First Decade of Supportive Services for Veteran Families Program and Homelessness, 2012-2022.

As homelessness remains an urgent public health crisis in the United States, specific programs in the US Department of Veterans Affairs (VA) system may serve as a roadmap for addressing it. We examine lessons learned from the first decade (2012-2022) of the Supportive Services for Veteran Families (SSVF) program, a cornerstone in the VA continuum of homeless services aimed at both preventing homelessness among those at risk and providing rapid rehousing for veterans and their families who are currently experiencing homelessness. Drawing on information from annual reports and other relevant literature, we have identified 3 themes of SSVF that emerged as features to comprehensively deliver support for homeless veterans and their families: (1) responsiveness and flexibility, (2) coordination and integration, and (3) social resource engagement. Using these strategies, SSVF reached nearly three quarters of a million veterans and their families in its first decade, thereby becoming one of the VA's most substantial programmatic efforts designed to address homelessness. We discuss how each feature might apply to addressing homelessness in the general population as well as future research directions. (Am J Public Health. 2024;114(6):610-618. https://doi.org/10.2105/AJPH.2024.307625).

Adaptive pathology: new insights into the physical examination and imaging of the thrower's shoulder and elbow.

Throwing with high velocity requires extremes of glenohumeral external rotation of the abducted arm where particularly high forces in the shoulder and elbow are endured. Repeated throwing leads to dominant-arm bony remodeling of the humerus, glenoid, and elbow, and multiple soft tissue changes that would be considered abnormal. Many of these features are thought to be adaptive and protective. The purpose of this work is to (1) define the concept of adaptive pathology; (2) review the mechanics of the throwing motion; (3) review pertinent physical examination and imaging findings seen in asymptomatic throwers' shoulders and elbows and describe how these changes develop and may be adaptive-allowing the thrower to perform at high levels; and then (4) review the principles of surgical treatment in the throwing athletes, which should focus on reducing symptoms, but not necessarily restoring the thrower's anatomy to normal.

Obesity and sex influence fatty infiltration of the rotator cuff: the Rotator Cuff Outcomes Workgroup (ROW) and Multicenter Orthopaedic Outcomes Network (MOON) cohorts.

BACKGROUND: Fatty infiltration (FI) is one of the most important prognostic factors for outcomes after rotator cuff surgery. Established risk factors include advancing age, larger tear size, and increased tear chronicity. A growing body of evidence suggests that sex and obesity are associated with FI; however, data are limited. METHODS: We recruited 2 well-characterized multicenter cohorts of patients with rotator cuff tears (Multicenter Orthopaedic Outcomes Network [MOON] cohort [n = 80] and Rotator Cuff Outcomes Workgroup [ROW] cohort [n = 158]). We used multivariable logistic regression to evaluate the relationship between body mass index (BMI) and the presence of FI while adjusting for the participant's age at magnetic resonance imaging, sex, and duration of shoulder symptoms, as well as the cross-sectional area of the tear. We analyzed the 2 cohorts separately and performed a meta-analysis to combine estimates. RESULTS: A total of 27 patients (33.8%) in the Multicenter Orthopaedic Outcomes Network (MOON) cohort and 57 patients (36.1%) in the Rotator Cuff Outcomes Workgroup (ROW) cohort had FI. When BMI < 25 kg/m2 was used as the reference category, being overweight was associated with a 2.37-fold (95% confidence interval [CI], 0.77-7.29) increased odds of FI and being obese was associated with a 3.28-fold (95% CI, 1.16-9.25) increased odds of FI. Women were 4.9 times (95% CI, 2.06-11.69) as likely to have FI as men. CONCLUSIONS: Among patients with rotator cuff tears, obese patients had a substantially higher likelihood of FI. Further research is needed to assess whether modifying BMI can alter FI in patients with rotator cuff tears. This may have significant clinical implications for presurgical surgical management of rotator cuff tears. Sex was also significantly associated with FI, with women having higher odds of FI than men. Higher odds of FI in female patients may also explain previously reported early suboptimal outcomes of rotator cuff surgery and higher pain levels in female patients as compared with male patients.

Techno-economic and sustainability analysis of siloxane removal from landfill gas used for electricity generation.

