Understanding shoulder pseudoparalysis. Part II: Treatment.

Decision-making for the treatment of pseudoparalytic shoulders is complex and a high level of experience in shoulder surgery and outcome evaluation is required. Management and results depend on clinical findings, tear and tissue quality, patient and surgeon criteria. Clinical findings determine the exact definition and direction of pseudoparesis and pseudoparalysis. Tear pattern and tissue quality determine if the rotator cuff is repairable or irreparable. Age and general health are important patient factors. Non-operative treatment is the first option for patients with a higher risk profile for reconstruction or arthroplasty, but delineation of its value requires better evidence. Tendon transfers are used for irreparable loss of the horizontal force couple balance (rotation). Options include latissimus dorsi, pectoralis minor and major for loss of active internal rotation, and latissimus dorsi ± teres major and lower trapezius for loss of active external rotation (AER). Partial cuff repair with or without superior capsular reconstruction using allograft or biceps tendon is an option for loss of active forward elevation. Treatment for the combined loss of elevation and external rotation patients is still not clear. Options include lateralised reverse shoulder arthroplasty (RSA) alone or combined RSA with a tendon transfer. RSA with loss of AER can be revised by adding a tendon transfer.

Understanding shoulder pseudoparalysis: Part I: Definition to diagnosis.

Variable definitions of pseudoparalysis have been used in the literature. Recent systematic reviews and biomechanical studies call for a grading of loss of force couple balance and the use of the terms 'pseudoparesis' and 'pseudoparalysis'. Pain should be excluded as the cause of loss of active function. Key players for loss of force couple balance seem to be the lower subscapularis as an anterior inferior checkrein and the teres minor as a posterior inferior fulcrum. Loss of three out of five muscle-tendon units counting upper and lower subscapularis separately is predictive of pseudoparalysis. Shoulder equator concept: loss of all three posterior, or all three superior, or all three anterior muscle-tendon units is predictive of pseudoparalysis (loss of fulcrum for deltoid force). Every effort should be made to prevent propagation of rotator cuff tears into the subscapularis and posterior rotator cuff (infraspinatus and teres minor) to maintain force couple balance (value of partial cuff repair). Clinical assessment of active forward elevation, active external rotation, and active internal rotation is important to define and grade the severity of loss of force couple balance. Additional features such as patient age, traumatic aetiology, chronicity, fatty infiltration, and stage of cuff tear arthropathy are useful for a specific diagnosis with implications for treatment.

Efficacy and safety of ipragliflozin in Japanese patients with type 2 diabetes and inadequate glycaemic control on sitagliptin.

AIMS: To assess the efficacy, safety and tolerability of ipragliflozin 50 mg once daily added to sitagliptin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: The results of two clinical trials are reported. In both trials, patients had glycated haemoglobin (HbA1c) levels of 7.0% to 10.0% on sitagliptin 50 mg once daily 2 weeks prior to addition of ipragliflozin or placebo. In one trial (Trial 843), patients were randomized 1:1 to addition of blinded ipragliflozin 50 mg once daily (n = 73) or placebo (n = 70) for 24 weeks; the primary endpoint was efficacy (change in HbA1c at Week 24). In the other trial (Trial 849), open-label ipragliflozin 50 mg once daily was added for 52 weeks (n = 77); the primary objective was to assess safety/tolerability. RESULTS: In Trial 843, baseline characteristics were similar between groups (mean age 60.5 years, HbA1c 8.0%); after 24 weeks, adding ipragliflozin provided significantly greater reduction in HbA1c compared to placebo: least squares mean difference -0.77% (95% confidence interval -0.98, -0.57; P <0.001). In Trial 843, the incidences of adverse events (AEs) overall and prespecified AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia, and polyuria/pollakiuria) were similar between groups. In Trial 849, specific AEs with incidence ≥5% were nasopharyngitis, pollakiuria, back pain, thirst, constipation, influenza and arthralgia; drug-related AEs reported in ≥2 patients were pollakiuria, thirst and constipation. CONCLUSIONS: Ipragliflozin 50 mg once daily added on to sitagliptin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated in Japanese patients with T2D. ClinicalTrials.gov: NCT02577003, NCT02564211.

