Evaluating the effects of two different kinesiology taping techniques on shoulder range of motion and proprioception in patients with hypermobile Ehlers-Danlos syndrome: a randomized controlled trial.

Background: Ehlers-Danlos syndrome (EDS) is a common group of inherited connective tissue disorders with a prevalence as high as 0.75%-2% of the population. Physical manifestations include pain and decreased proprioception, especially in more mobile joints, such as the shoulder. The kinesiology tape (K-Tape) is often used to treat patients with shoulder dysfunction. The effectiveness of the K-Tape is uncertain, and there is a lack of studies specifically studying the K-Tape in an EDS population. Purpose: The purpose of this study was to compare the short-term effects of two different K-Tape procedures on shoulder active joint reposition (AJR) and active range of motion (AROM) in patients with hypermobile EDS (hEDS) and shoulder pain. Methods: All participants were recruited from the EDS support groups and presented with shoulder pain. Baseline demographic information was obtained for each participant, after which AROM and AJR were assessed. The participants were randomized to receive one of two K-Tape procedures. Testing was repeated immediately post-taping and 48 h post-taping. Results: Significant improvements in shoulder external (F = 10.917, p < 0.001) and internal (F = 11.736, p < 0.001) rotations were seen from baseline to immediately post-taping and baseline to 48 h post-taping in the experimental K-Tape group. There were no significant differences in the shoulder rotation in the control K-Tape group and no significant differences in either group for shoulder flexion or AJR at any time point (p > 0.05). Conclusion: K-Tape may offer short-term improvements in shoulder rotation AROM in patients with hEDS and shoulder pain.

Let's Chalk About It: Introducing the TinyTalks Curriculum, a Paradigm for Short, Virtual Chalk Talks.

ABSTRACT: In busy clinical environments, educational opportunities must be designed to accommodate learner-specific needs. Many adult learners prefer short, relevant, technology-enhanced learning. As such, electronic learning (e-learning) experiences have become a prominent part of medical education. Yet, there remain challenges to e-learning experiences in the current educational landscape. To address these challenges, the authors developed the TinyTalks paradigm, which serves as the educational foundation for the TinyTalks curriculum.The TinyTalks paradigm was developed using the existing e-learning literature and foundational principles of adult learning and related theories. The TinyTalks paradigm includes 3 ground rules: (1) all TinyTalks videos must identify a category (approach to, explanation of, or application of) to clarify the focus of the topic, (2) all TinyTalks videos must be less than 7 minutes with all material presented on one virtual chalkboard screen, and (3) all TinyTalks videos must use the hook, frame, and delivery model, which guides the creation of the video. The resulting TinyTalks curriculum is an online repository of short, chalk talk-style educational videos, developed by interdisciplinary health professionals and targeted to the level of trainees, that is available to be used flexibly by learners for just-in-time learning, flipped classroom sessions, and/or self-study.The authors used Kern's 6-step approach to curriculum development as the conceptual framework for the development and implementation of the TinyTalks curriculum at Mass General for Children (June 2021-January 2023). While developing and implementing the curriculum, the authors focused on topic selection, stakeholder recruitment, establishing a process flow, and creating a virtual home.The authors believe the TinyTalks paradigm outlines an effective educational strategy that accommodates the unique needs of both learners and teachers in the medical education setting. The next steps are to scale the TinyTalks curriculum up by expanding the content library and to evaluate its efficacy.

National Profile of the ACGME Milestones 1.0 and 2.0 within General Surgery: A Seven-Year National Study from 2014 to 2021.

PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) introduced General Surgery Milestones 1.0 in 2014 and Milestones 2.0 in 2020 as steps toward competency-based training. Analysis will inform residency programs on curriculum development, assessment, feedback, and faculty development. This study describes the distributions and trends for Milestones 1.0 and 2.0 ratings and proportion of residents not achieving the level 4.0 graduation target. METHODS: A deidentified dataset of milestone ratings for all ACGME-accredited General Surgery residency programs in the United States was used. Medians and interquartile ranges (IQR) were reported for milestone ratings at each PGY level. Percentages of PGY-5s receiving final year ratings of less than 4.0 were calculated. Wilcoxon rank sum tests were used to compare 1.0 and 2.0 median ratings. Kruskal-Wallis and Bonferroni post-hoc tests were used to compare median ratings across time periods and PGY levels. Chi-squared tests were used to compare the proportion of level 4.0 nonachievement under both systems. RESULTS: Milestones 1.0 data consisted of 13,866 residents and Milestones 2.0 data consisted of 7,633 residents. For 1.0 and 2.0, all competency domain median ratings were higher for subsequent years of training. Milestones 2.0 had significantly higher median ratings at all PGY levels for all competency domains except Medical Knowledge. Percentages of PGY-5 residents not achieving the graduation target in Milestones 1.0 ranged from 27% to 42% and in 2.0 from 5% to 13%. For Milestones 1.0, all subcompetencies showed an increased number of residents achieving the graduation target from 2014 to 2019. CONCLUSIONS: This study of General Surgery Milestones 1.0 and 2.0 data uncovered significant increases in average ratings and significantly fewer residents not achieving the graduation target under the 2.0 system. We hypothesize that these findings may be related more to rating bias given the change in rating scales, rather than a true increase in resident ability.