A technoeconomic analysis (TEA) and life cycle assessment (LCA) was conducted on the use of landfill gas (LFG) for electricity generation using an internal combustion engine. This study provides insights that can guide LFG waste to energy (WTE) operators on decisions concerning installation of contaminant removal from LFG for electricity generation. Four scenarios were analyzed; the first (Scenario 1) was a facility with a single siloxane removal unit (SREU) sized for 6 months of continuous use, the second (Scenario 2) was a facility with parallel SREUs sized for one month of use, the third (Scenario 3) was a facility with no SREU, and the fourth was a facility that flared all LFG captured. The TEA revealed that the chiller cost was over 50% the total purchase cost of the LFG pre-treatment system. When the complete LFG to electricity process was analyzed, the internal combustion engine had the highest percentage of total capital investment and the total annual cost. For the base case, it became economically beneficial to install a SREU at facilities with LFG flowrates greater than ∼2000 m3/h. Sensitivity analysis showed that at a base case of 1700 m3/h, LFG (50% CH4), and 50 mg/m3 D4, the net income of facilities in Scenarios 1 to 3 became positive at an electricity sales price greater than 5.5 cents/kWh. LCA revealed that Scenario 2 had the greatest CO2 emission reduction. Scenario 3 is observed to save less CO2 emissions as biogas flowrate increases due to frequent engine shutdowns. Although there are differences in the global warming potential (GWP 100) for Scenarios 1 to 3, with Scenario 2 being the best and Scenario 3 being the worst, the differences are very small. For this reason, economics alone are sufficient in decision making.

Male Sex, Western Ontario Shoulder Instability Index Score, and Sport as Predictors of Large Labral Tears of the Shoulder: A Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability Cohort Study.

PURPOSE: To identify factors predictive of a large labral tear at the time of shoulder instability surgery. METHODS: As part of the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability cohort, patients undergoing open or arthroscopic shoulder instability surgery for a labral tear were evaluated. Patients with >270° tears were defined as having large labral tears. To build a predictive logistic regression model for large tears, the Feasible Solutions Algorithm was used to add significant interaction effects. RESULTS: After applying exclusion criteria, 1235 patients were available for analysis. There were 222 females (18.0%) and 1013 males (82.0%) in the cohort, with an average age of 24.7 years (range 12 to 66). The prevalence of large tears was 4.6% (n = 57), with the average tear size being 141.9°. Males accounted for significantly more of the large tears seen in the cohort (94.7%, P = .01). Racquet sports (P = .01), swimming (P = .02), softball (P = .05), skiing (P = .04), and golf (P = .04) were all associated with large labral tears, as was a higher Western Ontario Shoulder Instability Index (WOSI; P = .01). Age, race, history of dislocation, and injury during sport were not associated with having a larger tear. Using our predictive logistic regression model for large tears, patients with a larger body mass index (BMI) who played contact sports were also more likely to have large tears (P = .007). CONCLUSIONS: Multiple factors were identified as being associated with large labral tears at the time of surgery, including male sex, preoperative WOSI score, and participation in certain sports including racquet sports, softball, skiing, swimming, and golf. LEVEL OF EVIDENCE: I, prognostic study.

Nonoperative treatment of chronic, massive irreparable rotator cuff tears: a systematic review with synthesis of a standardized rehabilitation protocol.

PURPOSE: A massive, irreparable rotator cuff tear may cause significant pain and dysfunction. However, the efficacy of nonoperative treatment modalities in this subset of patients is not currently well known. Also, there is currently no gold standard nonoperative protocol to guide treatment. The goal of the present systematic review is to determine if there is any evidence to support the use of various nonoperative treatment modalities and synthesize a standardized nonoperative treatment protocol for the patient with a massive irreparable rotator cuff tear. METHODS: A comprehensive review of the literature utilizing PRISMA guidelines was performed. Studies involving clinical outcomes of nonoperative treatment of massive, irreparable rotator cuff tears were included. Articles were reviewed by 2 reviewers to determine inclusion or exclusion based on established criteria. Selected articles were reviewed for results of clinical and functional outcomes. The studies were also reviewed to determine their level of evidence and potential sources of bias. A standardized nonoperative treatment protocol was developed by taking described elements of the protocols used in studies that demonstrated clinical improvement beyond the MCID for the outcome scores used by the authors. RESULTS: A total of 10 studies met inclusion criteria for our studies. Of the included studies, 1 was Level III evidence and the remaining 9 were Level IV evidence. Multiple studies showed significant improvement exceeding the MCID for functional outcome scores following treatment. Also, several studies demonstrated significant improvements in strength and range of motion. The overall success of nonoperative treatment ranged from 32%-96%. The synthesized nonoperative treatment protocol is characterized by requiring some supervised physical therapy, often requiring 12 weeks or more, focusing on supine exercises with gradual progression to upright. Corticosteroid injections and nonsteroidal anti-inflammatory drugs may also be of benefit. CONCLUSION: Despite low-quality evidence, nonoperative treatment has been shown to be efficacious for patients with chronic, massive, irreparable rotator cuff tears. Using these results, a synthesized rehabilitation program was developed to guide clinicians when treating patients with massive irreparable rotator cuff tears.