A randomized, placebo-controlled trial to assess the efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes and inadequate glycaemic control on ipragliflozin.

AIMS: To investigate the efficacy, safety and tolerability of sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Japanese patients with T2D and glycated haemoglobin (HbA1c) 7.0% to 10.0% while treated with ipragliflozin 50 mg once daily were randomized 1:1 to additional treatment with sitagliptin 50 mg once daily (N = 70) or matching placebo (N = 71) for 24 weeks. The primary efficacy endpoint was change in HbA1c at Week 24. Secondary efficacy endpoints were changes in 2-hour post-meal glucose (PMG), total PMG 0- to 2-hour area under the curve (AUC0-2h ), and fasting plasma glucose (FPG). RESULTS: Baseline characteristics were similar in the two groups (mean age 55.5 years, mean baseline HbA1c 8.0%). After 24 weeks, the addition of sitagliptin provided significantly greater reduction in HbA1c compared to placebo (least squares [LS] mean difference -0.83% [95% confidence interval -1.05, -0.62]; P <0.001). Significant reductions were also observed in all secondary endpoints: LS mean differences from placebo in changes in 2-hour PMG, total PMG AUC0-2h , and FPG were -42.5 mg/dL, -67.0 mg·h/dL and -11.2 mg/dL, respectively (all P <0.001). The incidence of adverse events (AEs) overall and incidence of predefined AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia and polyuria/pollakiuria) were similar in the two groups. CONCLUSIONS: In Japanese patients with T2D, sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated. ClinicalTrials.gov: NCT02577016.

A randomized, placebo-controlled study to evaluate the efficacy and safety of adding omarigliptin to insulin therapy in Japanese patients with type 2 diabetes and inadequate glycaemic control.

AIM: To evaluate the efficacy and safety of adding the once-weekly oral dipeptidyl peptidase-4 inhibitor omarigliptin to treatment of Japanese patients with type 2 diabetes and inadequate glycaemic control on insulin monotherapy. MATERIALS AND METHODS: In a 52-week clinical trial, Japanese patients on insulin monotherapy were randomized to once-weekly omarigliptin 25 mg (N = 123) or placebo (N = 61) for a 16-week, double-blind, placebo-controlled period. After Week 16, patients continued or switched to omarigliptin for a 36-week open-label period. RESULTS: From a mean baseline of approximately 8.8%, the Week 16 least squares mean changes in HbA1c were -0.61% (omarigliptin) and 0.29% (placebo); the between-group difference was -0.90% (p < .001). At Week 52, the mean change from baseline in HbA1c was -0.57% in both the group on omarigliptin for 52 weeks and the group on omarigliptin for 36 weeks (switched from placebo at Week 16). During the first 16 weeks of treatment, the incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuation from trial medication because of an AE were similar in both groups. A slight increase in incidence of symptomatic hypoglycaemia was observed in the omarigliptin group (n = 13 [10.6%]) compared with placebo (n = 4 [6.6%]). No severe hypoglycaemia was reported during the study. No new safety signals emerged with treatment beyond Week 16 through Week 52. CONCLUSION: The addition of once-weekly omarigliptin to insulin therapy for up to 52 weeks was generally well tolerated and provided clinically meaningful improvement in glycaemic control throughout the trial period. ClinicalTrials.gov: NCT02906709.

Factors associated with the glucose-lowering efficacy of sitagliptin in Japanese patients with type 2 diabetes mellitus: Pooled analysis of Japanese clinical trials.

