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Treatment protocols for youth-internalizing disorders have been developed, however these protocols have yielded mixed findings in routine care settings. Despite increased recognition of the importance of flexibility when delivering evidence-based treatments (EBTs), little is known about the extent to which protocols offer guidance to providers in flexible EBT implementation. The current study examined the extent to which supported EBTs for youth internalizing disorders explicitly incorporate guidance for treatment modification.Supported treatment protocols for youth internalizing disorders were identified (N = 44), from which 4,021 modification guidelines were extracted and coded using a structured coding system to classify modification strategies (i.e., the forms that recommended modifications take), and associated tailoring factors (i.e., the rationale for which modifications are recommended).Across all EBTs, modification guidelines were quite common, with the average protocol including almost 91 text passages providing guidance for modification. The majority of modification guidelines functionallyFindings highlight critical gaps in the available guidance to modify EBTs for youth internalizing disorders, and suggest EBT protocols may not be optimally poised to flexibly address the broad diversity of children and adolescents across varied settings in need of mental health care.

Integrating animals into therapy is applied increasingly in patients in a minimally conscious state (MCS). This pilot study investigates the effect of animal presence on frontal brain activity in MCS patients compared to healthy subjects. O; 2; HB, HHb and tHb of two MCS patients and two healthy adults was measured in frontal cortex using functional near-infrared spectroscopy during three sessions with a live animal and three sessions with a mechanical toy animal present. Each session had five phases: (1) baseline, (2) watching animal, (3) passive contact, (4) active contact, (5) neutral. Data were descriptively analysed. All participants showed the largest hemodynamic response during direct contact with the live or toy animal compared to "baseline" and "watching." During active contact, three of the four participants showed a stronger response when stroking the live compared to the toy animal. All participants showed an inverted signal with higher HHb than O; 2; Hb concentrations while stroking the live or toy animal. Animal contact leads to a neurovascular reaction in both MCS patients and healthy subjects, indicating elevated neural activity in the frontal cortex. We conclude that while a toy animal can elicit attention processes, active contact to a living animal is combined with emotional processes.

The creation of an arteriovenous fistula in obese patients with end-stage-renal-disease, might not lead to a successful hemodialysis session, partly due to excess adipose tissue overlapping the enlarged vein. This review summarizes the available evidence on superficialization methods in studies dealing with obese patients.An English-language literature search was undertaken in the MEDLINE/SCOPUS databases looking for publications that described procedures of salvaging autologous arteriovenous access in upper extremities of obese patients. Perioperative outcomes including technical and clinical success, mean vein depth reduction, wound complications and patency rates were compared within all identified techniques.We identified 12 prospective and 8 retrospective studies. A total of 1149 patients with a mean age 57.2 (range: 49-68) years and a mean BMI 35.8 (range: 28.2-40.8) kg/mIn obese patients, all superficialisation techniques report high technical success rates. Although limited by the design of individual published studies and lack of a standard for reporting outcomes, these results lead to satisfactory postoperative and early outcomes. In aggregate, lipectomy and transposition are more clinically effective and more durable procedures.

The generation of retinal organoids from human pluripotent stem cells (hPSC) is now a well-established process that in part recapitulates retinal development. However, hPSC-derived photoreceptors that exhibit well-organized outer segment structures have yet to be observed. To facilitate improved inherited retinal disease modeling, we determined conditions that would support outer segment development in maturing hPSC-derived photoreceptors. We established that the use of antioxidants and BSA-bound fatty acids promotes the formation of membranous outer segment-like structures. Using new protocols for hPSC-derived retinal organoid culture, we demonstrated improved outer segment formation for both rod and cone photoreceptors, including organized stacked discs. Using these enhanced conditions to generate iPSC-derived retinal organoids from patients with X-linked retinitis pigmentosa, we established robust cellular phenotypes that could be ameliorated following adeno-associated viral vector-mediated gene augmentation. These findings should aid both disease modeling and the development of therapeutic approaches for the treatment of photoreceptor disorders.

Objective: To investigate whether the crossed-limb technique confers better or worse clinical outcomes compared to the standard straight limb configuration in standard endovascular aneurysm repair (EVAR). Methods: We conducted a systematic review to identify studies comparing outcomes of EVAR with the crossed versus standard limb configuration. MEDLINE, EMBASE, CINAHL, and CENTRAL were searched in March 2021 using the Healthcare Databases Advanced Search interface developed by the National Institute for Heath and Care Excellence. The risk of bias was assessed with the Newcastle-Ottawa scale (NOS) and the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool. Summary estimates were calculated using the odds ratio (OR), risk difference (RD), or mean difference (MD) and 95% confidence interval (CI), applying the Mantel-Haenszel or inverse variance statistical method. Random-effects models were employed. Results: Four observational studies qualified for inclusion, reporting a total of 1132 patients. All presented contemporary experiences. Baseline clinical characteristics were largely similar between patients with and without the crossed-limb configuration, but the anatomy tended to be less favourable in patients treated with the crossed-limb technique. No statistically significant difference was found in the primary outcomes: limb occlusion (OR 1.44, 95% CI 0.65 – 3.19), type Ib endoleak (RD 0.01, 95% CI -0.03 – 0.04), type III endoleak (RD 0.01, 95% CI -0.01 – 0.03); or secondary outcomes: perioperative mortality (RD 0.00, 95% CI -0.03 – 0.03), type Ia endoleak (RD 0.00, 95% CI -0.03 – 0.02), type II endoleak (OR 1.38, 95% CI 0.51 – 3.74), procedure duration (MD 18.07 min, 95% CI -1.14–37.29). Inconsistency across studies was low for all outcomes. The studies were judged to be of high quality on the NOS. The main bias identified using the ROBINS-I tool was due to confounding. Conclusion: The crossed-limb technique was not found to confer inferior clinical outcomes in the medium term compared to the standard limb configuration in patients who undergo standard EVAR.

