The Effects of Accessory Blood Flow Restriction Training on Muscle Size and Strength in Division III Soccer Athletes: A Preliminary Ecological Study.

Blood flow restriction training (BFRT) uses occlusion during low-intensity resistance training (< 50% of 1-repetition maximum, 1RM) to reduce arterial blood flow and venous return, imposing greater metabolic stress but similar muscular hypertrophy and strength gains as high-intensity resistance training (HIRT). However, no study, to date, has incorporated BFRT in a collegiate strength and conditioning setting to assess ecological validity. We aimed to investigate the effects of adding 6-weeks of accessory BFRT or HIRT to NCAA Division III soccer players prescribed resistance training regimen on muscle strength and size. Male and female (n = 17) athletes were randomly assigned to complete biceps curls 2x/week under BFRT or control (HIRT), following regularly scheduled strength training. Bicep strength (1RM) and circumference (BC) were assessed at weeks 0, 3, and 6 (men only). In men, for BC no significant interaction of condition x time was observed (p = 0.861), though condition (BFRT vs Control, p = 0.025) and time (p = 0.024) were significant. For 1RM, there was no significant interaction of condition x time (BFRT vs HIRT, p = 0.067) or of condition (p = 0.598), but there was a significant effect of time (p = 0.004). In women, there was no significant interaction between time and condition (p = 0.765) or of condition (p = 0.971) on BC, but time was significant (p = 0.045). For 1RM, there was no significant interaction of condition x time (p = 0.227) or of condition (p = 0.741), but time was (p = 0.018). In this preliminary ecological study, BFRT induced similar increases in muscle strength and circumference as HIRT in soccer players, suggesting that BFRT could be incorporated into collegiate athlete training.

Assessing the Added Therapeutic Benefit of Ultra-Expensive Drugs.

OBJECTIVES: While the United States does not have a method for assessing the added therapeutic benefit of drugs, France, Canada, and Germany do. We examined the added therapeutic benefit of the most expensive drugs prescribed to Medicare Part D beneficiaries in the United States. METHODS: We identified ultra-expensive drugs with annual Medicare spending that exceeded $62 794 (United States GDP per capita in 2018) using Medicare Part D Prescription Drug Spending and Utilization Data. We used added therapeutic benefit ratings assessed by health technology assessment agencies in France, Canada, and Germany. RESULTS: We identified 122 ultra-expensive drugs in 2018. Sixty-five percent of these drugs (n = 79) were assessed by at least one of the countries. Based on these assessments, approximately 75% received a low added therapeutic benefit rating. CONCLUSIONS: Most ultra-expensive drugs prescribed in the United States and assessed by France, Canada, and Germany provide low added therapeutic benefit. Policy reforms in the United States could use added therapeutic benefit to inform coverage and pricing decisions for ultra-expensive drugs. Similar to Germany, one approach would be to allow the company to set a market price for a limited period of time before requiring a price reduction if the added therapeutic benefit is below a certain threshold. Another approach would be to identify when drug prices are substantially more expensive in the United States and conduct an added therapeutic benefit assessment and price review on these drugs.

A Novel Visual Grading for Ureteral Encrusted Stent Classification to Help Decide the Endourologic Treatment.

Objective: The aim of the study is to propose a visual classification for encrusted stents (ESs) to help choose the appropriate endourologic treatment. Materials and Methods: A multicenter, retrospective, and descriptive study was performed. A total of 140 patients with encrusted Double-J stents were enrolled from 5 different institutions. The novel visual grading for ureteral encrusted stent (V-GUES) classification system ranges from A to D, increasing with severity of encrustation. Results: ESs could be removed with a single intervention in 112 patients (86.8%). Type A and B ESs could be removed in all patients (100% success). Type D stents had minor retrieval and stone-free rates (p = 0.006 and p < 0.0001, respectively). Flexible ureteroscopy had a low success rate (77.7%) for type C stents (odds ratio [OR]: 0.21). Combined access had a 100% success rate for retrieval of type C ESs and a 92.9% success rate for type D ESs (OR: 9.18). Type D stents were associated with patients requiring more than one session to retrieve the stent (OR: 0.11) and stones (OR: 0.21). Conclusions: The V-GUES system is associated with treatment success rates of ES retrieval and stone-free status. It is also associated with the complication rate and the number of sessions needed for patients to be stent and stone free. The V-GUES classification could help counsel patients about the best treatment options and their outcomes. Further prospective studies will be needed to provide external validation.

Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists.

Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.

2-Methoxylated FA Display Unusual Antibacterial Activity Towards Clinical Isolates of Methicillin-Resistant Staphylococcus aureus (CIMRSA) and Escherichia coli.

