Ancient DNA confirmation of lepromatous leprosy in a skeleton with concurrent osteosarcoma, excavated from the leprosarium of St. Mary Magdalen in Winchester, Hants., UK.

To establish a biological profile and disease aetiologies for one of four burials recovered during a Time Team dig at the St. Mary Magdalen leprosarium, Winchester, UK in AD 2000. Osteological techniques were applied to estimate age at death, biological sex, stature and pathology. Visual assessment of the material was supplemented by radiographic examination. Evidence for leprosy DNA was sought using ancient DNA (aDNA) analysis. The remains are those of a male individual excavated from a west-east aligned grave. The skeleton shows signs of two pathologies. Remodelling of the rhino-maxillary area and degenerative changes to small bones of the feet and reactive bone on the distal lower limbs suggest a multibacillary form of leprosy, whereas the right tibia and fibula show the presence of a primary neoplasm identified as an osteosarcoma. The aDNA study confirmed presence of Mycobacterium leprae in several skeletal elements, and the strain was genotyped to the 3I lineage, one of two main SNP types present in mediaeval Britain and ancestral to extant strains in America. This is a rare documentation of leprosy in association with a primary neoplasm.

Assessing the ability of an instrumental variable causal forest algorithm to personalize treatment evidence using observational data: the case of early surgery for shoulder fracture.

BACKGROUND: Comparative effectiveness research (CER) using observational databases has been suggested to obtain personalized evidence of treatment effectiveness. Inferential difficulties remain using traditional CER approaches especially related to designating patients to reference classes a priori. A novel Instrumental Variable Causal Forest Algorithm (IV-CFA) has the potential to provide personalized evidence using observational data without designating reference classes a priori, but the consistency of the evidence when varying key algorithm parameters remains unclear. We investigated the consistency of IV-CFA estimates through application to a database of Medicare beneficiaries with proximal humerus fractures (PHFs) that previously revealed heterogeneity in the effects of early surgery using instrumental variable estimators. METHODS: IV-CFA was used to estimate patient-specific early surgery effects on both beneficial and detrimental outcomes using different combinations of algorithm parameters and estimate variation was assessed for a population of 72,751 fee-for-service Medicare beneficiaries with PHFs in 2011. Classification and regression trees (CART) were applied to these estimates to create ex-post reference classes and the consistency of these classes were assessed. Two-stage least squares (2SLS) estimators were applied to representative ex-post reference classes to scrutinize the estimates relative to known 2SLS properties. RESULTS: IV-CFA uncovered substantial early surgery effect heterogeneity across PHF patients, but estimates for individual patients varied with algorithm parameters. CART applied to these estimates revealed ex-post reference classes consistent across algorithm parameters. 2SLS estimates showed that ex-post reference classes containing older, frailer patients with more comorbidities, and lower utilizers of healthcare were less likely to benefit and more likely to have detriments from higher rates of early surgery. CONCLUSIONS: IV-CFA provides an illuminating method to uncover ex-post reference classes of patients based on treatment effects using observational data with a strong instrumental variable. Interpretation of treatment effect estimates within each ex-post reference class using traditional CER methods remains conditional on the extent of measured information in the data.

Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study.

BACKGROUND: First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated. PATIENTS AND METHODS: RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed. RESULTS: In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events. CONCLUSIONS: Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.

Increased opioid use following rotator cuff repair associated with prior opioid use and surgeon prescription patterns.