The Incraft aortic stent graft (Cordis, Bridgewater, NJ, USA) is a trimodular endovascular stent graft with a conventional suprarenal active fixation specifically designed to overcome the anatomic limitation of small, stenotic, and tortuous iliac vessels.The present article provides a complete description of the Incraft stent graft, its clinical performance, its technical characteristics as well as a comparison with other competitive endografts.The Incraft stent graft is an EVAR ultra low-profile device initially designed for overcoming the limitation of the hostile iliac anatomy. Recently, the device is being increasingly used in real-world conditions and not only in complex iliac anatomies with good mid-term results. Whether it remains a useful EVAR toolbox or will become a workhorse endograft is yet to be determined.

Objective To determine the incidence of hospital readmission in a geriatric hip fracture population within 90 days. Methods Analysis of patients aged ≥60 years presenting with a fragility fracture of the hip from a prospective geriatric hip fracture program registry was performed. Demographics, diagnoses, treatments, complications, hospital events, and readmission for any cause within 30 and 90 days were collected. Readmission events were categorized as defined by Bundled Care Payment Initiative (BCPI)/Care for Joint Replacement payment model. Results The population included 305 patients. All-cause readmission at 30 and 90 days was 11.5% and 19.7%, respectively. Surgical site infection or prosthesis failure accounted for 2.6% of 90 days readmissions. Application of the BCPI rules identified 44 of 60 readmitted patients (73.3%) with causes attributable to the surgical event: medical (0.7%), hospital (12.1%), and mechanical (2.6%). Death within 30 days was the largest contributor to hospital-related events. Conclusions This study identified a 90-day readmission rate of nearly 20% in patients with geriatric fragility fractures. Application of the BCPI definitions currently used in the Care for Joint Replacement payment model will result in more readmissions being attributed to the index surgical event than classically considered. If bundled payment models remain the future, further investigation of this population's risk factors for readmission is needed in light of these findings. Level of evidence Prognostic and Epidemiological Level II. See Instructions for Authors for a complete description of levels of evidence.

AIM To expand upon previous validation of the Gait Outcomes Assessment List (GOAL) questionnaire in individuals with cerebral palsy (CP), to rank items by importance, and to summarize written-in (free text) goals. METHOD For this cross-sectional study, the parent-version 5.0 of the GOAL was completed by 310 consecutive caregivers of 310 individuals aged 3 to 25 years with CP (189 males, 121 females; mean [SD] age: 10y [4y 2mo]; Gross Motor Function Classification System [GMFCS] levels I-IV) concurrent with a gait analysis. Distribution properties and validity were quantified using questionnaires, kinematics, and oxygen consumption. Items classified as at least 'difficult' to perform and 'very important' to improve were considered caregiver priorities and rank ordered. Free text goals were categorized. Results were summarized for everyone and by GMFCS level. RESULTS Most scores were normally distributed. Validity was acceptable, with concurrent greater than construct validity. Among all 310 caregivers, fatigue was the highest priority, followed by gait pattern and appearance items. The rank of priorities varied by GMFCS level. Common free text goals included toileting independently as well as improved fine motor and ball sport skills. INTERPRETATION The GOAL is a valid tool that can help prioritize goals across GMFCS levels I to IV. Identifying the top goals may improve shared decision-making and prioritize research for this sample.

To perform a systematic search and review of the available literature on the learning curves (LCs) in laparoscopic and robot-assisted prostate surgery. Medline was systematically searched from 1946 to January 2021 to detect all studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, reporting on the LC in laparoscopic radical prostatectomy (LRP), laparoscopic simple prostatectomy (LSP), robot-assisted radical prostatectomy (RARP) and robot-assisted simple prostatectomy (RSP). In total, 47 studies were included for qualitative synthesis evaluating a single technique (LRP, RARP, LSP, RSP; 45 studies) or two techniques (LRP and RARP; 2 studies). All studies evaluated outcomes on real patients. RARP was the most widely investigated technique (30 studies), followed by LRP (17 studies), LSP (1 study), and RSP (1 study). In LRP, the reported LC based on operative time; estimated blood loss; length of hospital stay; positive surgical margin; biochemical recurrence; overall complication rate; and urinary continence rate ranged 40–250, 80–250, 58–200, 50–350, 110–350, 55–250, 70–350 cases, respectively. In RARP, the corresponding ranges were 16–300, 20–300, 25–200, 50–400, 40–100, 20–250, 30–200, while LC for potency rates was 80–90 cases. The definition of LC for laparoscopic and robot-assisted prostate surgery is not well defined with various metrics used among studies. Nevertheless, LCs appear to be steep and continuous. Implementation of training programs/standardization of the techniques is necessary to improve outcomes.