Consensus statement on the treatment of massive irreparable rotator cuff tears: a Delphi approach by the Neer Circle of the American Shoulder and Elbow Surgeons.

BACKGROUND: Management of massive irreparable rotator cuff tears (MIRCTs) remains controversial owing to variability in patient features and outcomes contributing to a lack of unanimity in treatment recommendations. The purpose of this study was to implement the Delphi process using experts from the Neer Circle of the American Shoulder and Elbow Surgeons to determine areas of consensus regarding treatment options for a variety of MIRCTs. METHODS: A panel of 120 shoulder surgeons were sent a survey regarding MIRCT treatments including arthroscopic débridement and partial cuff repair, graft augmentation, reverse shoulder arthroplasty (RSA), superior capsular reconstruction (SCR), and tendon transfer. An iterative Delphi process was then conducted with a first-round questionnaire consisting of 13 patient factors with the option for open-ended responses to identify important features influencing the treatment of MIRCTs. The second-round survey sought to determine the importance of patient factors related to the 6 included treatment options. A third-round survey asked participants to classify treatment options for 60 MIRCT patient scenarios as either preferred treatment, acceptable treatment, not acceptable/contraindicated, or unsure/no opinion. Patient scenarios were declared to achieve consensus for the preferred and not acceptable/contraindicated categories when at least 80% of the survey respondents agreed on a response, and a 90% threshold was required for the acceptable treatment category, defined by an acceptable treatment or preferred treatment response. RESULTS: Seventy-two members agreed to participate and were deemed to have the requisite expertise to contribute based on their survey responses regarding clinical practice and patient volume. There were 20 clinical scenarios that reached 90% consensus as an acceptable treatment, with RSA selected for 18 scenarios and arthroscopic débridement and/or partial repair selected for 2. RSA was selected as the singular preferred treatment option in 8 scenarios. Not acceptable/contraindicated treatment options reached consensus in 8 scenarios, of which, 4 related to SCR, 3 related to RSA, and 1 related to partial repair with graft augmentation. CONCLUSION: This Delphi process exhibited significant consensus regarding RSA as a preferred treatment strategy in older patients with pseudoparesis, an irreparable subscapularis, and dynamic instability. In addition, the process identified certain unacceptable treatments for MIRCTs such as SCR in older patients with pseudoparesis and an irreparable subscapularis or RSA in young patients with an intact or reparable subscapularis without pseudoparesis or dynamic instability. The publication of these scenarios and areas of consensus may serve as a useful guide for practitioners in the management of MIRCTs.

Surgical outcomes in the Frequency, Etiology, Direction, and Severity (FEDS) classification system for shoulder instability.