Encoding a magic state with beyond break-even fidelity.

To run large-scale algorithms on a quantum computer, error-correcting codes must be able to perform a fundamental set of operations, called logic gates, while isolating the encoded information from noise1-8. We can complete a universal set of logic gates by producing special resources called magic states9-11. It is therefore important to produce high-fidelity magic states to conduct algorithms while introducing a minimal amount of noise to the computation. Here we propose and implement a scheme to prepare a magic state on a superconducting qubit array using error correction. We find that our scheme produces better magic states than those that can be prepared using the individual qubits of the device. This demonstrates a fundamental principle of fault-tolerant quantum computing12, namely, that we can use error correction to improve the quality of logic gates with noisy qubits. Moreover, we show that the yield of magic states can be increased using adaptive circuits, in which the circuit elements are changed depending on the outcome of mid-circuit measurements. This demonstrates an essential capability needed for many error-correction subroutines. We believe that our prototype will be invaluable in the future as it can reduce the number of physical qubits needed to produce high-fidelity magic states in large-scale quantum-computing architectures.

Virtual training for small group facilitators.

BACKGROUND: In addition to providing patient care, interprofessional health care teams work collaboratively on a variety of projects. These projects often benefit from using facilitated small group project discussion sessions, such as the Harvard Macy Institute's (HMI) Step Back Process (SBP). Although having a trained facilitator is an important component of the SBP, only a limited number of health care professionals can attend HMI courses in person or virtually, limiting its impact. APPROACH: We developed three video-based education (VBE) modules to deliver facilitator training on the SBP, informed by principles of Mayer's cognitive theory of multimedia learning. For module development, we used a five-step approach. We evaluated effectiveness of the modules as a self-directed method to enhance SBP facilitator training. An initial survey collected demographic data and module feedback, a follow-up survey collected feedback on the modules' impact on facilitation and interviews focused on the participants' overall experience. EVALUATION: Survey results indicated that the modules were positively received and helped to improve participant confidence in facilitating. We identified four themes from the interviews: challenges of facilitating, value of group feedback, value of modules for experienced facilitators and the modules as part of a multi-modal approach to train new facilitators. IMPLICATIONS: This innovation provides insight on delivering facilitator training on the SBP using VBE. Health professions educators developing online facilitator training could adapt our development process and modify implementation guided by our results. Future work should evaluate the best methods to integrate VBE modules into a longitudinal virtual community and assess facilitation techniques.

Interrogation and validation of the interactome of neuronal Munc18-interacting Mint proteins with AlphaFold2.

Munc18-interacting proteins (Mints) are multidomain adaptors that regulate neuronal membrane trafficking, signaling, and neurotransmission. Mint1 and Mint2 are highly expressed in the brain with overlapping roles in the regulation of synaptic vesicle fusion required for neurotransmitter release by interacting with the essential synaptic protein Munc18-1. Here, we have used AlphaFold2 to identify and then validate the mechanisms that underpin both the specific interactions of neuronal Mint proteins with Munc18-1 as well as their wider interactome. We found that a short acidic α-helical motif within Mint1 and Mint2 is necessary and sufficient for specific binding to Munc18-1 and binds a conserved surface on Munc18-1 domain3b. In Munc18-1/2 double knockout neurosecretory cells, mutation of the Mint-binding site reduces the ability of Munc18-1 to rescue exocytosis, and although Munc18-1 can interact with Mint and Sx1a (Syntaxin1a) proteins simultaneously in vitro, we find that they have mutually reduced affinities, suggesting an allosteric coupling between the proteins. Using AlphaFold2 to then examine the entire cellular network of putative Mint interactors provides a structural model for their assembly with a variety of known and novel regulatory and cargo proteins including ADP-ribosylation factor (ARF3/ARF4) small GTPases and the AP3 clathrin adaptor complex. Validation of Mint1 interaction with a new predicted binder TJAP1 (tight junction-associated protein 1) provides experimental support that AlphaFold2 can correctly predict interactions across such large-scale datasets. Overall, our data provide insights into the diversity of interactions mediated by the Mint family and show that Mints may help facilitate a key trigger point in SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) complex assembly and vesicle fusion.