The endoplasmic-reticulum aminopeptidase ERAP1 processes antigenic peptides for loading on MHC-I proteins and recognition by CD8 T cells as they survey the body for infection and malignancy. Crystal structures have revealed ERAP1 in either open or closed conformations, but whether these occur in solution and are involved in catalysis is not clear. Here, we assess ERAP1 conformational states in solution in the presence of substrates, allosteric activators, and inhibitors by small-angle X-ray scattering. We also characterize changes in protein conformation by X-ray crystallography, and we localize alternate C-terminal binding sites by chemical crosslinking. Structural and enzymatic data suggest that the structural reconfigurations of ERAP1 active site are physically linked to domain closure and are promoted by binding of long peptide substrates. These results clarify steps required for ERAP1 catalysis, demonstrate the importance of conformational dynamics within the catalytic cycle, and provide a mechanism for the observed allosteric regulation and Lys/Arg528 polymorphism disease association., The endoplasmic-reticulum aminopeptidase ERAP1 processes peptides for antigen presentation. Here, the authors assess ERAP1 conformational states in solution, providing insight into the molecular mechanisms of ERAP1 substrate-length dependent catalytic activity and regulation, including the effects of autoimmune disease-associated polymorphism.

Genome editing of allogeneic T cells can provide “off-the-shelf” alternatives to autologous chimeric antigen receptor (CAR) T cell therapies. Disruption of T cell receptor α chain (TRAC) to prevent graft-versus-host disease (GVHD) and removal of CD52 (cluster of differentiation 52) for a survival advantage in the presence of alemtuzumab have previously been investigated using transcription activator–like effector nuclease (TALEN)-mediated knockout. Here, we deployed next-generation CRISPR-Cas9 editing and linked CAR expression to multiplexed DNA editing of TRAC and CD52 through incorporation of self-duplicating CRISPR guide RNA expression cassettes within the 3’ long terminal repeat of a CAR19 lentiviral vector. Three cell banks of TT52CAR19 T cells were generated and cryopreserved. A phase 1, open-label, non-randomized clinical trial was conducted and treated six children with relapsed/refractory CD19-positive B cell acute lymphoblastic leukemia (B-ALL) (NCT04557436). Lymphodepletion included fludarabine, cyclophosphamide, and alemtuzumab and was followed by a single infusion of 0.8 × 10 6 to 2.0 × 10 6 CAR19 T cells per kilogram with no immediate toxicities. Four of six patients infused with TT52CAR19 T cells exhibited cell expansion, achieved flow cytometric remission, and then proceeded to receive allogeneic stem cell transplantation. Two patients required biological intervention for grade II cytokine release syndrome, one patient developed transient grade IV neurotoxicity, and one patient developed skin GVHD, which resolved after transplant conditioning. Other complications were within expectations, and primary safety objectives were met. This study provides a demonstration of the feasibility, safety, and therapeutic potential of CRISPR-engineered immunotherapy.

Objectives: In patients with axial spondyloarthritis (axSpA) initiating their first tumor necrosis factor alpha-inhibitor (TNFi), we aimed to identify common baseline predictors of Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) inactive disease (primary objective) and clinically important improvement (CII) at 6 months, and drug retention at 12-months across 15 European registries. Methods: Baseline demographic and clinical characteristics were collected. Outcomes were investigated per registry and in pooled data using logistic regression analyses on multiply imputed data. Results: The consistency of baseline predictors in individual registries justified pooling the data. In the pooled dataset (n = 21,196), the 6-month rates for ASDAS inactive disease and ASDAS CII were 26% and 51%, and the 12-month drug retention rate 65% in patients with available data (n = 9,845, n = 6,948 and n = 21,196, respectively). Nine common baseline predictors of ASDAS inactive disease, ASDAS CII and 12-month drug retention were identified, and the odds ratios (95%-confidence interval) for ASDAS inactive disease were: age, per year: 0.97 (0.97–0.98), men vs. women: 1.88 (1.60–2.22), current vs. non-smoking: 0.76 (0.63–0.91), HLA-B27 positive vs. negative: 1.51 (1.20–1.91), TNF start year 2015–2018 vs. 2009–2014: 1.24 (1.06–1.45), CRP>10 vs. ≤10 mg/l: 1.49 (1.25–1.77), one unit increase in health assessment questionnaire (HAQ): 0.77 (0.58–1.03), one-millimeter (mm) increase in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) fatigue and spinal pain: 0.99 (0.99–1.00) and 0.99 (0.99–1.99), respectively Conclusion: Common baseline predictors of treatment response and adherence to TNFi could be identified across data from 15 European registries, indicating that they may be universal across different axSpA populations.

Strategies to reduce the burden of persistent pain in society are rooted in a biomedical paradigm. These strategies are located downstream, managing persistent pain once it has become a problem. Upstream activities that create social conditions to promote health and well-being are likely to help, yet health promotion discourse and research are lacking in pain literature. In this article, we argue that the subjective nature of pain has not sat comfortably with the objective nature of medical practice. We argue that the dominance of the biomedical paradigm, with a simplistic 'bottom-up' model of pain being an inevitable consequence of tissue damage, has been detrimental to the health and well-being of people living with persistent pain. Evidence from neuroscience suggests that bodily pain emerges as a perceptual inference based on a wide variety of contextual inputs to the brain. We argue that this supports community, societal and environmental solutions to facilitate whole-person care. We call for more salutogenic orientations to understand how people living with persistent pain can continue to flourish and function with good health. We suggest a need for 'upstream' solutions using community-based approaches to address cultural, environmental, economic and social determinants of health, guided by principles of equity, civil society and social justice. As a starting point, we recommend appraising the ways human society appreciates the aetiology, actions and solutions towards alleviating persistent pain.Persistent pain is a major healthcare challenge. Most approaches to tackle pain involve medical treatments to relieve pain once it has become a problem. There has been little research into the role of activities that promote health and well-being on pain. We argue that there needs to be more research on how people living with persistent pain can continue to flourish and function with good health. We suggest that there needs to be more attention given to health promotion and community-based approaches to tackle persistent pain and that more research is needed on cultural, environmental, economic and social factors that influence pain.

