Engaging Stakeholders to Develop a Roadmap for Dry Eye and MGD PCORI-Funded Research.

Introduction: Although affecting an estimated 35% of the population, Dry Eye is not well understood by patients and the medical community. As a result, both in research and clinical settings, diagnostic and treatment protocols tend to be non-specific, ad hoc, and inadequate, with a narrow industry-driven focus. The purpose of this convening was to propose a research roadmap that orients Dry Eye researchers toward a comprehensive patient-centered approach to diagnosing and treating Dry Eye, Meibomian gland dysfunction (MGD), and related comorbidities with a goal of improving clinical outcomes for Dry Eye/MGD patients. Methods: Sixteen participants, including Dry Eye/MGD patients, caregivers, and patient advocates together with a group of experts in Dry Eye, MGD and other fields identified gaps in research on Dry Eye and MGD diagnostic and treatment approaches (age range 20-80; male to female ratio of 7:11; patients: 7). During a 2-day virtual convening, participants were assigned to topic-specific focus-group sessions to discuss and develop research questions pertaining to Dry Eye and MGD. The research questions were compiled into a proposed patient-centered roadmap for Dry Eye and MGD research. Two additional participants contributed to the proposed roadmap following the convening. Results: The focus groups identified over 80 patient-centered research questions important to patients and other stakeholders and compiled these into a proposed research roadmap. Conclusion: The convened stakeholders aim to establish a cohesive and comprehensive patient-centered approach to treating Dry Eye, Meibomian Gland Dysfunction, and comorbidities. The research roadmap will serve as a reference for researchers, educational institutions, clinicians, and others evaluating diagnostic and treatment protocols in Dry Eye and MGD.

Exploring structure/property relationships to health and environmental hazards of polymeric polyisocyanate prepolymer substances-3. Aquatic exposure and hazard of aliphatic diisocyanate-based prepolymers.

The water extractability and acute aquatic toxicity of seven aliphatic diisocyanate-based prepolymer substances were investigated to determine if lesser reactivity of the aliphatic isocyanate groups, as well as increased ionization potential of the expected (aliphatic amine-terminated) polymeric hydrolysis products, would influence their aquatic behavior compared to that of previously investigated aromatic diisocyanate-based prepolymers. At loading rates of 100 and 1,000 mg/L, only the substances having log Kow ≤9 exhibited more than 1% extractability in water, and a maximum of 66% water extractability was determined for a prepolymer having log Kow = 2.2. For the more hydrophobic prepolymer substances (log Kow values from 18-37), water extractability was negligible. High-resolution mass spectrometric analyses were performed on the water-accommodated fractions (WAF) of the prepolymers, which indicated the occurrence of primary aliphatic amine-terminated polymer species having backbones and functional group equivalent weights aligned to those of the parent prepolymers. Measurements of reduced surface tension and presence of suspended micelles in the WAFs further supported the occurrence of these surface-active cationic polymer species as hydrolysis products of the prepolymers. Despite these characteristics, the water-extractable hydrolysis products were practically non-toxic to Daphnia magna. All of the substances tested exhibited 48-h EL50 values of >1,000 mg/L, with one exception of EL50 = 157 mg/L. The results from this investigation support a grouping of the aliphatic diisocyanate-based prepolymers as a class of water-reactive polymer substances having predictable aquatic exposure and a uniformly low hazard potential, consistent with that previously demonstrated for the aromatic diisocyanate-based prepolymers.

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Comparison of glenohumeral and scapulothoracic kinematics between fastballs and curveballs during baseball pitching.

