Urine Osmolality Is a Potential Marker of Longer-term Efficacy of Tolvaptan in ADPKD: A Post-hoc Analysis.

BACKGROUND: Total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) are measures of progression and treatment response in autosomal dominant polycystic kidney disease (ADPKD), but utility is limited by the long follow-up required for change assessment. In an analysis of data from the 3-year TEMPO 3:4 trial, we evaluated relationships among a short-term indicator of drug activity (change in urine osmolality [Uosm]) and longer-term outcomes to evaluate Uosm as a potential marker of efficacy. METHODS: Linear regression modeling and single-point analyses assessed relationships among change in Uosm to week 3, change in TKV to month 12, and change in eGFR to month 36 in subjects treated with tolvaptan (n=961) or placebo (n=483). Multivariate models evaluated the proportion of the tolvaptan treatment effect on eGFR attributable to change in Uosm. RESULTS: Change in TKV to month 12 and Uosm to week 3 each correlated with change in eGFR to month 36, regardless of treatment assignment. A greater decrease in Uosm from baseline to week 3 was indicative of a slower decrease in eGFR to month 36 (slope estimate of -0.01, P <0.00001). The effect of tolvaptan on Uosm accounted for 68.8% of the treatment effect on change in eGFR to month 36. Simulations of TEMPO 3:4 under the null hypothesis (i.e., replacement of all values for change in Uosm from baseline to week 3 with values from the placebo arm only) yielded a Type 1 error rate indicating an acceptable risk of falsely concluding treatment efficacy based on change in Uosm as a trial endpoint. CONCLUSIONS: Change in Uosm is a potential biomarker for long-term treatment outcome with tolvaptan and might expedite clinical trials and treatment decision-making for drugs with similar mechanisms of action.

Diagnosis, Etiology and Outcomes of Revision Distal Biceps Tendon Reattachment.

PURPOSE: To evaluate the incidence, etiology, and clinical outcomes after revision distal biceps tendon repair. We hypothesized that re-ruptures are rare and can be reattached with satisfactory results. METHODS: Cases were identified from the case log of the senior author. Demographic information, details regarding the primary repair and subsequent injury, time between reinjury and reattachment, and operative findings were recorded. Clinical outcomes were assessed using the Disabilities of the Arm, Shoulder, and Hand (DASH) and American Shoulder and Elbow Surgeons-Elbow (ASES-E) functional outcome scoring systems. Range of motion, strength, and ability to return to work were recorded. RESULTS: We identified 10 patients with re-rupture, all of whom were men. Average age was 46 years (range, 35-57 years). Four ruptures occurred in the dominant arm. Three patients had a history of bilateral ruptures. Incidence of primary failure was 1.1%. In 6 patients, re-rupture occurred 6 days to 11 months after the primary surgery. Three patients described a sense of ripping or tearing after a specific traumatic event. Four others had persistent pain after the primary reattachment. Re-rupture resulted from the loss of fixation owing to technical error, the suture pulling out from the tendon, or suture breakage. Two patients required an allograft. The hook test was abnormal in 3 patients. Magnetic resonance imaging results did not affect the operative plan. Nine patients returned to their former occupation. Five returned for follow-up evaluation and completion of the DASH and ASES-E self-assessment examinations. Average DASH score was 4.4 (range, 0-19) and average ASES-E was 93.2 (range, 74-100). Postoperative average elbow flexion was 141° (range, 135° to 145°), elbow extension was -12° (range, -5° to -30°), pronation was 70°, and supination was 80°. Postoperative average supination strength was 87.8% of the nonsurgical arm (range, 79% to 106%); average pronation strength was 79.2% of the nonsurgical arm (range, 50% to 110%). CONCLUSIONS: Revision reattachment resulted in acceptable functional outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Sodium-Glucose Cotransporter-2 Inhibitors: Lack of a Complete History Delays Diagnosis.

On 15 May 2015, the U.S. Food and Drug Administration (FDA) warned that administration of sodium-glucose cotransporter-2 (SGLT2) inhibitors could lead to ketoacidosis in patients with diabetes mellitus. This announcement came more than 2 years after the FDA's first approval of an SGLT2 inhibitor, although the phenomenon had been known for more than 125 years. Luminaries of diabetes research (including Josef von Mering, Frederick Allen, I. Arthur Mirsky, and George Cahill) had described ketosis and ketoacidosis induced by administration of the phytochemical phlorizin, the prototypical SGLT inhibitor, as well as in patients with familial renal glucosuria, a condition that is considered a natural model of SGLT2 inhibition. Neither government regulators nor manufacturers of SGLT2 inhibitors evinced an awareness of this extensive historical record. The absence of historical inquiry delayed notice of ketoacidosis as an adverse reaction, which could have reduced the burden of illness from these drugs.