Limb lengthening by distraction osteogenesis can be performed with motorized internal devices, but intramedullary implants risk avascular necrosis of the femoral head in young children. A method of internal limb lengthening using a motorized expandable plate has been developed and preliminary results are presented.Seven skeletally immature patients (ages 2.7 to 9.7 y) with congenital femoral deficiencies underwent femoral lengthening with the use of a magnetic expandable plate. Surgical details, lengthening parameters, Limb Lengthening and Reconstruction Society-Angular deformity, Infection, Motion index, and complications were reviewed and classified according to the modified Clavien-Dindo system.An average lengthening was 4.1 cm (range, 3.3 to 4.4 cm) comprising 18% of initial femoral segment length (range, 14% to 21%). The average lengthening phase was 50.2 days (range, 40 to 57 d) and weight-bearing was initiated at an average of 13 weeks from surgery (range, 8 to 18 wk). Limb deformities and length discrepancies were of moderate complexity, with an Limb Lengthening and Reconstruction Society-Angular deformity, Infection, Motion score of 6.57 (range, 6 to 7). Complication rates were comparable to previously reported methods of femoral lengthening. One patient underwent reoperation for patellar instability and 1 patient experienced radiographic hip subluxation which was observed. Small magnitude varus was observed in regenerate in 3 of 7 cases, none requiring treatment. Preoperative planning consisted of careful localization of the corticotomy site, acute deformity correction at the lengthening site in 3 cases, and implant orientation.Limb lengthening with motorized internal plates is feasible for young children with congenital femoral deficiency for whom intramedullary lengthening is unsafe or if external fixation is to be avoided. However, the fundamental principles of distraction osteogenesis and risks of lengthening for congenital discrepancies remain unchanged. Specific considerations herein include: careful planning of implant length and positioning, adjacent joint protection with adjunctive means, and mitigating deformity of the regenerate during distraction.Level IV, retrospective case series.

BackgroundAlthough problems that impair task completion — known as operational failures — are an important focus of concern in primary care, they have remained little studied.AimTo quantify the time GPs spend on different activities during clinical sessions; to identify the number of operational failures they encounter; and to characterise the nature of operational failures and their impact for GPs.Design and settingMixed-method triangulation study with 61 GPs in 28 NHS general practices in England from December 2018 to December 2019.MethodTime–motion methods, ethnographic observations, and interviews were used.ResultsTime–motion data on 7679 GP tasks during 238 hours of practice in 61 clinical sessions suggested that operational failures were responsible for around 5.0% (95% confidence interval [CI] = 4.5% to 5.4%) of all tasks undertaken by GPs and accounted for 3.9% (95% CI = 3.2% to 4.5%) of clinical time. However, qualitative data showed that time–motion methods, which depend on pre-programmed categories, substantially underestimated operational failures. Qualitative data also enabled further characterisation of operational failures, extending beyond those measured directly in the time–motion data (for example, interruptions, deficits in equipment/supplies, and technology) to include problems linked to GPs’ coordination role and weaknesses in work systems and processes. The impacts of operational failures were highly consequential for GPs’ experiences of work.ConclusionGPs experience frequent operational failures, disrupting patient care, impairing experiences of work, and imposing burden in an already pressurised system. This better understanding of the nature and impact of operational failures allows for identification of targets for improvement and indicates the need for coordinated action to support GPs.

Background Remote tele-proctoring has been conducted in neuro-endovascular surgery, however, evidence to support its use in the fellowship training is limited. We demonstrate a novel augmented reality tele-proctoring platform to enable a remote attending to guide a fellow. Methods A consecutive series of neuro-endovascular cases were performed by a neuro-endovascular fellow with remote guidance from an attending surgeon. The fellow and attending were connected using a commercially available cloud-based platform designed to capture and stream up to four live video feeds from a clinical environment to a remote user. In this setting, two video streams were obtained directly from the anteroposterior and lateral cameras on the biplane. Additional video of the operator from a telescopic camera was streamed live to the remote attending surgeon. The attending could provide immediate vocal feedback and also deploy the platform's augmented reality tools to communicate with the fellow in the angiography suite. Results A total of 10 cases were performed on eight patients utilizing the cloud-based tele-proctoring platform to facilitate instruction. The series included diagnostic angiograms and interventions such as intracranial balloon angioplasty, carotid stenting, and intracranial stenting. All cases were a technical success. No complications or deaths occurred. When compared to similar cohort of 10 cases prior to these which utilized a traditional instruction paradigm; we saw no differences in contrast use ( p = 0.38), fluoroscopy time ( p = 0.85), or technical success. Conclusions This study demonstrates successful use of an augmented reality tele-proctoring platform to guide a neuro-endovascular fellow through complex neuro-interventional procedures from a remote setting.

Traumatic vascular injury of the brachial artery by closed posterolateral complete elbow dislocation, without fracture is an unusual injury. Based on clinical and radiological evidence, emergency treatment is necessary. We present a case of complete brachial artery rupture, with a clot resulting from a closed posterolateral elbow dislocation, without fracture. We report the early assessment and operative treatment. A brachial artery injury due to a closed elbow dislocation, without fracture is uncommon. The diagnosis poses a dilemma and the operation is a challenge. It is addressed by Orthopaedic and Vascular team.

