, and fibular shortening were performed on the axial cuts of the computed tomography scans, 1 cm proximal to the roof of the plafond. There was no significant difference in fibular positioning with direct comparison of the reconstructions. Comparisons with their respective intact states, however, showed differences in their abilities to control reduction, most notably in the externally rotated and dorsiflexed positions of the foot. Neither reconstruction was clearly superior in restoring physiologic conditions. Only with a comparison of each technique to its respective intact state were differences between the techniques revealed, a benefit of this particular testing method.

The Postinjury Inflammatory State and the Bone Marrow Response to Anemia.

RATIONALE: The pathophysiology of persistent injury-associated anemia is incompletely understood, and human data are sparse. OBJECTIVES: To characterize persistent injury-associated anemia among critically ill trauma patients with the hypothesis that severe trauma would be associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, and decreased erythropoiesis. METHODS: A translational prospective observational cohort study comparing severely injured, blunt trauma patients who had operative fixation of a hip or femur fracture (n = 17) with elective hip repair patients (n = 22). Bone marrow and plasma obtained at the index operation were assessed for circulating catecholamines, systemic inflammation, erythropoietin, iron trafficking pathways, and erythroid progenitor growth. Bone marrow was also obtained from healthy donors from a commercial source (n = 8). MEASUREMENTS AND MAIN RESULTS: During admission, trauma patients had a median of 625 ml operative blood loss and 5 units of red blood cell transfusions, and Hb decreased from 10.5 to 9.3 g/dl. Compared with hip repair, trauma patients had higher median plasma norepinephrine (21.9 vs. 8.9 ng/ml) and hepcidin (56.3 vs. 12.2 ng/ml) concentrations (both P < 0.05). Bone marrow erythropoietin and erythropoietin receptor expression were significantly increased among patients undergoing hip repair (23% and 14% increases, respectively; both P < 0.05), but not in trauma patients (3% and 5% increases, respectively), compared with healthy control subjects. Trauma patients had lower bone marrow transferrin receptor expression than did hip repair patients (57% decrease; P < 0.05). Erythroid progenitor growth was decreased in trauma patients (39.0 colonies per plate; P < 0.05) compared with those with hip repair (57.0 colonies per plate; P < 0.05 compared with healthy control subjects) and healthy control subjects (66.5 colonies per plate). CONCLUSIONS: Severe blunt trauma was associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, erythroid progenitor growth suppression, and persistent injury-associated anemia. Clinical trial registered with www.clinicaltrials.gov (NCT 02577731).

Digital Interventions for Mental Disorders: Key Features, Efficacy, and Potential for Artificial Intelligence Applications.

Mental disorders are highly prevalent and often remain untreated. Many limitations of conventional face-to-face psychological interventions could potentially be overcome through Internet-based and mobile-based interventions (IMIs). This chapter introduces core features of IMIs, describes areas of application, presents evidence on the efficacy of IMIs as well as potential effect mechanisms, and delineates how Artificial Intelligence combined with IMIs may improve current practices in the prevention and treatment of mental disorders in adults. Meta-analyses of randomized controlled trials clearly show that therapist-guided IMIs can be highly effective for a broad range of mental health problems. Whether the effects of unguided IMIs are also clinically relevant, particularly under routine care conditions, is less clear. First studies on IMIs for the prevention of mental disorders have shown promising results. Despite limitations and challenges, IMIs are increasingly implemented into routine care worldwide. IMIs are also well suited for applications of Artificial Intelligence and Machine Learning, which provides ample opportunities to improve the identification and treatment of mental disorders. Together with methodological innovations, these approaches may also deepen our understanding of how psychological interventions work, and why. Ethical and professional restraints as well as potential contraindications of IMIs, however, should also be considered. In sum, IMIs have a high potential for improving the prevention and treatment of mental health disorders across various indications, settings, and populations. Therefore, implementing IMIs into routine care as both adjunct and alternative to face-to-face treatment is highly desirable. Technological advancements may further enhance the variability and flexibility of IMIs, and thus even further increase their impact in people's lives in the future.

Computed Tomography Analysis for Quantification of Displacement of the Distal Fibula in Different Foot Positions With Weightbearing and Sequentially Increased Instability: An Anatomic Cadaveric Study on Syndesmosis.