Sodium-Glucose Cotransporter 2 Inhibitors: A Case Study in Translational Research.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the most recently approved class of diabetes drugs. Unlike other agents, SGLT2 inhibitors act on the kidney to promote urinary glucose excretion. SGLT2 inhibitors provide multiple benefits, including decreased HbA1c, body weight, and blood pressure. These drugs have received special attention because they decrease the risk of major adverse cardiovascular events and slow progression of diabetic kidney disease (1-3). Balanced against these impressive benefits, the U.S. Food and Drug Administration-approved prescribing information describes a long list of side effects: genitourinary infections, ketoacidosis, bone fractures, amputations, acute kidney injury, perineal necrotizing fasciitis, and hyperkalemia. This review provides a physiological perspective to understanding the multiple actions of these drugs complemented by a clinical perspective toward balancing benefits and risks.

Interaction Between the Sodium-Glucose-Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects.

BACKGROUND: Dapagliflozin inhibits the sodium-glucose-linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium-glucose-linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide. METHODS AND RESULTS: Healthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d-1 of Na+ were randomized to bumetanide (1 mg·d-1), dapagliflozin (10 mg·d-1), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na+ excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d-1; P<0.005) but by more (P<0.005) with the first dose of bumetanide (74±7 mmol·d-1; P<0.005), which was not significantly different from both diuretics together (80±5 mmol·d-1; P<0.005). However, Na+ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1 week of bumetanide (64±6 mmol·d-1), and Na+ excretion with bumetanide was 36% greater (P<0.005) when added after 1 week of dapagliflozin (101±8 mmol·d-1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05). CONCLUSIONS: First-dose Na+ excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na+ excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide-induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865.

Inadvertent Harvest of the Median Nerve Instead of the Palmaris Longus Tendon.

BACKGROUND: The palmaris longus tendon is frequently used as a tendon graft or ligament replacement. In rare instances the median nerve has been inadvertently harvested instead of the palmaris longus for use as a tendon. METHODS: Nineteen cases in which the median nerve had been mistakenly harvested instead of the palmaris longus tendon were collected from members of the American Society for Surgery of the Hand (ASSH) Listserve. Surgeons involved in the subsequent care of the subject who had had an inadvertent harvest were contacted or the chart was reviewed. The reason for the initial procedure, the skill level of the primary surgeon, and when the inadvertent harvest was recognized were documented. When possible, the method of harvest and subsequent treatment were also documented. RESULTS: The most common initial procedure was a reconstruction of the elbow ulnar collateral ligament, followed by basal joint arthroplasty, tendon reconstruction, and reconstruction of the ulnar collateral ligament of the thumb metacarpophalangeal joint. Only 7 of the inadvertent harvests were recognized intraoperatively; in the remaining 12 cases the nerve was used as a tendon graft. The sensory loss was not recognized as being due to the inadvertent harvest until the first postoperative visit (2 subjects), 3 to 4 weeks (2 subjects), 2 to 3 months (2 subjects), 5 to 7 months (2 subjects), 1 year (1 subject), 3 years (1 subject), or 10 years (1 subject). Preoperative clinical identification of the presence or absence of a palmaris longus did not necessarily prevent an inadvertent harvest. CONCLUSIONS: Knowledge of the relevant anatomy is crucial to avoiding inadvertent harvest of the median nerve instead of the palmaris longus tendon.

Survival strategies in a changing practice environment.

A number of forces disrupt normal referral patterns to physicians, driving hospital consolidation, and changing the way medicine is practiced in the United States. Strategies have been implemented to keep services in-network and stem "leakage"-all in the name of population health management, reducing unit costs, and spreading financial risk among the insurers, hospitals, and physicians. To survive in the changing medical environment, independent unintegrated physicians need to consider different practice models. These models include accountable care organizations (ACOs), super groups, specialty networks, co-management agreements, professional service agreements (PSAs), and partnering with local hospitals. Each physician and physician group need to decide what works best for them and their geographical area. Physicians and physician groups may find that one or more of these models will improve their chance of economic survival.

Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes.

OBJECTIVE: To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODS: Subjects with type 2 diabetes (n=12) and matched healthy subjects (n=12) underwent pancreatic/SHC (plasma glucose range 5.5-30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTS: At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONS: The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.

Sex differences in suicides among children and youth: the potential impact of help-seeking behaviour.

OBJECTIVE: To describe sex differences in health service use among children and youth who died by suicide. METHOD: This is a retrospective study of children and youth (aged 10 to 25 years) living in Ontario who died by suicide between April 1, 2003, and December 31, 2007. Coroner records were individually linked to outpatient physician visit, emergency department (ED) presentation, and inpatient stay administrative health care records for 724 people (192 girls and 532 boys). Only 77 (10.6%) were aged 10 to 15 years. The health services types used, number of contacts made, and the last contact were compared in boys and girls. RESULTS: About 80% of subjects had contact with the health care system in the year before their death, typically to an outpatient physician and (or) the ED. However, not all were seen for mental health reasons. Girls had more outpatient physician and ED contact than boys and closer in time to their death. Further, girls were more likely than boys to have contact in more than one setting. Still, boys and girls did not differ in their use of an outpatient psychiatrist, some ED presentations, and in the nature and number of inpatient stays. CONCLUSIONS: While most people were seen by an outpatient physician and (or) in the ED in the year before their death, not all received mental health care. Further research is needed to determine whether boys and girls who died by suicide differ from their peers in their health service use to guide preventive interventions.

Objectif : Décrire les différences entre les sexes dans l'utilisation des services de santé chez des enfants et des adolescents qui sont décédés par suicide. Méthode : Il s'agit d'une étude rétrospective d'enfants et de jeunes (de 10 à 25 ans) habitant en Ontario qui sont décédés par suicide entre le 1er avril 2003 et le 31 décembre 2007. Les dossiers du coroner ont été individuellement liés à des visites chez le médecin en externe, à des présentations au service d'urgence (SU), et aux dossiers de santé administratifs des hospitalisations pour 724 personnes (192 filles et 532 garçons). Seulement 77 (10,6 %) d'entre eux avaient de 10 à 15 ans. Les types de services de santé utilisés, le nombre de contacts établis, et le dernier contact ont été comparés entre les garçons et les filles. Résultats : Quelque 80 % des sujets avaient eu un contact avec le système de santé dans l'année précédant leur mort, habituellement avec un médecin en externe et (ou) le SU. Toutefois, ils n'ont pas tous été vus pour des raisons de santé mentale. Les filles avaient plus de contacts avec les médecins en externe et le SU que les garçons, et de façon plus rapprochée du moment de leur mort. En outre, les filles étaient plus susceptibles que les garçons d'avoir un contact dans plus d'un contexte. Néanmoins, l'utilisation d'un psychiatre en externe, certaines présentations au SU, et la nature et le nombre d'hospitalisations ne différaient pas entre les garçons et les filles. Conclusions : Bien que la plupart de ces personnes aient été vues par un médecin en externe et (ou) au SU dans l'année précédant leur mort, elles n'ont pas toutes reçu des soins de santé mentale. Il faut plus de recherche pour déterminer si les garçons et les filles qui sont décédés par suicide sont différents de leurs pairs en ce qui concerne leur utilisation des services de santé, afin d'orienter les interventions préventives.

Child maltreatment and repeat presentations to the emergency department for suicide-related behaviors.