Background Vascular trauma comprises a diagnostic and surgical challenge. Aim of this study was to present the vascular traumas treated in our Tertiary Hospital during the last 5 years. Methods We retrospectively reviewed the surgical records of our vascular department and documented the site and type of vascular injuries of the extremities along with the concurrence of musculoskeletal injuries. The type and outcome of surgical interventions were also recorded. Results Fifty-eight cases of vascular trauma were recorded (39 in the upper and 19 in the lower extremities). Overall, iatrogenic traumas accounted for 41.3% of cases. The arterial injuries of the upper limb were blunt and penetrating in 27% and 67%, respectively. The most affected artery in the upper limb was the radial artery (37.8%), followed by the ulnar artery (27%) and the brachial artery (24.3%). Orthopedic injuries were recorded in 19% of patients. Management involved simple revascularization, bypass operations, patch arterioplasty and endovascular management in 48.7%, 33.3%, 5.1%, and 5.1%, respectively. The most affected site in the lower extremity was the common femoral artery (36.8%) followed by the popliteal artery (21%). Bone fractures were reported in 5 cases (26.3%). The surgical management involved bypass, simple revascularization, patch arterioplasty in 42.1%, 26.3%, and 21%, respectively. Endovascular management was performed in 10.5%. Conclusions A considerable percentage of iatrogenic vascular injuries was recorded, affecting both the upper and lower limbs. Despite the trend toward centralization of vascular services, a basic service of vascular surgery should be available in most sites to ensure that patients with vascular injuries receive fast and appropriate care.

Background Vascular access (VA)-related high flows (HF) are common with brachial artery based fistulas. Flow-reduction procedures are indicated in symptomatic patients or asymptomatic ones with flows >2L/min. However concomitant issues increase their complexity. We describe a case of a patient suffering congestive heart failure as a result of HF brachial-basilic fistula >3L/min. A simultaneous late basilic vein transposition and revision using distal inflow (RUDI) was performed. Case report/selected technique A large diameter un-transposed arterialized basilic vein was carefully and completely mobilized up to the proximal upper arm. After harvesting an autologous great saphenous vein (GSV) segment, a new inflow anastomosis was performed in the proximal ulnar artery. At the final stage, and after tunneling the mobilizing basilic vein in a subcutaneous semicircular configuration, an end-to-end anastomosis joining the two stumps (basilic vein outflow portion and GSV inflow arterial portion) was performed. A decision-making process in order to reach this complex option is discussed. Access flow and cardiac output were greatly attenuated following our approach. After a mean follow-up of 9 months no VA complications were observed, with flow still detected below 2L/min. All cardiac symptoms and ultrasound investigations improved. Conclusion Multiple VA issues including HF pose a risk for abandonment and a challenge for the vascular surgeon. An effort towards increasing the “upper extremity life span” is advised.

Background Microsurgical transplantation of vascularized lymph nodes (VLNT) or lymphatic vessels (VLVT) alongside derivative lymphaticovenous procedures are promising approaches for treatment of lymphedema. However, clinically relevant training models for mastering these techniques are still lacking. Here we describe a new training model in human cadaver and validate its use as training tool for microsurgical lymphatic reconstruction. Methods 10 surgeons with previous exposure to microsurgery were trained in a controlled environment. Lymphatic vessel mapping and dissection in 4 relevant body regions, harvesting of five different VLNTs and one VLVT were performed in 5 fresh-frozen cadavers. The number of lymphatic vessels and lymph nodes for each VLNT were recorded. Finally, the efficacy of this model as training tool was validated using the Dundee Ready Education Environment Measure (DREEM). Results The average cumulative DREEM score over each category was 30,75 (max = 40) while individual scoring for each relevant category revealed highly positive ratings from the perspective of teaching (39,3), training 40,5 (max = 48) and self perception of the training 30,5 (max = 32) from all participants. The groin revealed the highest number of lymphatic vessels (3.2 +/- 0.29) as all other regions on the upper extremity, while the gastroepiploic VLNT had the highest number of lymph nodes (4.2 +/- 0.37). Conclusions This human cadaver model represents a new, reproducible "all-in-one" tool for effective training in lymphatic microsurgery. Its unique diligence in accurately reproducing human lymphatic anatomy, should make this model worth considering for each microsurgeon willing to approach lymphatic reconstruction.

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin’s nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method’s sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures., Small-angle X-ray scattering (SAXS) combines the high tissue penetration of X-rays with specificity to periodic nanostructures. The authors use SAXS tensor tomography (SAXS-TT) on intact mouse and human brain tissue samples, to quantify myelin levels and determine myelin integrity, myelinated axon orientation, and fibre tracts non-destructively.