BACKGROUND: Prescription opioids are standard of care for postoperative pain management after musculoskeletal surgery, but there is no guideline or consensus on best practices. Variability in the intensity of opioids prescribed for postoperative recovery has been documented, but it is unclear whether this variability is clinically motivated or associated with provider practice patterns, or how this variation is associated with patient outcomes. This study described variation in the intensity of opioids prescribed for patients undergoing rotator cuff repair (RCR) and examined associations with provider prescribing patterns and patients' long-term opioid use outcomes. METHODS: Medicare data from 2010 to 2012 were used to identify 16,043 RCRs for patients with new shoulder complaints in 2011. Two measures of perioperative opioid use were created: (1) any opioid fill occurring 3 days before to 7 days after RCR and (2) total morphine milligram equivalents (MMEs) of all opioid fills during that period. Patient outcomes for persistent opioid use after RCR included (1) any opioid fill from 90 to 180 days after RCR and (2) the lack of any 30-day gap in opioid availability during that period. Generalized linear regression models were used to estimate associations between provider characteristics and opioid use for RCR, and between opioid use and outcomes. All models adjusted for patient clinical and demographic characteristics. Separate analyses were done for patients with and without opioid use in the 180 days before RCR. RESULTS: In this sample, 54% of patients undergoing RCR were opioid naive at the time of RCR. Relative to prior users, a greater proportion of opioid naive users had any opioid fill (85.7% vs. 75.4%), but prior users received more MMEs than naive users (565 vs. 451 MMEs). Providers' opioid prescribing for other patients was associated with the intensity of perioperative opioids received for RCR. Total MMEs received for RCR were associated with higher odds of persistent opioid use 90-180 days after RCR. CONCLUSIONS: The intensity of opioids received by patients for postoperative pain appears to be partially determined by the prescribing habits of their providers. Greater intensity of opioids received is, in turn, associated with greater odds of patterns of chronic opioid use after surgery. More comprehensive, patient-centered guidance on opioid prescribing is needed to help surgeons provide optimal postoperative pain management plans, balancing needs for short-term symptom relief and risks for long-term outcomes.

Risk Adjustment of the Modified Low Back Pain Disability Questionnaire and Neck Disability Index to Benchmark Physical Therapist Performance: Analysis From an Outcomes Registry.

BACKGROUND: Patient-reported outcomes (PROs) have been touted as the ultimate assessment of quality medical care and have been proposed as performance measures after appropriate risk adjustment. Although spine conditions represent the most common orthopedic disorders, the most used PROs for disabilities related to the back and neck-the Modified Low Back Pain Disability Questionnaire (MDQ) and the Neck Disability Index (NDI)-have not been evaluated as performance measures. OBJECTIVE: The objective of this study was to benchmark physical therapists' performance in the management of spine conditions not involving surgery through the use of risk-adjusted MDQ and NDI outcomes. DESIGN: This was a retrospective observational study. METHODS: Data were accessed for patients seeking physical therapy with no history of related surgery for back or neck pain (315,274 treatment episodes) between January 2015 and June 2018. Patients with complete data, including initial and matched final MDQ or NDI, were considered for analysis (182,276 patients; 2799 physical therapists). Linear models controlling for baseline PRO and patient characteristics predicted PRO change for each patient. An aggregated performance ratio of actual PRO change to predicted PRO change was calculated for each physical therapist, and then empirical bootstrapping was used to develop the median performance ratio and its confidence intervals. Physical therapists who met a 40-patient threshold for either cohort (MDQ or NDI) were classified as "outperforming," "meeting expectations," or "underperforming" relative to predicted values using these 95% confidence intervals. RESULTS: Performance ratios indicated that 10% and 11% of physical therapists outperformed, 79% and 78% met expectations, and 11% and 11% underperformed relative to the risk-adjusted predicted change in the MDQ (1240 therapists; 97,908 patients) and NDI (461 therapists; 26,123 patients), respectively. To demonstrate the clinical importance of risk adjustment, clinical performance was evaluated in the seemingly homogeneous subset of 208 physical therapists within 0.5 SD of the median baseline MDQ and the median actual change in the MDQ. Following risk adjustment, 2 physical therapists were classified in each of the outperforming and underperforming cohorts. LIMITATIONS: The secondarily obtained observational data used were not collected for research purposes. Additionally, the analyses were limited by missing baseline information and follow-up PROs. CONCLUSIONS: The risk-adjusted performance ratios for the MDQ and NDI resulted in disparate conclusions regarding the quality of care compared with the raw, unadjusted change scores. According to the baseline and unadjusted change in the MDQ, even physical therapists in the most homogeneous sample were differentiated following appropriate risk adjustment. Clinically important improvements in actual PROs were observed in the outperforming but not in the underperforming physical therapists. Clinically meaningful differences in the performance ratio are unknown and are a limitation to clinical application and an opportunity for future research.