AIMS/INTRODUCTION: To explore the factors associated with the glucose-lowering efficacy of sitagliptin treatment in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: This was a post-hoc analysis of pooled data from seven sitagliptin phase II and III clinical studies carried out in Japan. All studies were double-blind, randomized, placebo-controlled, parallel-group and of 12-week duration. The analysis population consisted of 1,075 type 2 diabetes mellitus patients. In two of the trials, sitagliptin 50 mg and/or 100 mg daily were used as monotherapy; in five others, sitagliptin 50 mg daily was used as add-on treatment to ongoing pioglitazone, glimepiride, metformin, voglibose or glinides. Efficacy (reduction in hemoglobin A1c [HbA1c]) was evaluated in 12 sets of subgroups defined by demographic, glycemic, pancreatic ß-cell function and insulin resistance parameters. An analysis of covariance model was used to evaluate the interaction between each parameter and efficacy. RESULTS: Sitagliptin consistently provided a clinically meaningful reduction in HbA1c relative to placebo across all subgroups. Within subgroups, a greater absolute HbA1c reduction was associated with higher baseline HbA1c, fasting plasma glucose and 2-h post-meal glucose. Lower ß-cell function, represented by homeostatic model assessment of ß-cell function and insulinogenic index, was also associated with greater HbA1c reduction. In contrast, age, sex, body mass index, duration of type 2 diabetes mellitus and insulin resistance-related parameters did not interact with HbA1c changes. CONCLUSIONS: Sitagliptin treatment was associated with clinically meaningful improvement in glycemic control in all subgroups of Japanese patients with type 2 diabetes mellitus that were evaluated. Higher baseline glycemic status and lower baseline ß-cell function were identified as factors associated with greater HbA1c reduction after sitagliptin treatment.

A Randomized, Placebo-Controlled Trial Evaluating the Safety and Efficacy of Adding Omarigliptin to Antihyperglycemic Therapies in Japanese Patients with Type 2 Diabetes and Inadequate Glycemic Control.

INTRODUCTION: Daily dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used with other orally administered antihyperglycemic agents (AHA), as combination therapy, to treat Japanese patients with type 2 diabetes. When combination therapy is indicated, use of a once-weekly (q.w.) orally administered DPP-4 inhibitor might be an appropriate therapeutic option for some patients. METHODS: A 52-week trial was conducted to assess the safety and tolerability (primary objectives) and glycemic efficacy (secondary objectives) of the q.w. DPP-4 inhibitor omarigliptin as add-on therapy to five different classes of orally administered AHA [sulfonylurea (SU), glinide (GL), biguanide (BG), thiazolidinedione (TZD), or α-glucosidase inhibitor (AGI)] commonly used in Japan and having different mechanisms of drug action from DPP-4 inhibitors. The trial consisted of an initial 24-week double-blind, placebo-controlled period during which patients (stratified by background AHA) were randomized to omarigliptin 25 mg q.w. or placebo, followed by a 28-week open-label period during which patients on placebo were switched to omarigliptin. RESULTS: After 24 weeks, the percentages of patients with adverse events (AEs), serious AEs, drug-related AEs, AEs of symptomatic hypoglycemia, or who discontinued from trial medication because of an AE were generally similar in the omarigliptin and placebo groups, in all background AHA strata and in the overall population. From a mean baseline HbA1c of approximately 8.0%, the placebo-adjusted least-squares mean changes from baseline ranged from -0.80% (AGI stratum) to -1.16% (TZD stratum); p < 0.001 for all background AHA strata. During the open-label period, no safety signals emerged with longer-term treatment. At week 52, the change from baseline in HbA1c in the omarigliptin/omarigliptin group was similar to that of the placebo/omarigliptin group. CONCLUSIONS: Addition of once-weekly omarigliptin to AHA therapy with an SU, GL, BG, TZD, or AGI for up to 52 weeks was generally safe and well tolerated, and provided persistent efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01697592. FUNDING: MSD K.K., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

A randomized, placebo- and sitagliptin-controlled trial of the safety and efficacy of omarigliptin, a once-weekly dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes.