Objectives Durability after endovascular aortic aneurysm repair (EVAR) is considered an ongoing topic of investigation and was always a point of concern with smaller profile devices. Recently released five-year clinical trial results using the Incraft® ultralow profile device are encouraging. However, additional real-life experience will need to assist these initial findings. Herein, we investigated the outcomes after EVAR, in real world practice using the Incraft® endograft (EG). Material and Methods Seventy-seven patients with infrarenal abdominal aortic aneurysms (AAA) ≥50 mm in diameter treated with the Incraft® device in three vascular centers were enrolled from November 2015 to July 2018. Follow-up was completed in August 2020. Selection of EVAR using the Incraft® device was individualized according to aorto-iliac morphologic features, comorbidities, history of previous abdominal surgery and preference of the patient. At the early phase of the study, we specifically opted for preferential use of this low profile EG mainly in cases of small and tortuous iliac vessels (more challenging access routes). At later stages, it was used according to surgeon preference and not specifically in complex anatomies (real-world conditions). End-points included technical success, perioperative complications, 30-day survival, endoleg patency, presence of endoleaks, sac enlargement >5 mm and clinical success. Results The primary technical success rate was 97.4% before the addition of an aortic cuff and iliac extension for a type Ia and type Ib endoleak respectively, and the repair of a maldeployment iliac component (primary-assisted and secondary technical success, 100%). Intraoperative small type II endoleaks (visible in final angiogram) were noted in 19 patients (24.7%). There were no intraoperative deaths from AAA rupture, primary conversions or conversions to aortounilateral grafts. Two complications occurred, necessitating hybrid techniques for repair (replaced of a dislodged endoleg and distal external iliac artery hemostasis). No deaths were reported within 30 days. Occlusion of an endoleg, was observed in two patients, 6 and 14 months respectively after implantation (2.6%), and were treated by femoral-femoral PTFE bypass after unsuccessful endovascular recanalization. The latter required open conversion, 3 mo later, to repair compromised flow to the inflow iliac axis. Three patients (3.9%) experienced sac enlargement >5 mm in diameter compared with the 1-month CT scan. All of these had type II endoleaks and two received embolization procedures. Eleven patients died from causes unrelated to AAA repair. Clinical success was 97.3%, 92.8% and 89.4% through 1, 2 and 3 years respectively. Conclusions EVAR with the Incraft® device might be considered a reliable option in real-world conditions and not specifically only in complex iliac anatomies.

Objective To assess the ability of ultrasound to predict successful tapering and successful discontinuation of biological DMARDs (bDMARDs) at the 2-year follow-up in RA patients in sustained remission. Methods Patients in sustained remission (DAS28-CRP ≤ 2.6) and with no radiographic progression the previous year tapered bDMARDs according to a standardized regime. A total of 119 of these patients were included in this ultrasound substudy. At baseline, clinical assessment, MRI, X-ray and ultrasound of 24 joints were performed. Ultrasound-detected synovitis was defined and scored 0–3 using the OMERACT scoring system at the joint level for both grey-scale and Doppler activity. Sum scores for each ultrasound modality were calculated for 24 joints at the patient level. The final state of treatment was assessed after 2 years. The predictive value of ultrasound measures for successful tapering and discontinuation at the 2-year follow-up was assessed via logistic regression analyses. Results Negative IgM-RF [odds ratio (OR) = 0.29, 95% CI: 0.10–0.85; P = 0.024] and lower Doppler sum score of 24 joints (OR = 0.44, 95% CI: 0.15, 0.87; P = 0.014) were independent predictors for successful discontinuation of bDMARDs at the 2-year follow-up. The predictive value of the Doppler sum score was independent of MRI findings. Previous numbers of bDMARDs were predictive of successful tapering (OR = 0.58, 95% CI: 0.35, 0.91; P = 0.018), whereas ultrasound was not. Clinical parameters were not predictive of successful tapering/discontinuation. Conclusion Doppler sum score was an independent predictor for successful discontinuation of bDMARDs at the 2-year follow-up—the odds for achieving successful discontinuation decreased by 56% per one-unit increase in Doppler sum score. Ultrasound could not predict successful tapering.

This collection of cases describes some unusual urological tumors and complications related to urological tumors and their treatment. Case 1: A case of uretero-arterial fistula in a patient with long-term ureteral stenting for ureteral oncological stricture and a second case associated to retroperitoneal fibrosis were described. Abdominal CT, pyelography, cystoscopy were useful to show the origin of the bleeding. Angiography is useful for confirming the diagnosis and for subsequent positioning of an endovascular prosthesis which represents a safe approach with reduced post-procedural complications. Case 2: A case of patient who suffered from interstitial pneumonitis during a cycle of intravesical BCG instillations for urothelial cancer. The patient was hospitalized for more than two weeks in a COVID ward for a suspected of COVID-19 pneumonia, but he did not show any evidence of SARS-CoV-2 infection during his hospital stay. Case 3: A case of a young man with a functional urinary bladder paraganglioma who was successfully managed with complete removal of the tumor, leaving the urinary bladder intact. Case 4: A case of a 61 year old male suffering from muscle invasive bladder cancer who was admitted for a radical cystectomy and on the eighth postoperative day developed microangiopathic hemolytic anemia and thrombocytopenia, which clinically defines thrombotic microangiopathy.

The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA), and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review methods with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified, and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOP into chemical risk assessment.

Blood clot formation initiates ischemic events, but coagulation roles during postischemic tissue repair are poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation, as well as immune and vascular signaling, by protease activated receptors (PARs). Here, we show that endothelial EPCR-PAR1 signaling supports reperfusion and neovascularization in hindlimb ischemia in mice. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated by biased PAR1 agonism in isolated primary endothelial cells. Loss of EPCR-PAR1 signaling upregulated hemoglobin expression and reduced endothelial nitric oxide (NO) bioavailability. Defective angiogenic sprouting was rescued by the NO donor DETA-NO, whereas NO scavenging increased hemoglobin and mesenchymal marker expression in human and mouse endothelial cells. Vascular specimens from patients with ischemic peripheral artery disease exhibited increased hemoglobin expression, and soluble EPCR and NO levels were reduced in plasma. Our data implicate endothelial EPCR-PAR1 signaling in the hypoxic response of endothelial cells and identify suppression of hemoglobin expression as an unexpected link between coagulation signaling, preservation of endothelial cell NO bioavailability, support of neovascularization, and prevention of fibrosis.