Protein Tyrosine Phosphatase σ Inhibitory Peptide Promotes Recovery of Diaphragm Function and Sprouting of Bulbospinal Respiratory Axons after Cervical Spinal Cord Injury.

Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality after cervical spinal cord injury (SCI). Upon SCI, inspiratory signals originating in the medullary rostral ventral respiratory group (rVRG) become disrupted from their phrenic motor neuron (PhMN) targets, resulting in diaphragm paralysis. Limited growth of both damaged and spared axon populations occurs after central nervous system trauma attributed, in part, to expression of various growth inhibitory molecules, some that act through direct interaction with the protein tyrosine phosphatase sigma (PTPσ) receptor located on axons. In the rat model of C2 hemisection SCI, we aimed to block PTPσ signaling to investigate potential mechanisms of axon plasticity and respiratory recovery using a small molecule peptide mimetic that inhibits PTPσ. The peptide was soaked into a biocompatible gelfoam and placed directly over the injury site immediately after hemisection and replaced with a freshly soaked piece 1 week post-SCI. At 8 weeks post-hemisection, PTPσ peptide significantly improved ipsilateral hemidiaphragm function, as assessed in vivo with electromyography recordings. PTPσ peptide did not promote regeneration of axotomized rVRG fibers originating in ipsilateral medulla, as assessed by tracing after adeno-associated virus serotype 2/mCherry injection into the rVRG. Conversely, PTPσ peptide stimulated robust sprouting of contralateral-originating rVRG fibers and serotonergic axons within the PhMN pool ipsilateral to hemisection. Further, relesion through the hemisection did not compromise diaphragm recovery, suggesting that PTPσ peptide-induced restoration of function was attributed to plasticity of spared axon pathways descending in contralateral spinal cord. These data demonstrate that inhibition of PTPσ signaling can promote significant recovery of diaphragm function after SCI by stimulating plasticity of critical axon populations spared by the injury and consequently enhancing descending excitatory input to PhMNs.

Geographic variation in the treatment of proximal humerus fracture: an update on surgery rates and treatment consensus.

BACKGROUND: Using a larger, more comprehensive sample, and inclusion of the reverse shoulder arthroplasty as a primary surgical approach for proximal humerus fracture, we report on geographic variation in the treatment of proximal humerus fracture in 2011 and comment on whether treatment consensus is being reached. METHODS: This was a retrospective cohort study of Medicare patients with an x-ray-confirmed diagnosis of proximal humerus fracture in 2011. Patients receiving reverse shoulder arthroplasty, hemiarthroplasty, or open reduction internal fixation within 60 days of their diagnosis were classified as surgical management patients. Unadjusted observed surgery rates and area treatment ratios adjusted for patient demographic and clinical characteristics were calculated at the hospital referral region level. RESULTS: Among patients with proximal humerus fracture (N = 77,053), 15.4% received surgery and 84.6% received conservative management. Unadjusted surgery rates varied from 1.7 to 33.3% across hospital referral regions. Among patients receiving surgery, 22.3% received hemiarthroplasty, 65.8% received open reduction internal fixation, and 11.8% received reverse shoulder arthroplasty. Patients that were female, were younger, had fewer medical comorbidities, had a lower frailty index, were white, or were not dual-eligible for Medicaid during the month of their index fracture were more likely to receive surgery (p < .0001). Geographic variation in the treatment of proximal humerus fracture persisted after adjustment for patient demographic and clinical differences across local areas. Average surgery rates ranged from 9.9 to 21.2% across area treatment ratio quintiles. CONCLUSIONS: Persistent geographic variation in surgery rates for proximal humerus fracture across the USA suggests no treatment consensus has been reached.

Astrocyte progenitor transplantation promotes regeneration of bulbospinal respiratory axons, recovery of diaphragm function, and a reduced macrophage response following cervical spinal cord injury.