Shoulder injuries are common in baseball pitchers and primarily involve the glenohumeral joint. Past analyses have examined shoulder biomechanics during different pitch types simply as the motion of the upper arm relative to the thorax. In this study, glenohumeral and scapulothoracic kinematics were compared between fastballs and curveballs at key timepoints throughout a pitch. Upper extremity kinematics of thirteen collegiate pitchers were collected during fastball and curveball pitches with motion capture. A linear model approach was utilised to estimate scapular kinematics based on measurable humerothoracic motion. Glenohumeral kinematics were computed from the scapular and humeral motion data. Comparisons of scapulothoracic and glenohumeral kinematic variables at times of maximum glenohumeral external rotation, ball release, and maximum glenohumeral internal rotation between pitch types were made using paired t-tests with Benjamini-Hochberg corrections. There were no significant differences in glenohumeral kinematics. Fastballs elicited significantly less scapulothoracic internal rotation and more posterior tilt at maximum glenohumeral external rotation. Fastballs produced significantly less scapulothoracic internal rotation and anterior tilt at maximum glenohumeral internal rotation. This study provides further evidence that risk of injury to the glenohumeral joint may be consistent between fastballs and curveballs and offers insights into subtle differences in scapular kinematics between pitch types.

Comparison of Windup and Stretch Pitching Biomechanics in Baseball With Implications for Safety and Performance.

BACKGROUND: Historically, it was assumed by some that high leg lift with windup pitching generated more ball velocity whereas pitching from the stretch was quicker to reduce the risk of base stealing but also more stressful on the arm. However, many now believe that velocity and stress do not differ between windup and stretch and always pitching from the stretch is simpler than mastering 2 techniques. PURPOSE/HYPOTHESIS: The purpose of this study was to compare windup and stretch fastball pitching biomechanics. It was hypothesized that there would be statistically significant and clinically important differences in ball velocity, timing of angular velocities, joint kinetics, and pitching kinematics. STUDY DESIGN: Controlled laboratory study. METHODS: Fastball pitching biomechanics previously captured for 221 healthy baseball pitchers (105 professional, 52 collegiate, and 64 high school level) were analyzed. For each pitcher, data for 3 to 10 windup trials and 3 to 10 stretch trials were available. Ball velocity was recorded using a radar gun. A 12-camera, 240-Hz automated motion capture system was used to track 39 reflective markers attached to the pitcher. A total of 24 kinematic parameters, 4 temporal parameters, and 5 kinetic parameters were calculated. Data for each parameter were compared across the 2 techniques and 3 competition levels using 2-way repeated-measures analysis of variance (P < .01). Based on previous studies and the expertise of the investigators, the minimal clinically important difference (MCID) was set as 2° for angle measurements, 20 deg/s for angular velocities, 0.5 m/s for fastball velocity, and 0.3% body height × weight for normalized joint torque. RESULTS: Fastball velocity was statistically greater from the windup than stretch for the collegiate subgroup but not for the other 2 levels. The collegiate level difference was below the MCID. Pitching from the windup generated greater front knee height and required more time from initiation of leg lift to front foot contact. From foot contact to ball release, there were 11 additional small, statistically significant differences between windup and stretch; however, each of these was well below the MCID. CONCLUSION: Pitching from the stretch was quicker and should be used with runners on base to prevent stealing. Pitching from the windup and stretch produced similar ball velocity, joint kinetics, and kinematics. Thus, pitchers may choose to use both techniques or stretch only based on comfort and personal preference. CLINICAL RELEVANCE: The decision to pitch from both the windup and stretch or only from the stretch should not affect a pitcher's performance or joint stress (and injury risk).

An Interval Throwing Program for Baseball Pitchers Based upon Workload Data.