OBJECTIVE To retrospectively review a large population of long cephalomedullary nails with special attention to distal implant position in the sagittal plane and assess the ability to avoid anterior cortical contact (ACC) by bending the distal tip of the nail intraoperatively. DESIGN Retrospective review of single surgeon experience. SETTING Single Level 1 trauma center. OUTCOMES Radiographic position of the cephalomedullary nail with respect to the anterior femoral cortex and the effects of intraoperative bending of the distal tip of the nail. PATIENTS A total of 215 patients who underwent long cephalomedullary nailing for peritrochanteric hip fractures between 2007 and 2017 were reviewed. RESULTS In the period between 2007 and October 2013, ACC of the distal portion of the nail in the sagittal plane was a common finding. Its incidence significantly decreased after intraoperative bending of long cephalomedullary nails was incorporated into practice in cases where sagittal plane impingement was detected (P < 0.0001). ACC was more prevalent if the final nail position was proximal to the level of the patella. CONCLUSION Careful attention should be paid to sagittal plane anatomy and distal ACC during insertion of a long cephalomedullary nail. One strategy to prevent anterior impingement or perforation may be intraoperative bending of the distal end of the nail. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Objective To assess the efficacy and safety of the IL-1b inhibitor canakinumab in all adults with refractory Still's disease identified from the National Organization For Medicines for off-label drug use. Methods : In a retrospective longitudinal multicenter cohort of 50 patients (median age 39 years) with active Still's disease despite treatment with corticosteroids (n = 11), conventional and synthetic (n = 34) and/or biologic disease modifying anti-rheumatic drugs (n = 30), we assessed the efficacy of canakinumab 150–300 mg administered every 4 (n = 47) or 8 weeks (n = 3) as combination therapy or monotherapy (n = 7) during a median follow-up of 27 (3–84) months. Results Α complete response was initially observed in 78% of patients within 3 months (median), irrespective of age at disease onset. A partial response was evident in 20%. One patient had resistant disease. Treatment de-escalation was attempted in 15 of 39 complete responders and a complete drug discontinuation in 21 patients for 8 months (median). Eleven patients (22%) relapsed during treatment, one during de-escalation process, and 11 after treatment discontinuation. Overall, 9 of 11 relapses were successfully treated with canakinumab treatment intensification or re-introduction. At last visit, 18% of patients were off treatment due to remission and 26% due to disease activity. Canakinumab had a significant corticosteroid sparing effect allowing weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient. Conclusion High rates of sustained remission were observed in this, largest so far, real-life cohort of adult patients with refractory Still's disease treated with canakinumab.

Methylation profiling has become a mainstay in brain tumor diagnostics since the introduction of the first publicly available classification tool by the German Cancer Research Center in 2017. We demonstrate the capability of this system through an example of a rare case of IDH wildtype glioblastoma diagnosed in a patient previously treated for T-cell acute lymphoblastic leukemia. Our novel in-house diagnostic tool EpiDiP provided hints arguing against a radiation-induced tumor, identified a novel recurrent genetic aberration, and thus informed about a potential therapeutic target.

Background In a previous article (10.1007/s00701-019-03888-3), preliminary results of a survey, aiming to shed light on the number of surgical procedures performed and assisted during neurosurgery residency in Europe were reported. We here present the final results and extend the analyses. Methods Board-certified neurosurgeons of European Association of Neurosurgical Societies (EANS) member countries were asked to review their residency case logs and participate in a 31-question electronic survey (SurveyMonkey Inc., San Mateo, CA). The responses received between April 25, 2018, and April 25, 2020, were considered. We excluded responses that were incomplete, from non-EANS member countries, or from respondents that have not yet completed their residency. Results Of 430 responses, 168 were considered for analysis after checking in- and exclusion criteria. Survey responders had a mean age of 42.7 ± 8.8 years, and 88.8% were male. Responses mainly came from surgeons employed at university/teaching hospitals (85.1%) in Germany (22.0%), France (12.5%), the United Kingdom (UK; 8.3%), Switzerland (7.7%), and Greece (7.1%). Most responders graduated in the years between 2011 and 2019 (57.7%). Thirty-eight responders (22.6%) graduated before and 130 responders (77.4%) after the European WTD 2003/88/EC came into effect. The mean number of surgical procedures performed independently, supervised or assisted throughout residency was 540 (95% CI 424–657), 482 (95% CI 398–568), and 579 (95% CI 441–717), respectively. Detailed numbers for cranial, spinal, adult, and pediatric subgroups are presented in the article. There was an annual decrease of about 33 cases in total caseload between 1976 and 2019 (coeff. − 33, 95% CI − 62 to − 4, p = 0.025). Variables associated with lesser total caseload during residency were training abroad (1210 vs. 1747, p = 0.083) and female sex by trend (947 vs. 1671, p = 0.111), whereas case numbers were comparable across the EANS countries (p = 0.443). Conclusion The final results of this survey largely confirm the previously reported numbers. They provide an opportunity for current trainees to compare their own case logs with. Again, we confirm a significant decline in surgical exposure during training between 1976 and 2019. In addition, the current analysis reveals that female sex and training abroad may be variables associated with lesser case numbers during residency.