Stem/progenitor cell transplantation delivery of astrocytes is a potentially powerful strategy for spinal cord injury (SCI). Axon extension into SCI lesions that occur spontaneously or in response to experimental manipulations is often observed along endogenous astrocyte "bridges," suggesting that augmenting this response via astrocyte lineage transplantation can enhance axon regrowth. Given the importance of respiratory dysfunction post-SCI, we transplanted glial-restricted precursors (GRPs)-a class of lineage-restricted astrocyte progenitors-into the C2 hemisection model and evaluated effects on diaphragm function and the growth response of descending rostral ventral respiratory group (rVRG) axons that innervate phrenic motor neurons (PhMNs). GRPs survived long term and efficiently differentiated into astrocytes in injured spinal cord. GRPs promoted significant recovery of diaphragm electromyography amplitudes and stimulated robust regeneration of injured rVRG axons. Although rVRG fibers extended across the lesion, no regrowing axons re-entered caudal spinal cord to reinnervate PhMNs, suggesting that this regeneration response-although impressive-was not responsible for recovery. Within ipsilateral C3-5 ventral horn (PhMN location), GRPs induced substantial sprouting of spared fibers originating in contralateral rVRG and 5-HT axons that are important for regulating PhMN excitability; this sprouting was likely involved in functional effects of GRPs. Finally, GRPs reduced the macrophage response (which plays a key role in inducing axon retraction and limiting regrowth) both within the hemisection and at intact caudal spinal cord surrounding PhMNs. These findings demonstrate that astrocyte progenitor transplantation promotes significant plasticity of rVRG-PhMN circuitry and restoration of diaphragm function and suggest that these effects may be in part through immunomodulation.

Treatment for Rotator Cuff Tear Is Influenced by Demographics and Characteristics of the Area Where Patients Live.

BACKGROUND: Atraumatic rotator cuff tear is a common orthopaedic complaint for people >60 years of age. Lack of evidence or consensus on appropriate treatment for this type of injury creates the potential for substantial discretion in treatment decisions. To our knowledge, no study has assessed the implications of this discretion on treatment patterns across the United States. METHODS: All Medicare beneficiaries in the United States with a new magnetic resonance imaging (MRI)-confirmed atraumatic rotator cuff tear were identified with use of 2010 to 2012 Medicare administrative data and were categorized according to initial treatment (surgery, physical therapy, or watchful waiting). Treatment was modeled as a function of the clinical and demographic characteristics of each patient. Variation in treatment rates across hospital referral regions and the presence of area treatment signatures, representing the extent that treatment rates varied across hospital referral regions after controlling for patient characteristics, were assessed. Correlations between measures of area treatment signatures and measures of physician access in hospital referral regions were examined. RESULTS: Among patients who were identified as having a new, symptomatic, MRI-confirmed atraumatic rotator cuff tear (n = 32,203), 19.8% were managed with initial surgery; 41.3%, with initial physical therapy; and 38.8%, with watchful waiting. Patients who were older, had more comorbidity, or were female, of non-white race, or dual-eligible for Medicaid were less likely to receive surgery (p < 0.0001). Black, dual-eligible females had 0.42-times (95% confidence interval [CI], 0.34 to 0.50) lower odds of surgery and 2.36-times (95% CI, 2.02 to 2.70) greater odds of watchful waiting. Covariate-adjusted odds of surgery varied dramatically across hospital referral regions; unadjusted surgery and physical therapy rates varied from 0% to 73% and from 6% to 74%, respectively. On average, patients in high-surgery areas were 62% more likely to receive surgery than the average patient with identical measured characteristics, and patients in low-surgery areas were half as likely to receive surgery than the average comparable patient. The supply of orthopaedic surgeons and the supply of physical therapists were associated with greater use of initial surgery and physical therapy, respectively. CONCLUSIONS: Patient characteristics had a significant influence on treatment for atraumatic rotator cuff tear but did not explain the wide-ranging variation in treatment rates across areas. Local-area physician supply and specialty mix were correlated with treatment, independent of the patient's measured characteristics.

A comparison of one-year treatment utilization for shoulder osteoarthritis patients initiating care with non-orthopaedic physicians and orthopaedic specialists.

