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.

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.

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.

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.

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.

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.

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.

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.

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.

Metabolic syndrome: historical perspectives.

The metabolic syndrome is an aggregation of biochemical and physical conditions that presage the development of atherosclerotic cardiovascular disease. The history of the metabolic syndrome is rooted in the recognition of adipose tissue as a heterogeneous, biologically active organ, as well as in the concepts of insulin resistance and its consequences. Establishment of the metabolic syndrome as a disease entity has been hindered by non-uniform criteria for its diagnosis.

Fragment-specific fixation of distal radius fractures using the Trimed device.

Fragment-specific fixation of the distal radius represents a new technique for addressing complex distal radius fractures. It signifies a substantial shift in the thought process of open reduction and internal fixation; each fracture fragment is addressed independently with small plates or wire forms, allowing comminuted fractures to be anatomically restored and early motion started. Although the system is at first daunting, its modularity provides flexibility for the surgeon to modify the fixation to the individual needs of the patient's specific fracture pattern and the surgeon's level of expertise. Once the technique has been learned, the surgeon will have in his or her armamentarium a powerful new tool to treat fractures that had before been difficult to address satisfactorily with conventional techniques.

Hypertension after kidney transplantation: impact, pathogenesis and therapy.

Hypertension (HTN) contributes to the high incidence of cardiovascular disease mortality as well as chronic allograft nephropathy (CAN) and late graft failure in renal transplant recipients. The mechanisms are complex and may involve pathogenic factors attributable to the host, allograft, and immunosuppressive drugs. Calcium channel blockers should be used to ameliorate the nephrotoxicity of calcineurin inhibitors in the early years after transplantation. Angiotensin-converting enzyme inhibitors and angiotensin-2 type-1 receptor blockers are safe and effective, have antiproteinuric effects, slow the progression of CAN, and may provide survival benefits. Diuretics and/or beta-adrenergic receptor blockers are frequently added in combination regimen. Appropriate adjustment of the immunosuppressive drugs should also be considered for the long-term care of kidney recipients with HTN.

Austin Flint in New Orleans and the origins of evidence-based medicine.

The famous nineteenth century American physician and medical educator, Austin Flint, Sr., was a professor at the New Orleans School of Medicine and a visiting physician at Charity Hospital in New Orleans from 1858 to 1861. Best remembered for the heart murmur that bears his name, Flint was also responsible for advances in the diagnosis and treatment of infectious diseases in the era that preceded the germ theory and the discovery of antibiotics. His experiences at Charity Hospital and his exposure to the French style of medicine as practiced by the Creole physicians of New Orleans encouraged him to advocate conservative treatment for pneumonia, in contrast to the bloodletting and other heroic measures that were popular at the time. His recommendations, based on statistical analysis of his clinical data from Charity Hospital, were one of the earliest examples of evidence-based medicine in America.

The Ashman phenomenon.

In the presence of atrial fibrillation, impulses of supraventricular origin that are transmitted through the ventricles during periods of relative refractoriness to impulse conduction exhibit anomalous configurations. These "aberrant beats" can be difficult to distinguish from ventricular ectopic beats, and groups of aberrant beats may be mistaken for ventricular tachycardia. Richard Ashman, PhD, a physiologist at Louisiana State University School of Medicine in New Orleans, noted that ventricular refractoriness varied with the lengths of cardiac cycles; that aberrant beats typically ended short cycles following long cycles; and that aberrant beats often have a right bundle branch block configuration. This observation, known as the "Ashman phenomenon," has become a principle of cardiology. Its recognition may allow clinicians to distinguish aberrant beats from ventricular ectopy. Ashman made a variety of other fundamental contributions to electrocardiography and was also an accomplished poet.