The naturally occurring (6Z)-(±)-2-methoxy-6-hexadecenoic acid (1) and (6Z)-(±)-2-methoxy-6-octadecenoic acid (2) were synthesized in 7-8 steps with 38 and 13% overall yields, respectively, by using an acetylide coupling approach, which made it possible to obtain a 100% cis-stereochemistry for the double bonds. In a similar fashion, the acetylenic analogs (±)-2-methoxy-6-hexadecynoic acid (3) and (±)-2-methoxy-6-octadecynoic acid (4) were also synthesized in 6-7 steps with 48 and 16% overall yields, respectively. The antibacterial activity of acids 1-4 was determined against clinical isolates of methicillin-resistant Staphylococcus aureus (ClMRSA) and Escherichia coli. Among the series of compounds, acid 4 was the most active bactericide towards CIMRSA displaying IC50s (half maximal inhibitory concentrations) between 17 and 37 µg/mL, in sharp contrast to the 6-octadecynoic acid, which was not bactericidal at all. On the other hand, acids 1 and 3 were the only acids that displayed antibacterial activity towards E. coli, but 1 stood out as the best candidate with an IC50 of 21 µg/mL. The critical micelle concentrations (CMCs) of acids 1-4 were also determined. The C18 acids 2 and 4 displayed a five-fold lower CMC (15-20 µg/mL) than the C16 analogs 1 and 3 (70-100 µg/mL), indicating that 4 exerts its antibacterial activity in a micellar state. None of the studied acids were inhibitory towards S. aureus DNA gyrase discounting this type of enzyme inhibition as a possible antibacterial mechanism. It was concluded that the combination of α-methoxylation and C-6 unsaturation increases the bactericidal activity of the C16 and C18 FA towards the studied bacterial strains. Acids 1 and 4 stand out as viable candidates to be used against E. coli and CIMRSA, respectively.

Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists.

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.

Screening for severe obstructive sleep apnea syndrome in hypertensive outpatients.

The authors attempted to validate a 2-stage strategy to screen for severe obstructive sleep apnea syndrome (s-OSAS) among hypertensive outpatients, with polysomnography (PSG) as the gold standard. Using a prospective design, outpatients with hypertension were recruited from medical outpatient clinics. Interventions included (1) assessment of clinical data; (2) home sleep testing (HST); and (3) 12-channnel, in-laboratory PSG. The authors developed models using clinical or HST data alone (single-stage models) or clinical data in tandem with HST (2-stage models) to predict s-OSAS. For each model, area under receiver operating characteristic curves (AUCs), sensitivity, specificity, negative likelihood ratio, and negative post-test probability (NPTP) were computed. Models were then rank-ordered based on AUC values and NPTP. HST used alone had limited accuracy (AUC=0.727, NPTP=2.9%). However, models that used clinical data in tandem with HST were more accurate in identifying s-OSAS, with lower NPTP: (1) facial morphometrics (AUC=0.816, NPTP=0.6%); (2) neck circumference (AUC=0.803, NPTP=1.7%); and Multivariable Apnea Prediction Score (AUC=0.799, NPTP=1.5%) where sensitivity, specificity, and NPTP were evaluated at optimal thresholds. Therefore, HST combined with clinical data can be useful in identifying s-OSAS in hypertensive outpatients, without incurring greater cost and patient burden associated with in-laboratory PSG. These models were less useful in identifying obstructive sleep apnea syndrome of any severity.

In-home, self-assembled sleep studies are useful in diagnosing sleep apnea in the elderly.

OBJECTIVES: Obstructive sleep apnea (OSA) is common and treatable among the elderly. Yet, few older adults seek evaluation for OSA at sleep disorders centers. The authors assessed the feasibility of a two-stage screening procedure for obstructive sleep apnea syndrome (OSAS) in a community-based sample of older adults. DESIGN: Prospective cohort study. SETTING: Participants' domicile (in-home) and academic sleep research center. PARTICIPANTS: There were 452 Medicare recipients residing in the greater Philadelphia metropolitan area with the complaint of daytime sleepiness. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: All participants underwent in-home unattended sleep studies that recorded airflow, and standard in-laboratory polysomnography. Additional measures included symptoms of sleep apnea, body mass index, neck circumference, age, and sex. When comparing diagnostic approaches, the best-performing single-stage model was one that combined apnea symptoms with age and neck circumference. This model had an area under the receiver operating characteristic curve (AUC) of 0.774 and negative posttest probability of 1.2%. The best-performing two-stage model combined symptoms, neck circumference, age, and sex in the first stage, followed by an unattended portable study with a corresponding AUC of 0.85 and negative posttest probability of 0.5%. CONCLUSIONS: Unattended, self-assembled, in-home sleep studies recording airflow and respiratory effort are most useful if applied in tandem with clinical data, including a carefully obtained sleep history. This two-stage model is accurate in identifying severe OSAS in older adults and represents a practical diagnostic approach for older adults. Incorporating clinical data was vital and increased accuracy well above that of unattended studies of airflow and effort alone.

Reconstruction of the premaxilla: an option for mutilated bilateral clefts.

The loss of the maxilla is a severe mutilation resulting from inadequate surgery of bilateral clefts of the lip and palate. It is usually associated with palatal fistulae, collapse of the maxillary segments, and limited facial growth.Functional rehabilitation can be achieved by reconstruction of the premaxilla with osteomucosal fibula grafts. Mucosal grafts are fixed to the fibula in a preliminary stage. The composite graft is transplanted to the maxilla 10 to 12 weeks later. Osteointegrated implants are placed 3 months later.The procedure was used in 7 patients, 1 holoprosencephaly and 6 with sequelae of bilateral clefts; mean age, 17.28 years, with a follow-up of 14 to 70 months.The mucosal grafts integrated successfully to the fibula in all the patients. The osteocutaneous graft achieved a solid maxillary arch in all the patients. Normal mastication was achieved with a prosthesis fixed to the osteointegrated implants. Facial proportions were greatly improved.