BACKGROUND: In this paper we investigate patients seeking care for a new diagnosis of shoulder osteoarthritis (OA) and the association between a patient's initial physician specialty choice and one-year surgical and conservative treatment utilization. METHODS: Using retrospective data from a single large regional healthcare system, we identified 572 individuals with a new diagnosis of shoulder OA and identified the specialty of the physician which was listed as the performing physician on the index shoulder visit. We assessed treatment utilization in the year following the index shoulder visit for patients initiating care with a non-orthopaedic physician (NOP) or an orthopaedic specialist (OS). Descriptive statistics were calculated for each group and subsequent one-year surgical and conservative treatment utilization was compared between groups. RESULTS: Of the 572 patients included in the study, 474 (83%) received care from an OS on the date of their index shoulder visit, while 98 (17%) received care from a NOP. There were no differences in baseline patient age, gender, BMI or pain scores between groups. OS patients reported longer symptom duration and a higher rate of comorbid shoulder diagnoses. Patients initiating care with an OS on average received their first treatment much faster than patients initiating care with NOP (16.3 days [95% CI, 12.8, 19.7] vs. 32.3 days [95% CI, 21.0, 43.6], Z = 4.9, p < 0.01). Additionally, patients initiating care with an OS had higher odds of receiving surgery (OR = 2.65, 95% CI: 1.42, 4.95) in the year following their index shoulder visit. CONCLUSIONS: Patients initiating care with an OS received treatment much faster and were treated with more invasive services over the year following their index shoulder visit. Future work should compare patient-reported outcomes across patient groups to assess whether more expensive and invasive treatments yield better outcomes for patients with shoulder OA.

Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI.

Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality in individuals suffering from traumatic cervical spinal cord injury (SCI). Repair of CNS axons after SCI remains a therapeutic challenge, despite current efforts. SCI disrupts inspiratory signals originating in the rostral ventral respiratory group (rVRG) of the medulla from their phrenic motor neuron (PhMN) targets, resulting in loss of diaphragm function. Using a rat model of cervical hemisection SCI, we aimed to restore rVRG-PhMN-diaphragm circuitry by stimulating regeneration of injured rVRG axons via targeted induction of Rheb (ras homolog enriched in brain), a signaling molecule that regulates neuronal-intrinsic axon growth potential. Following C2 hemisection, we performed intra-rVRG injection of an adeno-associated virus serotype-2 (AAV2) vector that drives expression of a constitutively-active form of Rheb (cRheb). rVRG neuron-specific cRheb expression robustly increased mTOR pathway activity within the transduced rVRG neuron population ipsilateral to the hemisection, as assessed by levels of phosphorylated ribosomal S6 kinase. By co-injecting our novel AAV2-mCherry/WGA anterograde/trans-synaptic axonal tracer into rVRG, we found that cRheb expression promoted regeneration of injured rVRG axons into the lesion site, while we observed no rVRG axon regrowth with AAV2-GFP control. AAV2-cRheb also significantly reduced rVRG axonal dieback within the intact spinal cord rostral to the lesion. However, cRheb expression did not promote any recovery of ipsilateral hemi-diaphragm function, as assessed by inspiratory electromyography (EMG) burst amplitudes. This lack of functional recovery was likely because regrowing rVRG fibers did not extend back into the caudal spinal cord to synaptically reinnervate PhMNs that we retrogradely-labeled with cholera toxin B from the ipsilateral hemi-diaphragm. Our findings demonstrate that enhancing neuronal-intrinsic axon growth capacity can promote regeneration of injured bulbospinal respiratory axons after SCI, but this strategy may need to be combined with other manipulations to achieve reconnection of damaged neural circuitry and ultimately recovery of diaphragm function.

Drug exposure and the risk of multiple sclerosis: A systematic review.