Giving Literal Thanks: An ACGME-Sponsored Initiative to Bring Residents Back to the Bedside.

Background Resident burnout is at an all-time high. In response, the Accreditation Council for Graduate Medical Education (ACGME) developed the Back to Bedside grant for resident-led burnout interventions that increase the time residents spend with patients. Objective We designed a resident-patient reading intervention, Giving Literal Thanks (GLT), intended to increase meaningful time residents spend with patients and thereby decrease burnout. Methods All 65 pediatric residents rotating through our academic hospital's inpatient units from Fall 2019 through Fall 2021 were invited to read and gift books to their patients. We studied our intervention's relationship to resident burnout using a convergent mixed-methods design, including anonymous, unlinked pre-, peri-, and post-intervention surveys and focus groups. Qualitative and quantitative data were analyzed separately, then integrated to describe burnout pre- and post-intervention. Results Forty-one of 65 residents (63.1%) completed pre-intervention surveys, and 8 of 65 (12.3%) completed post-intervention surveys. Twenty-seven resident-patient reading interactions were recorded, and 2 focus groups were held (1 pre- and 1 post-intervention). Five themes were identified: (1) limited opportunities exist to spend time at the bedside; (2) spending time at the bedside is valuable; (3) other responsibilities may preclude time at the bedside; (4) GLT could promote positive outcomes; and (5) GLT might not be the right tool to reduce burnout. Further quantitative data analysis was prevented by low survey response rates. While GLT was positively received and feasible, we were unable to show an improvement in burnout. Conclusions GLT was well-regarded but may not improve resident burnout.

The PDLIM family of actin-associated proteins and their emerging role in membrane trafficking.

The PDZ and LIM domain (PDLIM) proteins are associated with the actin cytoskeleton and have conserved in roles in metazoan actin organisation and function. They primarily function as scaffolds linking various proteins to actin and its binding partner α-actinin via two conserved domains; an N-terminal postsynaptic density 95, discs large and zonula occludens-1 (PDZ) domain, and either single or multiple C-terminal LIN-11, Isl-1 and MEC-3 (LIM) domains in the actinin-associated LIM protein (ALP)- and Enigma-related proteins, respectively. While their role in actin organisation, such as in stress fibres or in the Z-disc of muscle fibres is well known, emerging evidence also suggests a role in actin-dependent membrane trafficking in the endosomal system. This is mediated by a recently identified interaction with the sorting nexin 17 (SNX17) protein, an adaptor for the trafficking complex Commander which is itself intimately linked to actin-directed formation of endosomal recycling domains. In this review we focus on the currently understood structural basis for PDLIM function. The PDZ domains mediate direct binding to distinct classes of PDZ-binding motifs (PDZbms), including α-actinin and other actin-associated proteins, and a highly specific interaction with the type III PDZbm such as the one found in the C-terminus of SNX17. The structures of the LIM domains are less well characterised and how they engage with their ligands is completely unknown. Despite the lack of experimental structural data, we find that recently developed machine learning-based structure prediction methods provide insights into their potential interactions and provide a template for further studies of their molecular functions.

CRISPR-Cas9 Direct Fusions for Improved Genome Editing via Enhanced Homologous Recombination.

DNA repair in mammalian cells involves the coordinated action of a range of complex cellular repair machinery. Our understanding of these DNA repair processes has advanced to the extent that they can be leveraged to improve the efficacy and precision of Cas9-assisted genome editing tools. Here, we review how the fusion of CRISPR-Cas9 to functional domains of proteins that directly or indirectly impact the DNA repair process can enhance genome editing. Such studies have allowed the development of diverse technologies that promote efficient gene knock-in for safer genome engineering practices.

Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome.

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

Evaluating the effects of two different kinesiology taping techniques on shoulder pain and function in patients with hypermobile Ehlers-Danlos syndrome.