AIMS: To assess the safety and efficacy of omarigliptin in Japanese patients with type 2 diabetes (T2D). METHODS: In a 24-week double-blind trial, 414 patients with T2D were randomized to omarigliptin 25 mg once weekly, sitagliptin 50 mg once daily or placebo. The double-blind period was followed by a 28-week open-label extension during which all patients received omarigliptin 25 mg once weekly. Efficacy endpoints were glycated haemoglobin (HbA1c), 2-hour postprandial glucose (PPG) and fasting plasma glucose (FPG) levels. RESULTS: After 24 weeks, the least squares (LS) mean change from baseline in HbA1c was -0.66% for omarigliptin, -0.65% for sitagliptin and 0.13% for placebo. The difference in LS mean for omarigliptin vs placebo was -0.80% ( P < .001). The difference in LS mean for omarigliptin vs sitagliptin was -0.02% (95% confidence interval -0.15, 0.12), which met the criterion for non-inferiority to sitagliptin. Both active treatments provided significant reductions in FPG and 2-hour PPG compared with placebo (P < .001). Over the 24-week double-blind period, there were no clinically meaningful differences in the incidence rates of adverse events among the treatment groups. There was 1 episode of symptomatic hypoglycaemia in the sitagliptin group and none in the omarigliptin or placebo groups. In the 28-week open-label period, omarigliptin provided persistent improvements in glycaemic control without notable change in safety profile compared with the double-blind period. Omarigliptin had no meaningful effect on body weight. CONCLUSIONS: In Japanese patients with T2D, omarigliptin 25 mg once weekly provided significant glucose-lowering compared with placebo and was non-inferior to sitagliptin 50 mg once daily. Omarigliptin was generally well tolerated for up to 52 weeks.

Day-of-Surgery Mobilization Reduces the Length of Stay After Elective Hip Arthroplasty.

BACKGROUND: To determine the effect of mobilization on the day of surgery on the readiness for discharge and length of stay after elective total hip arthroplasty (THA). METHODS: We devised a randomized control trial with concealed allocation and intention-to-treat analysis. Overall, 126 patients who underwent THA and met the criteria for mobilization on the day of surgery were randomly allocated into 2 groups; the intervention group was mobilized on the day of surgery, n = 58 and the control group was mobilized on the day after surgery, n = 68. Apart from timing of mobilization, both groups received the same postoperative management. The primary outcome measures were length of hospital stay and time to readiness for discharge. RESULTS: The early mobilization group was ready for discharge 63 hours (standard deviation [SD] = 15 hours) after surgery, compared to 70 hours (SD = 18 hours) for the control group (P = .03, 95% CI, 0.7-12.8). There was no significant difference in hospital stay in the early mobilization group (77 hours [SD = 30 hours]), compared to the control group (87 hours [SD = 35 hours]; P = .11, 95% CI, -2.1 to 21.6). Despite this at any point in time after the surgery, the intervention group was 1.8 times (P = .003, 95% CI, = 1.2-2.7) more likely to have been discharged. CONCLUSION: Mobilization on the day of THA surgery significantly increases the probability of discharge at any singular point in time compared with mobilization on the day after surgery and decreases the time to readiness for discharge.

Long-period ocean-bottom motions in the source areas of large subduction earthquakes.

Long-period ground motions in plain and basin areas on land can cause large-scale, severe damage to structures and buildings and have been widely investigated for disaster prevention and mitigation. However, such motions in ocean-bottom areas are poorly studied because of their relative insignificance in uninhabited areas and the lack of ocean-bottom strong-motion data. Here, we report on evidence for the development of long-period (10-20 s) motions using deep ocean-bottom data. The waveforms and spectrograms demonstrate prolonged and amplified motions that are inconsistent with attenuation patterns of ground motions on land. Simulated waveforms reproducing observed ocean-bottom data demonstrate substantial contributions of thick low-velocity sediment layers to development of these motions. This development, which could affect magnitude estimates and finite fault slip modelling because of its critical period ranges on their estimations, may be common in the source areas of subduction earthquakes where thick, low-velocity sediment layers are present.