BACKGROUND: Several environmental and lifestyle factors have been associated with multiple sclerosis (MS) risk, including some pharmacological treatments. We systematically reviewed the literature on prescription drug exposure and MS risk. METHODS: Six databases were searched for original observational studies reporting drug exposure and MS risk published before 2017. RESULTS: Thirteen articles fulfilled inclusion criteria. Exposure to neither amiloride nor valproic acid was associated with MS (adjusted hazard ratio (adj.HR = 1.34;95% CI:0.81-2.20; adj.HR = 1.30;95%CI:0.44-3.80, respectively). Four studies explored oral contraceptive exposure and reported no association with MS; while a single study found an increased risk (odds ratio [adj.OR] = 1.52;95%CI:1.21-1.91). While penicillin exposure was associated with reduced risk of developing MS (adj.OR = 0.5;95%CI:0.3-0.9), a later study observed an elevated risk for penicillin (adj.OR = 1.21;95%CI:1.10-1.27) and all antibiotics (adj.OR = 1.41;95%CI:1.29-1.53), which was potentially attributed to underlying infection. Anti-tumor necrosis factor-alpha (TNFα) was not associated with MS risk in persons with inflammatory bowel disease (standard morbidity ratio = 4.2;95%CI:0.1-23.0) and arthritis (standardized incidence ratio = 1.38;95%CI:0.69-2.77); however, men exposed to anti-TNFα who also had arthritis and individuals with ankylosing spondylitis were at an increased risk (standardized incidence ratios = 3.91;95%CI:1.47-10.42 and 3.48;95%CI:1.45-8.37, respectively). A reduced risk of MS was observed with exposure to the beta2-adrenergic agonist fenoterol (adj.OR = 0.58;95%CI:0.45-0.76), and the sedating histamine 1-receptor antagonists (adj.OR = 0.2;95%CI:0.1-0.8), but not the non-sedating equivalent (adj.OR = 0.8;95%CI:0.4-1.6). CONCLUSIONS: The suggestion that some drugs may prevent MS is intriguing and warrants further study. In addition, further pharmacovigilance is needed to assess the safety of anti-TNFα drugs in specific populations in the context of MS risk.

The Influence of Patient Choice of First Provider on Costs and Outcomes: Analysis From a Physical Therapy Patient Registry.

Study Design Retrospective study. Background Alternative models of care that allow patients to choose direct access to physical therapy have shown promise in terms of cost reduction for neck and back pain. However, real-world exploration within the US health care system is notably limited. Objectives To compare total claims paid and patient outcomes for patients with neck and back pain who received physical therapy intervention via direct access versus medical referral. Methods Data were accessed for patients seeking care for neck or back pain (n = 603) between 2012 and 2014, who chose to begin care either through traditional medical referral or direct access to a physical therapy- led spine management program. All patients received a standardized, pragmatic physical therapy approach, with patient-reported measures of pain and disability assessed before and after treatment. Patient demographics and outcomes data were obtained from the medical center patient registry and combined with total claims paid calculated for the year after the index claim. Linear mixed-effects modeling was used to analyze group differences in pain and disability, visits/time, and annualized costs. Results Patients who chose to enter care via the direct-access physical therapy-led spine management program displayed significantly lower total costs (mean difference, $1543; 95% confidence interval: $51, $3028; P = .04) than those who chose traditional medical referral. Patients in both groups showed clinically important improvements in pain and disability, which were similar between groups (P>.05). Conclusion The initial patient choice to begin care with a physical therapist for back or neck pain resulted in lower cost of care over the next year, while resulting in similar improvements in patient outcomes at discharge from physical therapy. These findings add to the emerging literature suggesting that patients' choice to access physical therapy through direct access may be associated with lower health care expenditures for patients with neck and back pain. Level of Evidence Economic and decision analyses, level 4. J Orthop Sports Phys Ther 2018;48(2):63-71. Epub 26 Oct 2017. doi:10.2519/jospt.2018.7423.

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Shoulder arthroplasty in the US Medicare population: a 1-year evaluation of surgical complications, hospital admissions, and revision surgery.