Background: Ehlers-Danlos Syndrome (EDS) is a group of inherited connective tissue disorders which predominantly affects women and has a prevalence as high as 1 in 5,000 individuals. Hypermobile EDS (hEDS) is the most common subtype of EDS and is characterized by multi-joint pain, particularly in large joints such as the shoulder. Physical therapy is often utilized to address the pain, physical impairments, and functional loss in patients with EDS. Kinesiology Tape (KT) is an intervention commonly used by physical therapists for treating shoulder pain and dysfunction. Studies related to the effectiveness of KT in patients with shoulder pain is equivocal and there are a lack of studies specifically studying the effects of KT in an EDS population. Purpose: The purpose of this study was to assess the efficacy and short-term effects of two different KT techniques on shoulder pain and function in individuals with hEDS and shoulder pain. Methods: Participants were recruited from EDS support groups in the New England area of the United States; were diagnosed with hEDS by their physician; and had shoulder pain. Baseline demographic information was obtained for each participant followed by completion of 4 patient reported outcome (PRO) measures: the Upper Extremity Functional Index, QuickDASH (Disabilities of the Arm, Shoulder, & Hand), Shoulder Pain and Disability Index, and the Western Ontario Shoulder Instability Index. Current pain level, average pain over the past 24 h, and worst pain over the past 24 h were recorded using the numeric pain rating scale (NPRS). Subjects were randomly assigned to receive either an experimental shoulder KT procedure or a control shoulder taping. Immediately after taping, the NPRS was reassessed. Subjects then returned 48 h later to repeat the NPRS and PRO measures. Results: There was no significant difference between the experimental and control tape groups for any outcome measure. There was a significant improvement from pre-taping to 48-hours post taping for each of the 4 PRO measures with large effect sizes (p < 0.001; ƞ p 2 = .517-.719). Likewise, average, and worst pain over the last 24 h significantly improved with large effect sizes over the same period (p = 0.005; ƞ p 2 = .225 and p < 0.001; ƞ p 2 = .382, respectively). Current NPRS levels significantly improved from pre-tape to immediately post-tape (p = .023, ƞ p 2 = .131) and was maintained through the 48-hour follow up, although no further improvement was seen. Conclusion: KT is an inexpensive and relatively safe intervention that is easy to apply and can offer temporary improvements in pain and function for patients with EDS and shoulder pain.

Effect of Increased Interprofessional Familiarity on Team Performance, Communication, and Psychological Safety on Inpatient Medical Teams: A Randomized Clinical Trial.

Importance: In large academic centers, medical residents work on multiple clinical floors with transient interactions with nursing colleagues. Although teamwork is critical in delivering high-quality medical care, little research has evaluated the effect of interprofessional familiarity on inpatient team performance. Objective: To determine the effectiveness of increased familiarity between medical residents and nurses on team performance, psychological safety, and communication. Design, Setting, and Participants: A 12-month randomized clinical trial in an inpatient general medical service at a large academic medical center was completed from June 25, 2019, to June 24, 2020. Participants included 33 postgraduate year (PGY)-1 residents in an internal medicine residency program and 91 general medicine nurses. Interventions: Fifteen PGY-1 residents were randomized to complete all 16 weeks of their general medicine inpatient time on 1 medical nursing floor (intervention group with 43 nurses). Eighteen PGY-1 residents completed 16 weeks on 4 different general medical floors as per usual care (control group with 48 nurses). Main Outcomes and Measures: The primary outcome was an assessment of team performance in physician-nurse simulation scenarios completed at 6 and 12 months. Interprofessional communication was assessed via a time-motion study of both work rounds and individual resident clinical work. Psychological safety and teamwork culture were assessed via surveys of both residents and nurses at multiple time points. Results: Of the intervention and control PGY-1 residents, 8 of 15 (54%) and 8 of 18 (44%) were women, respectively. Of the nurses in the intervention and control groups with information available, 37 of 40 (93%) and 34 of 38 (90%) were women, respectively, and more than 70% had less than 10 years of clinical experience. There was no difference in overall team performance during the first simulation. At the 12-month simulation, the intervention teams received a higher mean overall score in leadership and management (mean [SD], 2.47 [0.53] vs 2.17 [0.39]; P = .045, Cohen d = 0.65) and on individually rated items were more likely to work as 1 unit (100% vs 62%; P = .003), negotiate with the patient (61% vs 10%; P = .001), support other team members (61% vs 24%; P = .02), and communicate as a team (56% vs 19%; P = .02). The intervention teams were more successful in achieving the correct simulation case outcome of negotiating a specific insulin dose with the patient (67% vs 14%; P = .001). Time-motion analysis noted intervention teams were more likely to have a nurse present on work rounds (47% vs 28%; P = .03). At 6 months, nurses in the intervention group were more likely to report their relationship with PGY-1 residents to be excellent to outstanding (74% vs 40%; P = .003), feel that the input of all clinical practitioners was valued (95% vs 53%; P < .001), and say that feedback between practitioners was delivered in a way to promote positive interactions (90% vs 60%; P = .003). These differences diminished at the 12-month survey. Conclusions and Relevance: In this randomized clinical trial, increased familiarity between nurses and residents promoted more rapid improvement of nursing perception of team relationships and, over time, led to higher team performance on complex cognitive tasks in medical simulations. Medical centers should consider team familiarity as a potential metric to improve physician-nursing teamwork and patient care. Trial Registration: ClinicalTrials.gov Identifier: NCT05213117.

Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins.

The sorting nexin SNX17 controls endosomal recycling of transmembrane cargo proteins including integrins, the amyloid precursor protein, and lipoprotein receptors. This requires association with the Commander trafficking complex and depends on the C terminus of SNX17 through unknown mechanisms. Using proteomics, we find that the SNX17 C terminus is sufficient for Commander interaction and also associates with members of the PDZ and LIM domain (PDLIM) family. SNX17 contains a type III PDZ binding motif that binds specifically to the PDLIM proteins. The structure of the PDLIM7 PDZ domain bound to the SNX17 C terminus reveals an unconventional perpendicular peptide interaction mediated by electrostatic contacts and a uniquely conserved proline-containing loop sequence in the PDLIM protein family. Our results define the mechanism of SNX17-PDLIM interaction and suggest that the PDLIM proteins may play a role in regulating the activity of SNX17 in conjunction with Commander and actin-rich endosomal trafficking domains.

Finding my people: Effects of student identity and vulnerability to Stereotype Threat on sense of belonging in surgery.

BACKGROUND: Diversity in surgery lags behind the medical student population. We documented first-year medical students' vulnerability to stereotype threat (VST) and its impact on a sense of belonging in surgery. METHODS: All first-year medical students at a single academic institution were surveyed. Demographics, VST, anticipated clerkship experience, and sense of belonging were assessed. RESULTS: 44% of students were vulnerable to ST in upcoming clerkships, with the majority worried about surgical clerkships. More student from races/ethnicities underrepresented in medicine (URM; 74%) and sexual minorities (62%) were vulnerable than white (30%) and heterosexual (38%) students respectively (p = 0.001 and p = 0.017). Knowing a surgeon with a shared identity would enhance belonging for most students (84%). VST was higher for those who do not anticipate working with (p < 0.001) or do not know a surgeon (p = 0.0001) who shares their identity. CONCLUSION: VST significantly influences a student's sense of belonging in surgery. More research is needed to promote inclusivity in surgery.

Passing the Scalpel: Lessons on retirement planning from retired academic surgeons.

BACKGROUND: Almost half of practicing surgeons in the United States are currently older than 55, but guidelines on how to prepare for retirement are limited. We sought to identify possible facilitators for, and obstacles to, surgeons' preparations for retirement. METHODS: A qualitative study was conducted using semi-structured interviews with clinically inactive academic surgeons. Emergent themes were identified via a grounded theory approach. RESULTS: We interviewed 12 surgeons (83% male; median age 75 years). Major barriers to retirement from surgery included uncertainty about when to retire, limited identity outside of surgery, and perception of retirement as strictly individual/private. Facilitators of a successful retirement identified by the participants included early career financial planning, awareness of career trajectory, development of post-surgery goals, and utilization of collective knowledge. CONCLUSION: There are numerous barriers encountered by surgeons seeking to transition from clinical practice to retirement that could be overcome by dedicated departmental and institutional efforts.

Eyes of the Beholders: First-year medical students' perceptions of surgeons and the field of surgery.

BACKGROUND: Medical students have negative perceptions of surgery prior to their clerkships. To explore possible explanations, we examined the association between these perceptions, individual identity and vulnerability to stereotype threat (ST). METHODS: All first-year medical students at a single school received an electronic survey which assessed identity groups, vulnerability to ST and perceptions of surgeons/surgery. Multi-method analyses examined these associations. RESULTS: Women held more negative than positive views about the field of surgery (p = 0.007) but not surgeons. Students vulnerable to ST had negative views about both surgeons (p < 0.0001) and surgery (p = 0.007). They were also less interested in pursuing a surgical career compared to non-vulnerable students (56% vs. 80% p = 0.03). CONCLUSION: For some students, negative views of surgeons and surgery appear to be associated with individual identity and ST. Future research should aim to confirm these findings and identify strategies to develop positive perceptions for these populations.