Background: Interval throwing programs (ITP) have been used for decades to enable baseball pitchers to return to competition after injury or surgery by gradually applying load to the throwing arm. Past programs have been based on personal experience; however, advances in our understanding of the biomechanics and workloads of throwing allow for a more modern data-based program to be developed. Hypothesis/Purpose: To 1) develop a updated ITP for rehabilitation of modern baseball pitchers based upon biomechanical and throwing workload data, and 2) compare the updated program with a past program to determine differences in chronic workload and acute:chronic workload ratios (ACWR). Study Design: Cross-sectional study. Methods: Workloads (i.e. daily, acute, chronic, and ACWR) for the original ITP were built from the prescribed throwing schedule. Elbow varus torque per throw was calculated based upon a relationship between elbow varus torque and throwing distance. Throw counts, daily/chronic/acute workloads, and ACWR were calculated and plotted over time. A new ITP was built to model current pitcher's throwing schedules and gradually increased ACWR over time. Results: The original ITP had a throwing schedule of 136 days, final chronic workload 15.0, and the ACWR above or below the "safe" range (i.e. 0.7 - 1.3) for 18% of the program with a peak of 1.61. The updated ITP was built to consist of a 217-day schedule, final chronic workload of 10.8, and deviated from the safe range for 9% of the program, with a peak of 1.33. Conclusion: The newly created ITP is more familiar to modern baseball pitchers while exhibiting a more gradual buildup of chronic workload than traditional ITP programs. This ITP may be used to return baseball pitchers back to competition as safely and efficiently as possible, and potentially with less risk of setbacks or reinjury. The ITP may be used following common injuries or surgeries to the throwing shoulder and elbow, such as Tommy John surgery, while also serving as a basis for future development of shorter duration ITPs. Level of Evidence: 2c.

Transgressive segregation, hopeful monsters, and phenotypic selection drove rapid genetic gains and breakthroughs in predictive breeding for quantitative resistance to Macrophomina in strawberry.

Two decades have passed since the strawberry (Fragaria x ananassa) disease caused by Macrophomina phaseolina, a necrotrophic soilborne fungal pathogen, began surfacing in California, Florida, and elsewhere. This disease has since become one of the most common causes of plant death and yield losses in strawberry. The Macrophomina problem emerged and expanded in the wake of the global phase-out of soil fumigation with methyl bromide and appears to have been aggravated by an increase in climate change-associated abiotic stresses. Here we show that sources of resistance to this pathogen are rare in gene banks and that the favorable alleles they carry are phenotypically unobvious. The latter were exposed by transgressive segregation and selection in populations phenotyped for resistance to Macrophomina under heat and drought stress. The genetic gains were immediate and dramatic. The frequency of highly resistant individuals increased from 1% in selection cycle 0 to 74% in selection cycle 2. Using GWAS and survival analysis, we found that phenotypic selection had increased the frequencies of favorable alleles among 10 loci associated with resistance and that favorable alleles had to be accumulated among four or more of these loci for an individual to acquire resistance. An unexpectedly straightforward solution to the Macrophomina disease resistance breeding problem emerged from our studies, which showed that highly resistant cultivars can be developed by genomic selection per se or marker-assisted stacking of favorable alleles among a comparatively small number of large-effect loci.

Secreted in xylem 6 (SIX6) mediates Fusarium oxysporum f. sp. fragariae race 1 avirulence on FW1-resistant strawberry cultivars.

Fusarium oxysporum f.sp. fragariae (Fof) race 1 is avirulent on cultivars with the dominant resistance gene, FW1, while Fof race 2 is virulent on FW1-resistant cultivars. We hypothesized there was a gene-for-gene interaction between a gene at the FW1 locus and an avirulence gene (AvrFW1) in Fof race 1. To identify a candidate AvrFW1, we compared genomes of twenty-four Fof race 1 and three Fof race 2 isolates. We found one candidate gene that was present in race 1, absent in race 2, highly expressed in planta, and homologous to a known effector, secreted in xylem 6 (SIX6). We knocked out SIX6 in two Fof race 1 isolates by homologous recombination. All SIX6 knockout transformants (ΔSIX6) gained virulence on FW1/fw1 cultivars, whereas ectopic transformants and the wildtype isolates remained avirulent. ΔSIX6 isolates were quantitatively less virulent on FW1/fw1 cultivars Fronteras and San Andreas than fw1/fw1 cultivars. Seedlings from an FW1/fw1 × fw1/fw1 population were genotyped for FW1 and tested for susceptibility to a SIX6 knockout isolate. Results suggested that additional minor-effect quantitative resistance genes could be present at the FW1 locus. This work demonstrates that SIX6 acts as an avirulence factor interacting with a resistance gene at the FW1 locus. The identification of AvrFW1 enables surveillance for Fof race 2 and provides insight into the mechanisms of FW1-mediated resistance.