BACKGROUND: The objective of this study was to describe patients receiving each shoulder arthroplasty procedure and to assess surgical complications, hospital admissions for surgical complications, and surgical revisions among Medicare beneficiaries undergoing shoulder arthroplasty. METHODS: Medicare patients receiving shoulder arthroplasty in the United States in 2011 were identified from Medicare administrative data and classified by surgery type: shoulder hemiarthroplasty (HA), anatomic total shoulder arthroplasty (TSA), or reverse shoulder arthroplasty (RSA). Surgical complications, hospital admissions, and revisions were identified during the year after the index arthroplasty procedure. RESULTS: There were 24,441 patients who met all inclusion criteria, and of those, 20.0% received HA, 42.5% received TSA, and 37.4% received RSA. Compared with RSA and TSA recipients, HA recipients tended to be older and sicker and were more likely to be Medicaid eligible. The rate of new surgical complications and related hospital admissions was greatest during the first 50 days after surgery but remained significant and stable throughout the remainder of the year. Rates of complications and related hospital admissions were greatest for HA recipients (17.4% and 6.6%, respectively), followed by RSA (14.2% and 5.1%) and TSA (9.4% and 4.0%). CONCLUSIONS: The rate of adverse surgical outcomes after shoulder arthroplasty differed across populations that received HA, TSA, and RSA and across patients within each group by comorbidity burden. The finding that the rate of surgical complications and related hospital admissions remained meaningful during the entire year after surgery suggests that a postoperative follow-up period longer than the traditional 90 days may be warranted.

Variation in geographic access to chemotherapy by definitions of providers and service locations: a population-based observational study.

BACKGROUND: An aging population, with its associated rise in cancer incidence and strain on the oncology workforce, will continue to motivate patients, healthcare providers and policy makers to better understand the existing and growing challenges of access to chemotherapy. Administrative data, and SEER-Medicare data in particular, have been used to assess patterns of healthcare utilization because of its rich information regarding patients, their treatments, and their providers. To create measures of geographic access to chemotherapy, patients and oncologists must first be identified. Others have noted that identifying chemotherapy providers from Medicare claims is not always straightforward, as providers may report multiple or incorrect specialties and/or practice in multiple locations. Although previous studies have found that specialty codes alone fail to identify all oncologists, none have assessed whether various methods of identifying chemotherapy providers and their locations affect estimates of geographic access to care. METHODS: SEER-Medicare data was used to identify patients, physicians, and chemotherapy use in this population-based observational study. We compared two measures of geographic access to chemotherapy, local area density and distance to nearest provider, across two definitions of chemotherapy provider (identified by specialty codes or billing codes) and two definitions of chemotherapy service location (where chemotherapy services were proven to be or possibly available) using descriptive statistics. Access measures were mapped for three representative registries. RESULTS: In our sample, 57.2 % of physicians who submitted chemotherapy claims reported a specialty of hematology/oncology or medical oncology. These physicians were associated with 91.0 % of the chemotherapy claims. When providers were identified through billing codes instead of specialty codes, an additional 50.0 % of beneficiaries (from 23.8 % to 35.7 %) resided in the same ZIP code as a chemotherapy provider. Beneficiaries were also 1.3 times closer to a provider, in terms of driving time. Our access measures did not differ significantly across definitions of service location. CONCLUSIONS: Measures of geographic access to care were sensitive to definitions of chemotherapy providers; far more providers were identified through billing codes than specialty codes. They were not sensitive to definitions of service locations, as providers, regardless of how they are identified, generally provided chemotherapy at each of their practice locations.

Multiple pathological fractures and delayed union associated with lead exposure in a German Shepherd Dog.

CASE REPORT: An 8-year-old 40.8-kg intact male German Shepherd Dog was evaluated for bilateral antebrachial fractures. Radiographs revealed osteopenia and comminuted proximal diaphyseal fractures of the left radius and ulna, and proximal articular fracture of the right ulna. A dual energy X-ray absorptiometry scan confirmed decreased bone mineral density. Bone mineral analysis collected at the time of definitive surgical repair demonstrated high lead concentration. Analysis further demonstrated normal bone calcium and phosphorus concentrations. Serum lead concentration was normal. The left radial and ulnar fractures were surgically stabilised with an external fixator. The right ulnar fracture was splinted. The left antebrachial fractures were palpably unstable at 12 weeks after surgery. Moderate callus formation and incomplete bone union were present at 17 weeks postoperatively. The dog was re-presented 15 months later for right metacarpal and left metatarsal fractures, which were managed conservatively. Complete bone union of the right radial and ulnar fractures was not present at that time. CONCLUSION: Excessive lead accumulation in bone should be considered as a differential diagnosis for increased susceptibility to pathologic fracture and delayed fracture healing in dogs.

Pancreatectomy predicts improved survival for pancreatic adenocarcinoma: results of an instrumental variable analysis.