Syndesmotic injuries are quite common, but accurate diagnosis and treatment can be difficult, in part because of individual anatomic variation and complex movements of the fibula in the incisura. The current cadaveric study was designed to investigate changes in the position of the fibula in the incisura during simulated weightbearing in different foot positions and with sequential sectioning of syndesmotic and deltoid ligaments. Sixteen paired, fresh-frozen cadaveric limbs were embedded in polymethylmethacrylate mid-calf and placed in a weightbearing simulation frame. Computed tomography scans were obtained while the legs were in a simulated foot-flat position (75 N) and single-leg stance (700 N) in 5 foot positions: neutral, 15° external rotation, 15° internal rotation, 20° dorsiflexion, and 20° plantar flexion. The anterior-inferior tibiofibular ligament, posterior tibiofibular ligament complex, deltoid, and interosseous membranes were sectioned sequentially and rescanned. Measurements of fibular diastasis, rotation, anterior-posterior and medial-lateral translation, and fibular shortening were performed. The most destructive state resulted in the largest displacement at the syndesmosis. The degree of subluxation in all ligament states was dependent on the foot position. External rotation created statistically significant displacement at all levels of injury. There were no significant differences between sides of the same donor. Our data demonstrate the importance of foot position in reduction at the syndesmosis under weightbearing. The current ex vivo model could be used to evaluate other aspects of this injury or the value of reconstructive techniques in the future.

Friedreich and dominant ataxias: quantitative differences in cerebellar dysfunction measurements.

BACKGROUND: Sensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction. METHODS: We evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively. RESULTS: There were 383 patients with Friedreich's ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123±0.123 per year vs 0.163±0.179, P<0.001; SARA index: 1.5±1.2 vs 1.7±1.7, P<0.001), indicating slower cerebellar dysfunction indexes for FRDA than for SCA. Patients with SCA2 had higher CCFS scores than patients with SCA1 and SCA3, but similar SARA scores. CONCLUSIONS: Cerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02069509.

Influence of tibialis posterior muscle activation on foot anatomy under axial loading: A biomechanical CT human cadaveric study.

BACKGROUND: Collapse of the medial longitudinal arch and subluxation of the subtalar joint are common occurrences in adult flatfoot deformity. Controversy exists about the role of the tibialis posterior (TP) tendon as first and/or essential lesion. Subtle changes in the foot configuration can occur under weight bearing. PURPOSE: This human cadaveric study is designed to investigate the effect that isolated actuation of the TP tendon has on the medial longitudinal arch and the hindfoot configuration under simulated weight bearing. METHODS: A radiolucent frame was developed to apply axial loading on cadaveric lower legs during computer tomography (CT) examinations. Eight pairs of fresh-frozen specimens were imaged in neutral position under foot-flat loading (75N) and under single-leg stance weight bearing (700N) without and with addition of 150N pulling force on the TP tendon. Measurements of subtalar joint subluxation, forefoot arch angle and talo-first metatarsal angle were conducted on each set of CT scans. RESULTS: Subtalar subluxation, talo-first metatarsal angle and talo-navicular coverage angle significantly increased under single-leg stance weight bearing, whereas forefoot arch angle significantly decreased. Actuation of the TP tendon under weight bearing did not restore the forefoot arch angle or correct subtalar subluxation and talo-metatarsal angle. CONCLUSION: Significant effect that weight bearing has on the medial longitudinal arch and the subtalar joint configuration is demonstrated in an ex-vivo model. In absence of other medial column derangement, actuation of the TP tendon alone does not seem to reconstitute the integrity of the medial longitudinal arch or correct the hindfoot subluxation under weight bearing. CLINICAL RELEVANCE: The findings of this study together with the developed model for ex-vivo investigation provide a further insight in foot anatomy.

Does Surgical Stabilization of Lateral Compression-type Pelvic Ring Fractures Decrease Patients' Pain, Reduce Narcotic Use, and Improve Mobilization?