OBJECTIVES: To identify factors associated with repeat emergency department (ED) presentations for suicide-related behaviors (SRB) - hereafter referred to as repetition - among children/youth to aid secondary prevention initiatives. To compare rates of repetition in children/youth with substantiated maltreatment requiring removal from their parental home with their peers in the general population. METHODS: A population-based (retrospective) cohort study was established for children/youth with a first ED SRB presentation at risk for repetition in the Province of Ontario, Canada between 1 January 2004 and 31 December 2008. Children/youth legally removed from their parental home because of substantiated maltreatment (n=179) and their population-based peers (n=6,305) were individually linked to administrative health care records over time to ascertain social, demographic, and clinical information and subsequent ED presentations for SRB during follow-up. These children/youth were described and their repetition-free probabilities over time compared. To identify factors associated with repetition we fit multivariable, recurrent event survival analysis models stratified by repetition and present unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Children/youth with substantiated maltreatment (as noted) were two times more likely to have repetition than their peers after adjustments for social, demographic, and clinical factors (conditional on prior ED SRB presentations). A number of these factors were independently associated with repetition. No one factor distinguished between having a first and second repetition nor was more strongly associated with repetition than another. CONCLUSIONS: The risk of repetition is higher in children with substantiated maltreatment (as noted) than their peers. No one factor stood out as predictive of repetition. Implications for secondary prevention initiatives include a non-selective approach, sensitive to family difficulties and the need to better contextualize repetition and harness data linkages.

Sex differences in suicides among children and youth: the potential impact of misclassification.

OBJECTIVES: We examined whether established sex differences in suicide rates persist when adjustments are made for potential misclassification of deaths in children and youth. METHODS: This is a retrospective, descriptive study of 1294 suicides, 961 accidental and 254 undetermined deaths occurring between January 1, 2000 and December 31, 2007, among persons aged 10 to 25 years in Ontario, Canada. Using data from Coroner's records, causes of death were reclassified based on two different misclassification criteria. Actual and reclassified suicide rates were calculated by sex and age group (with 95% confidence intervals) and by year of death. RESULTS: Males aged 16-25 years accounted for the majority of suicides (68.9%). Asphyxia was the most common cause of suicide in both sexes. While suicides by shooting were almost exclusive to males, suicides due to alcohol/drug toxicity were significantly higher in females. Both before and after reclassification of suicide deaths, sex differences in suicide rates emerged in the 16-25 years age group. In each study year, both actual and reclassified suicide rates were higher in males than females. CONCLUSIONS: Sex differences in suicide rates emerging in adolescence are unlikely to be due to misclassification. Other proposed explanations for sex differences in youth suicide rates should be investigated further.

Child maltreatment and onset of emergency department presentations for suicide-related behaviors.

OBJECTIVES: To determine whether the rates of a first presentation to the emergency department (ED) for suicide-related behavior (SRB) are higher among children/youth permanently removed from their parental home because of substantiated maltreatment than their peers. To describe the health care settings accessed by these children/youth before a first SRB presentation to help design preventive interventions. METHODS: A population-based (retrospective) cohort of 12-17-year-olds in Ontario, Canada was established. Children/youth removed from their parental home because of the above noted maltreatment (n=4683) and their population-based peers (n=1,034,546) were individually linked to administrative health care records over time to ascertain health service use and subsequent ED presentations for SRB during follow-up. Person-time incidence rates were calculated and Cox regression models used to estimate adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI). RESULTS: After controlling for demographic characteristics and prior health service use, maltreated children/youth were about five times more likely to have a first ED presentation for SRB compared to their peers, in both boys (HR: 5.13, 95% CI: 3.94, 6.68) and girls (HR: 5.36, 95% CI: 4.40, 6.54). CONCLUSIONS: Children/youth permanently removed from their parental home because of substantiated child maltreatment are at an increased risk of a first presentation to the ED for SRB. The prevention of child maltreatment and its recurrence and the promotion of resilience after maltreatment has occurred are important avenues to study toward preventing ED SRB presentations in children/youth. Provider and system level linkages between care sectors may prevent the need for such presentations by providing ongoing environmental support.

Bilateral distal biceps tendon ruptures.

PURPOSE: To determine the incidence of bilateral distal biceps tendon ruptures. METHODS: A retrospective review of 321 patients who underwent operative repair of a distal biceps tendon rupture between 1988 and 2010 identified 26 patients with bilateral ruptures. We recorded patient age, mechanism of injury, time between symptom onset before the first surgery and subsequent contralateral symptoms, and time between surgeries. RESULTS: Twenty-two bilateral ruptures were confirmed intra-operatively, 3 by MRI, and 1 was lost to follow up. A total of 23 bilateral ruptures (92%) occurred in men. The average age at the initial rupture was 44 years (range, 29-74 y). The average age at subsequent rupture was 48 years (range, 36-79 y). Excluding the 2 women (age 72 and 79 y), the average age at the initial rupture was 42 years and the average age at subsequent rupture was 46 years. The average interval between ruptures was 4.1 years (range, 0.8-13.9 y). The initial rupture occurred in the dominant extremity in 12 cases (50%) and in the nondominant extremity in 10 cases (42%); in 3 patients (8%) the dominance was not documented or ambidextrous. Thirty-three percent were heavy laborers, 3 patients had a smoking history, and 1 patient reported a history of steroid use. Twenty-two patients (88%) had the second side repaired, where we noted that 12 (55%) of the second tendon ruptures were partial tears. CONCLUSIONS: The 8% cumulative incidence of bilateral biceps tendon ruptures in a consecutive series of biceps tendon repairs may be higher because not all patients were contacted, which introduced a sampling bias. This 8% rate is markedly higher than the reported rate of 1.2 per 100,000 for an isolated distal biceps tendon rupture. This implies that patients with a distal biceps tendon rupture are at risk for a rupture on the contralateral side. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III.