BACKGROUND AND OBJECTIVE: Pancreatic resection is the standard treatment option for patients with stage I/II pancreatic ductal adenocarcinoma (PDA), yet many studies demonstrate low rates of resection. The objective of this study was to evaluate whether increasing resection rates would result in an increase in average survival in patients with stage I/II PDA. METHODS: SEER (Surveillance, Epidemiology, and End Results) data were analyzed for patients with stage I/II pancreatic head cancers treated from 2004 to 2009. Pancreatectomy rates were examined within Health Service Areas (HSAs) across 18 SEER regions. An instrumental variable analysis was performed, using HSA rates as an instrument, to determine the impact of increasing resection rates on survival. RESULTS: Pancreatectomy was performed in 4322 of 8323 patients evaluated with stage I/II PDA (overall resection rate = 51.9%). The resection rate across HSAs ranged from an average of 38.6% (lowest quintile) to 67.3% (highest quintile). Median survival was improved in HSAs with higher resection rates. Instrumental variable analysis revealed that, for patients whose treatment choices were influenced by rates of resection in their geographic region, pancreatectomy was associated with a statistically significant increase in overall survival. CONCLUSIONS: When controlling for confounders using instrumental variable analysis, pancreatectomy is associated with a statistically significant increase in survival for patients with resectable PDA. On the basis of these results, if resection rates were to increase in select patients, then average survival would also be expected to increase. It is important that this information be provided to physicians and patients so that they can properly weigh the risks and advantages of pancreatectomy as treatment of PDA.

Supplement timing of cranberry extract plays a key role in promoting Caenorhabditis elegans healthspan.

Consumption of nutraceuticals is a major and potent dietary intervention for delaying aging. As the timing of administration is critical for the efficacy of bioactive compounds in medicine, the effectiveness of nutraceuticals may also be dramatically affected by the timing of supplementation. Cranberry exact (CBE), rich in polyphenols, is consumed as a nutraceutical, and possesses anti-aging properties. Here, we examined the influence of timing on the beneficial effects of CBE supplementation in C. elegans. The prolongevity effect of CBE in different aged worms, young adults, middle-age adults, and aged adults, was determined. Early-start intervention with CBE prolonged the remaining lifespan of worms of different ages more robustly than late-start intervention. The effectiveness of CBE on stress responses and physiological behaviors in different aged worms was also investigated. The early-start intervention prominently promoted motility and resistance to heat shocks and V. cholera infection, especially in aged worms. Together, these findings suggest that the timing of CBE supplementation critically influences its beneficial effects on C. elegans lifespan and healthspan. It is of interest to further investigate whether the similar results would occur in humans.

Selective dorsal rhizotomy for children with cerebral palsy: the Oswestry experience.

BACKGROUND: Although three randomised control trials have shown that selective dorsal rhizotomy (SDR) reduces spasticity in children with cerebral palsy, a meta-analysis of the results demonstrated that the procedure conferred only small functional benefit on the patient. AIM: To determine whether applying strict criteria for patient selection as practised in Oswestry leads to improved outcomes, using gait analysis as an outcome measure. METHODS: Ambulant children with cerebral palsy were selected for SDR using very strict clinical criteria. Instrumented gait analysis was used as the main outcome measure. RESULTS: Of 53 children referred for the procedure, only 19 (35%) fulfilled our strict criteria for selection. These children underwent surgery and when pre- and post-SDR data were compared, they showed improvement in cosmesis of gait, clinical examination and temporal, kinetic and kinematic parameters of gait. After SDR the children walked, on average, 0.15 m/s faster, with a step length improvement of 0.11 m. Changes were seen at hip, knee and ankle, with those at the knee being most marked. A 0.3 grade improvement in knee extensor power on clinical examination led to a 13 degrees improvement in stance phase knee extension. Knees also became less stiff, with an 82 degrees /s improvement in the rate of flexion into swing phase. A functional tool (the GMFCS) applied retrospectively also confirmed post-operative improvement, with 15 of the 19 children improving by at least one level. CONCLUSION: Application of strict selection criteria when considering children for SDR leads to encouraging results as demonstrated by gait analysis and other measures.