BACKGROUND: Debate remains over the role of surgical treatment in minimally displaced lateral compression (Young-Burgess, LC, OTA 61-B1/B2) pelvic ring injuries. Lateral compression type 1 (LC1) injuries are defined by an impaction fracture at the sacrum; type 2 (LC2) are defined by a fracture that extends through the posterior iliac wing at the level of the sacroiliac joint. Some believe that operative stabilization of these fractures limits pain and eases mobilization, but to our knowledge there are few controlled studies on the topic. QUESTIONS/PURPOSES: (1) Does operative stabilization of LC1 and LC2 pelvic fractures decrease patients' narcotic use and lower their visual analog scale pain scores? (2) Does stabilization allow patients to mobilize earlier with physical therapy? METHODS: This retrospective study of LC1 and LC2 fractures evaluated patients treated definitively at one institution from 2007 to 2013. All patients treated surgically, all nonoperative LC2, and all nonoperative LC1 fractures with complete sacral injury were included. In general, LC1 or LC2 fractures with greater than 10 mm of displacement and/or sagittal/axial plane deformity on static radiographs were treated surgically. One hundred fifty-eight patients in the LC1 group (107 [of 697 screened] nonoperative, 51 surgical) and 123 patients in the LC2 group (78 nonoperative, 45 surgical) met inclusion criteria. The surgical and nonoperative groups were matched for fracture type. To account for differences between patients treated surgically and nonoperatively, we used propensity modeling techniques incorporating treatment predictors. Propensity scores demonstrated good overlap and were used as part of multiple variable regression models to account for selection bias between the surgically treated and nonoperative groups. Patient-reported pain scores and narcotic administration were tallied in 24-hour increments during the first 24 hours of hospitalization, at 48 hours after intervention, and in the 24 hours before discharge. Time from intervention to mobilization out of bed was recorded; intervention was defined as the date of definitive surgical intervention or the day the surgeon determined the patient would be treated without surgery. RESULTS: There was no difference in the narcotics distributed to any of the groups with the exception that the patients with surgically treated LC2 fractures used, on average (mean [95% confidence interval]) 40.2 (-72.9 to -7.6) mg morphine less at the 48-hour mark (p = 0.016). In general, there were no differences between the groups' pain scores. The surgically treated patients with LC1 fractures mobilized 1.7 (-3.3 to -0.01) days earlier (p = 0.034) than their nonoperative counterparts. There was no difference in the LC2 cohort in terms of time to mobilization between those treated with and without surgery. CONCLUSIONS: There were few differences in pain scores and morphine use between the surgical and nonoperative groups, and the differences observed likely were not clinically important. We found no evidence that surgical stabilization of certain LC1 and LC2 pelvic fractures improves patients' pain, decreases their narcotic use, and improves time to mobilization. A randomized trial of patients with similar fractures and similar degrees initial displacement would help remove some of the confounders present in this study. LEVEL OF EVIDENCE: Level III, therapeutic study.

Chorein Sensitive Arrangement of Cytoskeletal Architecture.

BACKGROUND/AIMS: Chorein is a protein expressed in various cell types. Loss of function mutations of the chorein encoding gene VPS13A lead to chorea-acanthocytosis, an autosomal recessive genetic disease characterized by movement disorder and behavioral abnormalities. Recent observations revealed that chorein is a powerful regulator of actin cytoskeleton in erythrocytes, platelets, K562 and endothelial HUVEC cells. METHODS: In the present study we have used Western blotting to study actin polymerization dynamics, laser scanning microscopy to evaluate in detail the role of chorein in microfilaments, microtubules and intermediate filaments cytoskeleton architecture and RT-PCR to assess gene transcription of the cytoskeletal proteins. RESULTS: We report here powerful depolymerization of actin microfilaments both, in erythrocytes and fibroblasts isolated from chorea-acanthocytosis patients. Along those lines, morphological analysis of fibroblasts from chorea-acanthocytosis patients showed disarranged microtubular network, when compared to fibroblasts from healthy donors. Similarly, the intermediate filament networks of desmin and cytokeratins showed significantly disordered organization with clearly diminished staining in patient's fibroblasts. In line with this, RT-PCR analysis revealed significant downregulation of desmin and cytokeratin gene transcripts. CONCLUSION: Our results provide for the first time evidence that defective chorein is accompanied by significant structural disorganization of all cytoskeletal structures in human fibroblasts from chorea-acanthocytosis patients.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

Safety and tolerability of carbamylated erythropoietin in Friedreich's ataxia.

BACKGROUND: Erythropoietin (EPO) derivatives have been found to increase frataxin levels in Friedreich's ataxia (FRDA) in vitro. This multicenter, double-blind, placebo-controlled, phase II clinical trial aimed to evaluate the safety and tolerability of Lu AA24493 (carbamylated EPO; CEPO). METHODS: Thirty-six ambulatory FRDA patients harboring >400 GAA repeats were 2:1 randomly assigned to either CEPO in a fixed dose (325 µg thrice-weekly) or placebo. Safety and tolerability were assessed up to 103 days after baseline. Secondary outcome measures of efficacy (exploration of biomarkers and ataxia ratings) were performed up to 43 days after baseline. RESULTS: All patients received six doses of study medication. Adverse events were equally distributed between CEPO and placebo. There was no evidence for immunogenicity of CEPO after multiple dosing. Biomarkers, such as frataxin, or measures for oxidative stress and ataxia ratings did not differ between CEPO and placebo. CONCLUSION: CEPO was safe and well tolerated in a 2-week treatment phase. Secondary outcome measures remained without apparent difference between CEPO and placebo.