Non-Cardiac Amyloidosis Findings Are Not Increased in African American Carriers of TTR V142I with Heart Failure and/or Arrhythmia.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive systemic disease involving the extracellular deposition of misfolded transthyretin protein. The hereditary subtype is caused by mutations in the transthyretin (TTR) gene. An estimated 2-3% of individuals of African American (AA) ancestry carry the p.Val142Ile (V142I, also referred to as V122I) TTR pathogenic variant. The non-specific clinical nature of ATTR-CM makes it challenging to diagnose clinically, and the high allele frequency of TTR V142I suggests that many patients with hereditary ATTR-CM may not have been tested. An analysis of electronic health record data from over 13,000 AA patients with a diagnostic code for heart disease or arrhythmia who also had additional amyloid-related findings were not diagnosed with amyloidosis at higher rates than those with heart failure or arrhythmia who did not have additional amyloid-related clinical diagnoses. Similarly, after genotyping 666 AA patients with heart failure or arrhythmia, TTR V142I carriers appeared to be clinically indistinguishable based on amyloid-related non-cardiac diagnoses from those who did not carry the allele. No additional TTR gene sequence variants were found in the TTR wildtype V142V patients with heart failure or arrhythmia who had additional amyloid-related diagnoses. Genetic testing for ATTR-CM may be important for timely diagnosis.

Genetic gains underpinning a little-known strawberry Green Revolution.

The annual production of strawberry has increased by one million tonnes in the US and 8.4 million tonnes worldwide since 1960. Here we show that the US expansion was driven by genetic gains from Green Revolution breeding and production advances that increased yields by 2,755%. Using a California population with a century-long breeding history and phenotypes of hybrids observed in coastal California environments, we estimate that breeding has increased fruit yields by 2,974-6,636%, counts by 1,454-3,940%, weights by 228-504%, and firmness by 239-769%. Using genomic prediction approaches, we pinpoint the origin of the Green Revolution to the early 1950s and uncover significant increases in additive genetic variation caused by transgressive segregation and phenotypic diversification. Lastly, we show that the most consequential Green Revolution breeding breakthrough was the introduction of photoperiod-insensitive, PERPETUAL FLOWERING hybrids in the 1970s that doubled yields and drove the dramatic expansion of strawberry production in California.

Workload Comparison of Contemporary Interval Throwing Programs and a Novel Optimized Program for Baseball Pitchers.

Background: In the rehabilitation of injured baseball pitchers, there is lack of consensus on how to guide a player back to pitching. It is unknown how different contemporary interval throwing programs (ITPs) progress in the amount of throwing workload. Purposes: To 1) evaluate three prominent ITPs commonly employed in baseball pitcher rehabilitation and assess whether these ITPs produce training loads that increase in a controlled, graduated manner and 2) devise an ITP that produced training loads which increased steadily over time. Study Design: Cross-sectional study. Methods: Three publicly available ITPs from prominent sports medicine institutions were analyzed. Elbow varus torque per throw was calculated from a 2nd order polynomial regression based upon a relationship between recorded torque measurements and throwing distance measured from a database of 111,196 throws. The relative rate of workload increase was measured as an acute:chronic workload ratio (ACWR). For each ITP, throw counts, daily/acute/chronic workloads, and ACWR were calculated and plotted over time. Finally, an original ITP was devised based upon a computational model that gradually increases ACWR over time and finished with an optimal chronic workload. Results: Each ITP exhibited a unique progression of throwing distances, quantities, and days to create different workload profiles. The three ITPs had throwing schedules ranging from 136 days to 187 days, ACWR spiked above or fell below a literature-defined "safe" range (i.e. 0.7 - 1.3) 19, 21, and 23 times. A novel ITP, predicated on a 146-day schedule and with a final chronic workload of 14.2, was designed to have no spikes outside of the safe range. Conclusion: Existing ITPs widely utilized for rehabilitation of baseball pitchers exhibit significantly inconsistent variation in the rate of throwing load progression. Computational modeling may facilitate more incremental workload progression in ITPs, thereby reducing injury during rehabilitation and more efficiently condition a pitcher for return to competition. Level of Evidence: 3b.