BACKGROUND: The Frequency, Etiology, Direction, and Severity (FEDS) system was developed as a simple but reliable method for classifying shoulder instability based on 4 factors attainable by history and physical examination: frequency (solitary, occasional, or frequent); etiology (traumatic or atraumatic); direction (anterior, posterior, or inferior); and severity (subluxation or dislocation). This study investigated the epidemiology and 2-year surgical outcomes for the FEDS categories in the prospective Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability cohort. METHODS: At the time of surgery, 1204 patients were assigned to the FEDS categories. Follow-up data were available for 636 of 734 patients (86.6%) who had undergone surgery at least 2 years prior to analysis. The most common categories were further analyzed by patient-reported outcomes (PROs) (American Shoulder and Elbow Surgeons, Western Ontario Shoulder Instability index, Single Assessment Numeric Evaluation scores) and rates of recurrent subluxation, recurrent dislocation, and revision surgery. RESULTS: Of the 36 FEDS categories, 16 represented at least 1% of patients. Occasional traumatic anterior dislocation (OTAD) was the most common category, with 16.4% of patients. Five other anterior categories (solitary traumatic anterior subluxation, occasional traumatic anterior subluxation [OTAS], frequent traumatic anterior subluxation [FTAS], solitary traumatic anterior dislocation, and frequent traumatic anterior dislocation) and one posterior category (solitary traumatic posterior subluxation [STPS]) represented at least 5% of patients. PROs improved significantly for each category. The highest rates of recurrent subluxation occurred in FTAS, OTAS, and OTAD cases; dislocation, OTAS and FTAS cases; and further surgery, OTAD cases. The lowest rates of failure occurred in STPS cases. Downward trends in PROs and higher failure rates were noted with an increasing number of preoperative dislocations. CONCLUSION: Different FEDS categories showed varying degrees of improvement and failure rates, indicating that the system can be used to provide prognostic insight for presurgical education. Overall, outcomes decreased with a higher number of preoperative dislocations.

Decision making in treatment after a first-time anterior glenohumeral dislocation: A Delphi approach by the Neer Circle of the American Shoulder and Elbow Surgeons.

BACKGROUND: The treatment of patients who sustain a first-time anterior glenohumeral dislocation (FTAGD) is controversial. The purpose of this study was to find consensus among experts using a validated iterative process in the treatment of patients after an FTAGD. METHODS: The Neer Circle is an organization of shoulder experts recognized for their service to the American Shoulder and Elbow Surgeons. Consensus among 72 identified experts from this group was sought with a series of surveys using the Delphi process. The first survey used open-ended questions designed to identify patient-related features that influence treatment decisions after an FTAGD. The second survey used a Likert scale to rank each feature's impact on treatment decisions. The third survey used highly impactful features to construct 162 clinical scenarios. For each scenario, experts recommended surgery or not and reported how strongly they made their recommendation. These data were analyzed to find clinical scenarios that had >90% consensus for recommending treatment. These data were also used in univariate and multivariate mixed-effects models to identify odds ratios (ORs) for different features and to assess how combining these features influenced the probability of surgery for specific populations. RESULTS: Of the 162 scenarios, 8 (5%) achieved >90% consensus for recommending surgery. All of these scenarios treated athletes with meaningful bone loss at the end of their season. In particular, for contact athletes aged > 14 years who were at the end of the season and had apprehension and meaningful bone loss, there was >90% consensus for recommending surgery after an FTAGD, with surgeons feeling very strongly about this recommendation. Of the scenarios, 22 (14%) reached >90% consensus for recommending nonoperative treatment. All of these scenarios lacked meaningful bone loss. In particular, surgeons felt very strongly about recommending nonoperative treatment after an FTAGD for non-athletes lacking apprehension without meaningful bone loss. The presence of meaningful bone loss (OR, 6.85; 95% confidence interval, 6.24-7.52) and apprehension (OR, 5.60; 95% confidence interval, 5.03-6.25) were the strongest predictors of surgery. When these 2 features were combined, profound effects increasing the probability of surgery for different populations (active-duty military, non-athletes, noncontact athletes, and contact athletes) were noted, particularly non-athletes. CONCLUSION: Consensus for recommending treatment of the FTAGD patient was not easily achieved. Certain combinations of patient-specific factors, such as the presence of meaningful bone loss and apprehension, increased the probability of surgery after an FTAGD in all populations. Over 90% of shoulder instability experts recommend surgery after an FTAGD for contact athletes aged > 14 years at the end of the season with both apprehension and meaningful bone loss. Over 90% of experts would not perform surgery after a first dislocation in patients who are not athletes and who lack apprehension without meaningful bone loss.

A randomized, controlled phase II trial of neoadjuvant ado-trastuzumab emtansine, lapatinib, and nab-paclitaxel versus trastuzumab, pertuzumab, and paclitaxel in HER2-positive breast cancer (TEAL study).

BACKGROUND: Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. METHODS: Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. RESULTS: The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm (p = 0.0035). Adverse events were similar between the two arms. CONCLUSION: In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. TRIAL REGISTRATION: Clinicaltrials.gov NCT02073487 , February 27, 2014.