Background The Altura (Alt) endograft is a new design, lacking the classic main body with the flow divider. Instead, 2 proximal D-shaped endografts form a round circumference in the aortic neck for secure sealing and land in the iliac arteries in a cross-limb fashion. The aim of this computational study was to compare hemodynamically this model with the classic bifurcated (Bif) and cross-limb (Cx) endograft designs of equal total length. Methods All 3D endograft models were created using the finite volume analysis application ANSYS CFX (Ansys Inc., Canonsburg, PA, USA). The Alt inlet was constructed as 2 opposing D-shaped sections. The flow was quantified by time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and helicity. The displacement forces were also compared for all models with computational fluid dynamics analysis. Results The Alt design was associated with lower forces (range 4.0–5.9Ν) than Bif (4.17–6.15 N) and Cx (4.43–6.53 N). The 2-piece inlet site of the separated limbs of Alt has higher TAWSS than the uniform inlet segment of the Cx and the Bif model. Most importantly, the mid-segment and distal segment of the limbs in the Alt design present higher TAWSS in a greater area than the other 2 models. The inlet of the Alt design showed higher OSI than the other accommodations and similar or comparable OSI values along their mid-limb and distal limb segments. The range, location, and values or RRT were comparable between the 3 models. Helicity in the iliac limbs is more prominent in the crossed accommodations (Alt and Cx). Conclusions Only small differences in the hemodynamic indices and displacement forces were detected between the Alt and classic accommodations. From this point of view, the Alt design could be theoretically considered not inferior to other widely used endograft configurations.

BACKGROUND: The ultrasound-guided retroclavicular block (RCB) is a recently described alternative approach to brachial plexus blockade at the level of the cords. Although more distal blockade of the brachial plexus is thought to be associated with a lower incidence of phrenic nerve block, the impact of RCB on ipsilateral diaphragmatic function has not been formally investigated. OBJECTIVE: To compare the effects of supraclavicular and retroclavicular brachial plexus block on diaphragmatic function. SETTING: A single tertiary hospital, study period from December 2017 to May 2019. DESIGN: Double-blinded, randomised study. PATIENTS: A total of 40 patients undergoing upper extremity surgery below the axilla. Exclusion criteria included significant pulmonary disease, BMI more than 40 and contraindication to peripheral nerve block. INTERVENTIONS: Patients were randomised to supraclavicular or retroclavicular brachial plexus block with ropivacaine 0.5%. OUTCOME MEASURES: Phrenic block was assessed by measuring changes in diaphragmatic excursion using M-mode ultrasound, and maximum inspiratory volume on incentive spirometry from baseline, at 15 and 30 min postblock, and postoperatively. Comparative assessment of block characteristics included timing and distribution of sensory and motor block onset in the upper extremity, and scanning and block performance times. RESULTS: The incidence of phrenic block in the supraclavicular group was higher by ultrasound imaging (70 vs. 15%) and also by pulmonary function testing (55 vs. 5%), with both diaphragmatic excursion and maximum inspiratory volume decreasing to a greater extent after supraclavicular block (SCB) compared with RCB at 15, 30 min and postoperative time points (repeated measures analysis of variance, P < 0.001). There was no difference in timing and extent of distal arm block, but suprascapular and axillary nerves were more consistently blocked after SCB than after RCB. CONCLUSION: The current study confirms the hypothesis that a RCB is significantly less likely to affect ipsilateral diaphragmatic function than a SCB. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02631122

Anecdotal evidence suggests that sexual attraction is flexible, and that high levels of sexual arousal can promote sexual willingness and approach tendencies toward a priori low attractive mates. This experimental study tested whether heightened sexual arousal can lower the threshold for sexual willingness and automatic approach tendencies toward potential sex partners of low and medium attractiveness. Heterosexual male (n =54) and female (n =61) participants were randomly assigned to a sexual arousal or control condition. Approach tendencies were indexed using a reaction time task. Sexual willingness was indexed using participant ratings of willingness to kiss and to consider having sex with same- and other-sex models of low, medium, and high attractiveness. Overall, participants showed stronger approach to models of high and medium than of low attractiveness. Sexual arousal weakened this differential responding but did not result in a robust increase of approach toward less attractive other-sex or same-sex models. Sexual willingness toward less attractive models was not affected by sexual arousal. Independent of condition, women reported greater sexual willingness toward same-sex models. The current pattern of findings does not support the notion that sexual arousal promotes automatic approach and sexual willingness to a broader array of sex partners.

Background Limb lengthening by distraction osteogenesis is now achievable via motorized intramedullary devices, mitigating many complications of lengthening by external fixation. In young patients, antegrade intramedullary nailing of the femur risks avascular necrosis of the femoral head. A method of extramedullary placement of a motorized expandable intramedullary nail has been employed by the senior author to safely achieve femoral lengthening without the use of an external fixator in young patients. Methods Eleven skeletally immature patients with lower limb length discrepancy were reviewed who underwent extramedullary placement of a magnetic, expandable intramedullary nail for lengthening of the femur. Surgical details, lengthening parameters, and complications were reviewed and classified according to the modified Clavien-Dindo Classification. Results Average lengthening was 32.3 mm (range: 27 to 40 mm) comprising an average 14.8% of femoral segment length. The average lengthening duration was 6.3 weeks, and average full weight-bearing began at 12.6 weeks. All but 1 patient underwent early removal of the device at an average of 4.5 months, and 5 had immediate plating of the femur. Complications rates were comparable to other methods of femoral lengthening, including varus or procurvatum through the regenerate, and unplanned reoperation in 3 of 11 cases. Preoperative considerations included careful planning of implant length due to short femoral segments and protection of the knee joint from contracture or iatrogenic instability. Conclusions Extramedullary placement of a magnetic expandable intramedullary lengthening nail can achieve lengthening of the femur without the use of external fixation. Considerations with this technique include careful planning of implant length relative to trochanteric-physeal distance, protection against knee subluxation during lengthening, and mitigating deformity of the regenerate. Off-label, extramedullary use of these devices can be considered to decrease the burdens of external fixation in young children. The technique begs the advent of future all-internal technology specifically designed for safe limb lengthening in this age group. Level of evidence Level IV-retrospective case series.