Sitagliptin added to voglibose monotherapy improves glycemic control in patients with type 2 diabetes.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a progressive disease that frequently requires patients to use more than one oral antihyperglycemic agent to achieve adequate glycemic control. The present multicenter, randomized study assessed the efficacy and safety of the addition of sitagliptin to ongoing voglibose monotherapy (0.2-0.3 mg three times daily) in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control (glycated hemoglobin ≥6.9% and <10.5%). MATERIALS AND METHODS: The present study had an initial 12-week, double-blind treatment period in which patients were randomized (1:1) to sitagliptin 50 mg/day (n = 70) or placebo (n = 63), followed by a 40-week, open-label treatment period during which all patients received sitagliptin 50 mg/day, that could have been increased to 100 mg/day for patients meeting predefined glycemic criteria. RESULTS: After 12 weeks, treatment with sitagliptin resulted in placebo-subtracted mean changes from baseline in glycated hemoglobin (the primary end-point), fasting plasma glucose and 2-h postmeal glucose of -0.9%, -22.5 mg/dL and -51.3 mg/dL, respectively (all, P < 0.001). During the double-blind period, adverse experiences were reported with similar frequency in both treatment groups, and the occurrences of hypoglycemia and gastrointestinal adverse experiences were low. In the open-label period, sustained improvements in glycemic parameters were observed with sitagliptin treatment, and sitagliptin was generally well tolerated. CONCLUSIONS: Sitagliptin added on to ongoing voglibose monotherapy provided significant improvements in glycemic parameters and was well tolerated in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control. This trial was registered with ClinicalTrials.gov (no. NCT00837577).

Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus.

Sitagliptin is an oral, potent, highly selective, once-daily DPP-4 inhibitor indicated for the treatment of type 2 diabetes mellitus (T2DM). To assess the dose-ranging efficacy and safety/tolerability profile of once-daily sitagliptin 25, 50, 100, and 200 mg in Japanese patients with T2DM. In this randomized, double-blind, placebo-controlled study, 363 Japanese patients with inadequate glycemic control (HbA(1c)=6.5-10%; FPG< or =270 mg/dL) were randomized (1:1:1:1:1) to placebo, sitagliptin 25, 50, 100, or 200 mg q.d. for 12 weeks. The primary endpoint was change from baseline in HbA(1c) at Week 12. At Week 12, treatment with sitagliptin at all doses tested provided significant (p<0.001) reductions in HbA(1c) (-0.69 to -1.04%) from baseline (7.49 to 7.65%) relative to placebo. Sitagliptin significantly (p<0.001) reduced fasting plasma glucose (FPG; -15.9 to -23.2 mg/dL) and 2-hour postprandial glucose (2-hr PPG; -40.3 to -65.0 mg/dL) relative to placebo, in a dose-dependent manner. At doses > or =50 mg, differences in HbA(1c), FPG, and 2-hr PPG between the sitagliptin groups were not statistically significant. Sitagliptin was generally well tolerated with a low and similar incidence of hypoglycemia and minimal weight gain relative to placebo. Treatment with sitagliptin for 12 weeks provided significant and clinically meaningful reductions in HbA(1c), FPG, and 2-hr PPG across the dose range studied and was generally well tolerated in Japanese patients with T2DM.

Valproic acid induces apoptosis dependent of Yca1p at concentrations that mildly affect the proliferation of yeast.

Valproic acid (VPA) inhibited the growth of yeast in a dose-dependent manner with complete inhibition attained at 100 mM. When cells were exposed to 25 mM VPA, the wild-type died showing apoptotic markers, while yca1Delta deleted of YCA1 encoding yeast caspase 1 survived. On the other hand, when cells were exposed to 50 mM VPA, both the wild-type and yca1Delta died showing morphological features similar to those of the autophagic death of cdc28 which was also independent of YCA1. Thus, these results suggested that yeast cells die via YCA1-dependent apoptosis when their proliferative activity is mildly impaired.