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.

Which Is the Best Outcome Measure for Rotator Cuff Tears?

BACKGROUND: The American Shoulder and Elbow Surgeons Standardized Shoulder Form (ASES), the Shoulder Pain and Disability Index (SPADI), and the shortened Disability of the Arm, Shoulder, and Hand (quickDASH) are patient-reported upper extremity-specific outcome scales currently used to evaluate patients with rotator cuff tears. This heterogeneity does not allow for a uniform metric for research and patient care. QUESTIONS/PURPOSES: Our objective was to determine psychometric properties (reliability, convergent and discriminant validity, and responsiveness) of five commonly used outcome instruments (the ASES, the SPADI, the quickDASH, the SF-12, and the EuroQol-5D) in a longitudinal study of patients undergoing treatment for rotator cuff tears. METHODS: From February 2011 through June 2015, 120 patients completed a standardized history, the five outcome scales under study, a physical examination, and an MRI. Of these, 47 (39%) were lost to followup before 18 months, and another 24 (20%) were accounted for at 18 months but had missing data at one or more of the earlier prespecified followup intervals (3, 6, or 12 months). Reliability (the reproducibility of an outcome instrument between subjects; tested by Cronbach's alpha), convergent and discriminant validity (determining which outcome measures correlate most strongly with others; tested by Spearman's correlation coefficients), and responsiveness (the change in outcome scales over time based on percent improvement in shoulder functionality using the minimal clinically important difference [MCID] and the subjective shoulder value) were calculated. RESULTS: All outcomes measures had a Cronbach's alpha above 0.70 (range, 0.74-0.94) and therefore were considered reliable. Convergent validity was demonstrated as the upper extremity-specific measures (SPADI, ASES, and quickDASH) were more strongly correlated with each other (rho = 0.74-0.81; p < 0.001) than with any of the other measures. Discriminant validity was demonstrated because the Spearman's correlation coefficients were stronger for the relationships between upper extremity measures compared with the correlations between upper extremity measures and general health measures for 53 of the 54 correlations that were compared. Both internal and external responsiveness of the measures was supported. Patients who achieved the MCID and at least a 30% change on the subjective shoulder value had more positive change in scores over time compared with those who did not. Mixed model linear regressions revealed that all three upper extremity-specific measures had a group by time interaction for the MCID, indicating that patients who achieved the MCID had greater change over time compared with those who did not achieve the MCID. Results showed that the measure with the best discrimination between groups, or best internal responsiveness, was the ASES (beta = -8.26, 95% confidence interval [CI], -11.39 to -5.14; p < 0.001; η = 0.089) followed by the SPADI (beta = 6.88, 95% CI, 3.78-9.97; p < 0.001; η = 0.088) then the quickDASH (beta = 3.43, 95% CI, 0.86-6.01; p = 0.009, η = 0.027). Measures with the best external responsiveness followed the same pattern of results. CONCLUSIONS: All the upper extremity-specific scales had acceptable psychometric properties. Correlations were high and thus only one upper extremity-specific instrument is needed for outcome assessment. Given the overall psychometric assessment, we recommend SPADI be the shoulder-specific instrument used to assess outcomes in patients with rotator cuff tears. LEVEL OF EVIDENCE: Level III, diagnostic study.

Navigating the Research in Rotator Cuff Disease: An Evidence-Based Approach to Improved Patient Outcomes.

Rotator cuff tears are prevalent injuries, yet their management and identifying patients who will benefit from surgical intervention are controversial topics. Population studies demonstrate high rates of asymptomatic tears that, with time, show a general progression of the pathologic state. However, not all tears are or will become symptomatic or require surgical intervention. Surgeons should be aware of the natural history of rotator cuff tears and be able to identify injuries at risk of progression or causing symptoms, be able to determine the cellular level of tear characteristics and healing, understand current management strategies and outcomes, and be familiar with future directions for therapies and research.

Epidemiology of the Frequency, Etiology, Direction, and Severity (FEDS) system for classifying glenohumeral instability.