Sex differences in childhood sexual abuse and suicide-related behaviors.

Child sexual abuse and suicide-related behaviors are associated, but it remains unclear if the strength of this association differs in boys and girls. In a systematic review of this association in children and youth, we identified 16 relevant studies, all cross-sectional surveys of students. The association is stronger in boys specific to suicide attempt(s). Adjustments for potential confounding variables explained some, but not all of this sex difference. While additional research would strengthen causal inferences, this sex difference may be influenced by the nature and timing of child sexual abuse as well as the sex of the perpetrator, which in turn shapes the disclosure of these events.

Distal biceps tendon tears in women.

HYPOTHESIS: Is the presentation and outcome of surgical treatment of distal biceps tendon tears different in women than men? MATERIALS AND METHODS: From 1999 to 2008, 15 cases of distal biceps tendon tears in 13 female patients were treated surgically at a single institution. Mean age was 63 years (range, 48-79 years). A retrospective review evaluated patient presentation, diagnosis, and treatment. Postoperative outcomes were assessed by physical examination, a patient satisfaction survey, the American Shoulder and Elbow Surgeons (ASES) elbow assessment form, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. RESULTS: Two-thirds of the tears were in the dominant arm, of which 7 resulted from a single injury, and 8 reported insidious onset of symptoms. All patients presented with pain in the antecubital fossa. A distinct cystic mass was palpable in 6. Of the 15 cases, 13 were partially detached, 1 was completely detached, and 1 was weakly attached. Fourteen regained full strength, and all had nearly complete range of motion. Mean follow-up was 46 months (range, 2-117 months). Eleven completed a postoperative patient satisfaction survey, ASES elbow, and DASH questionnaire. Mean scores were 95 (range, 58-100) for ASES and 7 (range, 0-43) for DASH. The only complication was a transient lateral antebrachial cutaneous nerve sensory palsy. DISCUSSION: Distal biceps tendon tears in women present at an advanced age with no history of an acute injury. They are frequently associated with a cystic mass and have a predominance of partial tears. CONCLUSIONS: Distal biceps tendon tears in women present differently than in men. The tears are rarely complete and they respond well to surgical repair.

Effectiveness of magnetic resonance imaging in detecting partial and complete distal biceps tendon rupture.

PURPOSE: A magnetic resonance imaging (MRI) scan of the elbow is often obtained to confirm the clinical suspicion of a distal biceps tendon rupture. The goal of this study was to evaluate the effectiveness of MRI in diagnosing partial and complete distal biceps tendon ruptures as determined at the time of surgery. METHODS: We identified 22 partial and 24 complete distal biceps tendon ruptures operated on by a single surgeon. The preoperative MRIs of these patients were obtained, along with MRIs of the elbow in 10 asymptomatic individuals. Two musculoskeletal radiologists read each MRI without knowledge of the diagnosis or the surgical findings. Their interpretations were compared with the intraoperative findings and the results were statistically analyzed. RESULTS: The overall sensitivity and specificity of MRI were 92.4% and 100%, respectively, in detecting distal biceps tendon ruptures. The sensitivity and specificity of MRI for complete tears were 100% and 82.8%, respectively. The sensitivity and specificity of MRI for partial tears were 59.1% and 100%, respectively. CONCLUSIONS: Magnetic resonance imaging is an effective tool for diagnosing distal biceps tendon ruptures. Although MRI is extremely sensitive in diagnosing complete tears, it is substantially less sensitive in diagnosing partial tears. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.