Treatment of Chronic Extensor Carpi Ulnaris Stenosing Tenosynovitis Using Ultrasound-Guided Retinaculum Release: A Case Report.

CASE: A 65-year-old man with chronic extensor carpi ulnaris (ECU) stenosing tenosynovitis who had failed treatments for 3 years was successfully treated with an ultrasound-guided retinaculum release of the sixth dorsal compartment. CONCLUSION: There are limited options in the literature for treating chronic, recalcitrant ECU tenosynovitis. We describe a novel technique in which the retinaculum overlying the ECU tendon was successfully incised under ultrasound guidance to release the sixth dorsal compartment stenosis. There was no recurrence of symptoms in the following 2 years of follow-up.

Ulnar Collateral Ligament Repair With Suture Tape Augmentation: Can You Overtighten?

BACKGROUND: There has been a renewed interest and, recently, wider implementation of ulnar collateral ligament (UCL) repair in throwing athletes because of improvement in ligament repair technology and corresponding outcome data. PURPOSE: To compare the biomechanical parameters and failure mode between 2 brace-tightening techniques for UCL repair. STUDY DESIGN: Controlled laboratory study. METHODS: Eleven matched pairs of cadaveric arms were procured. One limb from each pair underwent UCL repair with suture tape augmentation with either (1) attempted restoration of physiologic ligament tension or (2) maximal tension. Each specimen was subjected to 10 cycles of subfailure valgus torque at 90º of flexion in the intact state after UCL avulsion and then after UCL repair. Specimens were then torqued to failure. Articular contact mechanics, linear gap distance, angular displacement, failure torque, failure stiffness, and suture tape pull-through length were recorded. Two-way analysis of variance and paired t tests were used to test for statistical differences. RESULTS: There was a significant effect (P = .01) of tightening on joint contact area. There was a significant decrease in gap distance (P = .03) and angular displacement (P = .004) from the torn condition to the repaired condition for the maximum tension group, without a significant difference in gap distance from the intact condition. Failure torque and stiffness were not significantly different between groups, although there was a significant difference (P = .001) in the overall suture tape pull-through length. CONCLUSION: Although there are potential physiologic changes at time zero-including significant decreases in contact area, normalized gap distance, and normalized angular displacement with maximal tension repair-examination of failure biomechanics suggests that these effects may be mitigated over time within the construct by suture tape pull-through at the tape-anchor interface. Neither method of UCL repair with suture tape augmentation resulted in overconstraint of the elbow joint compared with the native ligament biomechanics. CLINICAL RELEVANCE: As more long-term outcome data from UCL repair with suture tape augmentation emerge, there will be wider implementation with various techniques to tension the suture tape. Examining the potential biomechanical sequelae of the UCL repair construct applied under maximal tension will help further refine recommendations for surgeons who utilize this technique for UCL repair.

Is povidone-iodine pleurodesis as effective, safe and well tolerated as talc pleurodesis for recurrent malignant pleural effusions?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'For patients with malignant pleural effusion is chemical pleurodesis with povidone-iodine as effective, safe and well tolerated as talc pleurodesis for prevention of recurrent malignant pleural effusions?'. A total of 124 papers were found during the search, of which 8 represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. At present, medical-grade talc is the most commonly used agent for chemical pleurodesis due to its high success rate, extensive history of clinical use and well-known side-effect profile. However, studies using povidone-iodine seek to establish it as a readily available,low-cost alternative to talc that can be easily administered through an intercostal catheter at the bedside. The summation of available evidence suggests that povidone-iodine is a safe, well-tolerated and equally efficacious agent for pleurodesis in the setting of malignant pleural effusion, when compared to talc.

Delivering Multidisciplinary Rehabilitation Care in Parkinson's Disease: An International Consensus Statement.