Implementation of competence by design in Canadian neurosurgery residency programs.

OBJECTIVE: The Royal College of Physicians and Surgeons of Canada (RCPSC) recently redesigned the Canadian neurosurgery residency training curriculum by implementing a competency-based model of training known as Competence by Design (CBD) centered around the assessment of Entrustable Professional Activities (EPAs). This sequential explanatory mixed-methods study evaluated potential benefits and pitfalls of CBD in Canadian neurosurgery residency education. METHODS: Two four-month interval surveys were distributed to all Canadian neurosurgery residents participating in CBD. The surveys assessed important educational components: CBD knowledge of key stakeholders, potential system barriers, and educational/psychological impacts on residents. Paired t-tests were done to assess changes over time. Based on longitudinal survey responses, semi-structured interviews were conducted to investigate in-depth residents' experience with CBD in neurosurgery. The qualitative analysis followed an explanatory approach, and a thematic analysis was performed. RESULTS: Surveys had 82% average response rate (n = 25). Over time, most residents self-reported that they retrospectively understood concepts around CBD intentions (p = 0.02). Perceived benefits included faculty evaluations with more feedback that was clearer and more objective (53% and 51%). Pitfalls included the amount of time needed to navigate through EPAs (90%) and residents forgetting to initiate EPA forms (71%). There was no significant change over time. During interviews, five key themes were found. Potential solutions identified by residents to enhance their experience included learning analytics data availability, mobile app refinement, and dedicated time to integrate EPAs in the workflow. CONCLUSION: This study was the first to assess resident-perceived benefits and pitfalls of the neurosurgery CBD training program in an educational framework context. In general, residents believed that theoretical principles behind CBD were valuable, but that technological ability and having enough time to request EPA assessments were significant barriers to success. Long-term studies are required to determine the definitive outcomes of CBD on residents' performance and ultimately, on patient care.

De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex.

The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes late-onset Parkinson's disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function, we have created a novel series of macrocyclic peptides that bind retromer with high affinity and specificity. Crystal structures show that most of the cyclic peptides bind to Vps29 via a Pro-Leu­containing sequence, structurally mimicking known interactors such as TBC1D5 and blocking their interaction with retromer in vitro and in cells. By contrast, macrocyclic peptide RT-L4 binds retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting retromer. Last, tagged peptides can be used to probe the cellular localization of retromer and its functional interactions in cells, providing novel tools for studying retromer function.

Long-term functional outcomes after an external femoral derotation osteotomy in individuals with cerebral palsy.

BACKGROUND: It is unknown how a femoral derotation osteotomy (FDO) during childhood affects functional outcomes in adulthood among individuals with bilateral cerebral palsy (CP). RESEARCH QUESTIONS: How do long-term functional outcomes after an FDO compare to matched individuals who did not have an FDO? How do outcomes change over time? METHODS: We queried the gait laboratory database for individuals who underwent an external FDO in childhood and were currently ≥25 years old. Participants returned for a long-term analysis (gait, physical examination, functional tests, imaging, questionnaires). The matched non-FDO group included only individuals in Gross Motor Function Classification System levels I-II, yielding three groups (non-FDO I-II, FDO I-II, FDO III-IV). RESULTS: Sixty-one adults (11 non-FDO, 34 FDO I-II, 16 FDO III-IV) returned 13-25 years after baseline (non-FDO) or surgery (FDO). The non-FDO and FDO I-II groups were matched at baseline on most variables, except the FDO group had weaker hip abductors. At long-term, groups were similar on gait variables (median long-term hip rotation [primary outcome], non-FDO: -4°, FDO I-II: -4°, FDO III-IV: -5°), hip abduction test, fear of falling, and most pain measures despite anteversion being 29° greater in the non-FDO group. The FDO I-II group reported more falls than the non-FDO group. All groups improved on hip rotation, foot progression, and hip abductor strength. Speed and step length decreased/tended to decrease for all three groups. Hip abduction moment and gait deviation index did not change. Improvements in the FDO groups were maintained from short- to long-term. SIGNIFICANCE: These results challenge the notion that an FDO is necessary to correct mean stance hip rotation for higher functioning individuals since nearly identical results were achieved by adulthood in the non-FDO I-II group. However, an FDO provides improvement earlier and maintenance from short- to long-term. This should factor into the shared decision-making process.