HYPOTHESIS: The purpose of this multicenter epidemiologic study was to determine the distribution of patients within the Frequency, Etiology, Direction, and Severity (FEDS) classification system to determine which categories are of clinical importance. METHODS: Shoulder instability patients were identified using International Classification of Diseases, Ninth Revision coding data from 3 separate institutions from 2005-2010. Data were collected retrospectively. Details of instability were recorded in accordance with the FEDS classification system. Each patient was assigned a classification within the FEDS system. After all patients were assigned to a group, each group was individually analyzed and compared with the other groups. RESULTS: There are a total of 36 possible combinations within the FEDS system. Only 16 categories were represented by at least 1% of our patient population. Six categories captured at least 5% of all patients with shoulder instability. Only 2 categories represented greater than 10% of the population: solitary, traumatic, anterior dislocation, with 95 patients (24.8%), and occasional, traumatic, anterior dislocation, with 63 patients (16.4%). CONCLUSIONS: There are 16 categories within the FEDS classification that are clinically significant. Solitary, traumatic, anterior dislocation and occasional, traumatic, anterior dislocation were the most frequently observed in our cohort.

Physical therapy versus natural history in outcomes of rotator cuff tears: the Rotator Cuff Outcomes Workgroup (ROW) cohort study.

BACKGROUND: We compared the outcomes of patients who performed physical therapy versus those who did not in a longitudinal cohort of patients undergoing nonoperative treatment of rotator cuff tears. We also assessed whether there was a dose effect in which the pain and functional outcomes in patients performing physical therapy plateaued. METHODS: From February 2011 to June 2015, a multicenter cohort of patients with rotator cuff tears undergoing nonoperative treatment completed a detailed health and demographic questionnaire and the Shoulder Pain and Disability Index (SPADI) at baseline and 3, 6, 12, and 18 months. Longitudinal mixed models were used to assess whether physical therapy in the first 3 months predicted SPADI scores and dose effect. RESULTS: Among the 55 patients in our cohort, the performance of physical therapy within the first 3 months predicted better SPADI scores versus nonperformance of physical therapy at 3 months (P = .02). Scores were similar between groups at 6, 12, and 18 months. A threshold of 16 physical therapy sessions was observed for pain and functional improvement during follow-up, after which significant improvement was not seen. CONCLUSIONS: Patients who performed physical therapy within the first 3 months had statistically significant improvements in pain and function as measured by the SPADI score at 3 months compared with patients who did not report performing physical therapy. Depending on the minimal clinically important difference used for the SPADI score, our results could be interpreted as meeting the minimal clinically important difference threshold or not. Improvement in outcomes was observed up to 16 sessions of physical therapy, after which outcomes plateaued.

Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study.

BACKGROUND: Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies. METHODS: We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766. FINDINGS: Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0-14·0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib. INTERPRETATION: Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting. FUNDING: TG Therapeutics.

Personalized Medicine in Nasal Delivery: The Use of Patient-Specific Administration Parameters To Improve Nasal Drug Targeting Using 3D-Printed Nasal Replica Casts.

Effective targeting of nasal spray deposition could improve local, systemic, and CNS drug delivery; however, this has proven to be difficult due to the anatomical features of the nasal cavity, including the nasal valve and turbinate structures. Furthermore, nasal cavity geometries and dimensions vary between individuals based on differences in their age, gender, and ethnicity. The effect of patient-specific administration parameters was evaluated for their ability to overcome the barriers of targeted nasal drug delivery. The nasal spray deposition was evaluated in 10 3D-printed nasal cavity replicas developed based on the CT-scans of five pediatric and five adult subjects. Cromolyn sodium nasal solution, USP, modified with varying concentrations of hypromellose was utilized as a model nasal spray to evaluate the deposition pattern from formulations producing a variety of plume angles. A central composite design of experiments was implemented using the formulation with the narrowest plume angle to determine the patient-specific angle for targeting the turbinate region in each individual. The use of the patient-specific angle with this formulation significantly increased the turbinate deposition efficiency compared to that found for all subjects using an administration angle of 30°, around 90% compared to about 73%. Generally, we found turbinate deposition increased with decreases in the administration angle. Deposition to the upper regions of the replica was poor with any formulation or administration angle tested. Effective turbinate targeting of nasal sprays can be accomplished with the use of patient-specific administration parameters in individuals. Further research is required to see if these parameters can be device-controlled for patients and if other regions can be effectively targeted with other nasal devices.

Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.