BACKGROUND: Parkinson's disease (PD) is a complex neurodegenerative disorder impacting everyday function and quality of life. Rehabilitation plays a crucial role in improving symptoms, function, and quality of life and reducing disability, particularly given the lack of disease-modifying agents and limitations of medications and surgical therapies. However, rehabilitative care is under-recognized and under-utilized in PD and often only utilized in later disease stages, despite research and guidelines demonstrating its positive effects. Currently, there is a lack of consensus regarding fundamental topics related to rehabilitative services in PD. OBJECTIVE: The goal of the international Parkinson's Foundation Rehabilitation Medicine Task Force was to develop a consensus statement regarding the incorporation of rehabilitation in PD care. METHODS: The Task Force, comprised of international multidisciplinary experts in PD and rehabilitation and people directly affected by PD, met virtually to discuss topics such as rehabilitative services, existing therapy guidelines and rehabilitation literature in PD, and gaps and needs. A systematic, interactive, and iterative process was used to develop consensus-based statements on core components of PD rehabilitation and discipline-specific interventions. RESULTS: The expert-based consensus statement outlines key tenets of rehabilitative care including its multidisciplinary approach and discipline-specific guidance for occupational therapy, physical therapy, speech language pathology/therapy, and psychology/neuropsychology across all PD stages. CONCLUSIONS: Rehabilitative interventions should be an essential component in the comprehensive treatment of PD, from diagnosis to advanced disease. Greater education and awareness of the benefits of rehabilitative services for people with PD and their care partners, and further evidence-based and scientific study are encouraged.

Accelerating genetic gains for quantitative resistance to verticillium wilt through predictive breeding in strawberry.

Verticillium wilt (VW), a devastating vascular wilt disease of strawberry (Fragaria × $\times$ ananassa), has caused economic losses for nearly a century. This disease is caused by the soil-borne pathogen Verticillium dahliae, which occurs nearly worldwide and causes disease in numerous agriculturally important plants. The development of VW-resistant cultivars is critically important for the sustainability of strawberry production. We previously showed that a preponderance of the genetic resources (asexually propagated hybrid individuals) preserved in public germplasm collections were moderately to highly susceptible and that genetic gains for increased resistance to VW have been negligible over the last 60 years. To more fully understand the challenges associated with breeding for increased quantitative resistance to this pathogen, we developed and phenotyped a training population of hybrids ( n = 564 $n = 564$ ) among elite parents with a wide range of resistance phenotypes. When these data were combined with training data from a population of elite and exotic hybrids ( n = 386 $n = 386$ ), genomic prediction accuracies of 0.47-0.48 were achieved and were predicted to explain 70%-75% of the additive genetic variance for resistance. We concluded that breeding values for resistance to VW can be predicted with sufficient accuracy for effective genomic selection with routine updating of training populations.

Nerve Transfer Surgery in Acute Flaccid Myelitis: Prognostic Factors, Long-Term Outcomes, Comparison With Natural History.

BACKGROUND: Nerve transfer surgery is sometimes offered to patients with acute flaccid myelitis (AFM). The objectives of this study were to evaluate surgical efficacy, assess which clinical and neurophysiological data are valuable for preoperative planning, and report long-term outcomes. METHODS: This is a single-center, retrospective case series of patients with AFM who received nerve transfer surgery. All patients had preoperative electromyography and nerve conduction studies (EMG/NCS). Matched control muscles that did not receive nerve transfer surgery were defined in the same cohort. RESULTS: Ten patients meeting inclusion criteria received a total of 23 nerve transfers (19 upper extremity, four lower extremity). The mean age at symptom onset was 3.8 years, surgery was 0.5 to 1.25 years after diagnosis, and mean follow-up was 2.3 years (range 1.3 to 4.5 years). Among muscles with preoperative strength Medical Research Council (MRC) grade 0, muscles receiving nerve transfers performed significantly better than those that did not (MRC grade 2.17 ± 0.42 vs 0 ± 0, respectively, P = 0.0001). Preoperative EMG/NCS predicted worse outcomes in recipient muscles with more abundant acute denervation potentials (P = 0.0098). Donor nerves found to be partially denervated performed equally well as unaffected nerves. Limited data suggested functional improvement accompanying strength recovery. CONCLUSIONS: Nerve transfer surgery is an effective strategy to restore strength for patients with AFM with persistent, severe motor deficits. Postoperative outcomes in patients with complete paralysis are better than the natural history of disease. This study demonstrates the utility of preoperative clinical and electrophysiological data in guiding patient selection for nerve transfer surgery.

Methods for Estimating Personal Disease Risk and Phylogenetic Diversity of Hematopoietic Stem Cells.

An individual's chronological age does not always correspond to the health of different tissues in their body, especially in cases of disease. Therefore, estimating and contrasting the physiological age of tissues with an individual's chronological age may be a useful tool to diagnose disease and its progression. In this study, we present novel metrics to quantify the loss of phylogenetic diversity in hematopoietic stem cells (HSCs), which are precursors to most blood cell types and are associated with many blood-related diseases. These metrics showed an excellent correspondence with an age-related increase in blood cancer incidence, enabling a model to estimate the phylogeny-derived age (phyloAge) of HSCs present in an individual. The HSC phyloAge was generally older than the chronological age of patients suffering from myeloproliferative neoplasms (MPNs). We present a model that relates excess HSC aging with increased MPN risk. It predicted an over 200 times greater risk based on the HSC phylogenies of the youngest MPN patients analyzed. Our new metrics are designed to be robust to sampling biases and do not rely on prior knowledge of driver mutations or physiological assessments. Consequently, they complement conventional biomarker-based methods to estimate physiological age and disease risk.

Is Ultrahypofractionated Whole Pelvis Radiation Therapy (WPRT) as Well Tolerated as Conventionally Fractionated WPRT in Patients With Prostate Cancer? Early Results From the HOPE Trial.

OBJECTIVE: The aim of this work was to evaluate the acute toxicity and quality-of-life (QOL) impact of ultrahypofractionated whole pelvis radiation therapy (WPRT) compared with conventional WPRT fractionation after high-dose-rate prostate brachytherapy (HDR-BT). METHODS AND MATERIALS: The HOPE trial is a phase 2, multi-institutional randomized controlled trial of men with prostate-confined disease and National Comprehensive Cancer Network unfavorable intermediate-, high-, or very-high-risk prostate cancer. Patients were randomly assigned to receive conventionally fractionated WPRT (standard arm) or ultrahypofractionated WPRT (experimental arm) in a 1:1 ratio. All patients underwent radiation therapy with 15 Gy HDR-BT boost in a single fraction followed by WPRT delivered with conventional fractionation (45 Gy in 25 daily fractions or 46 Gy in 23 fractions) or ultrahypofractionation (25 Gy in 5 fractions delivered on alternate days). Acute toxicities measured during radiation therapy and at 6 weeks posttreatment were assessed using the clinician-reported Common Terminology Criteria for Adverse Events version 5.0, and QOL was measured using the Expanded Prostate Cancer Index Composite (EPIC-50) and International Prostate Symptom Score (IPSS). RESULTS: A total of 80 patients were enrolled and treated across 3 Canadian institutions, of whom 39 and 41 patients received external radiation therapy with conventionally fractionated and ultrahypofractionated WPRT, respectively. All patients received androgen deprivation therapy except for 2 patients treated in the ultrahypofractionated arm. The baseline clinical characteristics of the 2 arms were similar, with 51 (63.8%) patients having high or very-high-risk prostate cancer disease. Treatment was well tolerated with no significant differences in the rate of acute adverse events between arms. No grade 4 adverse events or treatment-related deaths were reported. Ultrahypofractionated WPRT had a less detrimental impact on the EPIC-50 bowel total, function, and bother domain scores compared with conventional WPRT in the acute setting. By contrast, more patients treated with ultrahypofractionated WPRT reached the minimum clinical important difference on the EPIC-50 urinary domains. No significant QOL differences between arms were noted in the sexual and hormonal domains. CONCLUSIONS: Ultrahypofractionated WPRT after HDR-BT is a well-tolerated treatment strategy in the acute setting that has less detrimental impact on bowel QOL domains compared with conventional WPRT.