Modelling and optimization of biodiesel production from waste fish oil using nano immobilized rPichiapastoris whole cell biocatalyst with response surface methodology and hybrid artificial neural network based approach.

In this study, zinc oxide (ZnO) nano particle immobilized recombinant whole cell biocatalyst (rWCB) was used for bioconversion of waste fish oil in to biodiesel in a lab scale packed bed reactor (PBR). Central composite design and hybrid artificial neural network (ANN) models were explored to optimize the production of biodiesel. Developed rWCB exhibited maximum lipase activity at 15 % (v/v) of glutaraldehyde concentration and 6 % (w/v) of ZnO nanoparticles at pH of 7. Maximum biodiesel yield reached about 91.54 ± 1.86 % after 43 h in PBR using hybrid ANN model predicted process conditions of 13.2 % (w/v) of nano immobilized rWCB concentration and 4.7:1 of methanol to oil ratio at 33 °C. Importantly, developed nano immobilized rWCB was adequately stable for commercialization. Thus, production of biodiesel from waste fish oil using ZnO nano immobilized rWCB could become potential candidate for commercialization.

Expanding the Anti-Phl p 7 Antibody Toolkit: An Anti-Idiotype Nanobody Inhibitor.

We have previously produced a toolkit of antibodies, comprising recombinant human antibodies of all but one of the human isotypes, directed against the polcalcin family antigen Phl p 7. In this work, we complete the toolkit of human antibody isotypes with the IgD version of the anti-Phl p 7 monoclonal antibody. We also raised a set of nanobodies against the IgD anti-Phl p 7 antibody and identify and characterize one paratope-specific nanobody. This nanobody also binds to the IgE isotype of this antibody, which shares the same idiotype, and orthosterically inhibits the interaction with Phl p 7. The 2.1 Å resolution X-ray crystal structure of the nanobody in complex with the IgD Fab is described.

Crystal structures of the human IgD Fab reveal insights into CH1 domain diversity.

Antibodies of the IgD isotype remain the least well characterized of the mammalian immunoglobulin isotypes. Here we report three-dimensional structures for the Fab region of IgD, based on four different crystal structures, at resolutions of 1.45-2.75 Å. These IgD Fab crystals provide the first high-resolution views of the unique Cδ1 domain. Structural comparisons identify regions of conformational diversity within the Cδ1 domain, as well as among the homologous domains of Cα1, Cγ1 and Cµ1. The IgD Fab structure also possesses a unique conformation of the upper hinge region, which may contribute to the overall disposition of the very long linker sequence between the Fab and Fc regions found in human IgD. Structural similarities observed between IgD and IgG, and differences with IgA and IgM, are consistent with predicted evolutionary relationships for the mammalian antibody isotypes.

Recommendations for inversion table therapy.

In the USA, low back pain related illness accounts for approximately 149 million workdays lost each year. Initial management of back pain typically involves allied healthcare professionals who implement various treatments, such as chiropractic manipulation, physiotherapy, and acupuncture which have varying outcomes and levels of supporting evidence. Another passive treatment for back pain is inversion table therapy (ITT). It is a form of spinal traction which is thought to have a role in relieving low back pain due to the gravity-facilitated traction of the spine which distracts the lumbar vertebrae. However, ITT is not without risk. According to the Food and Drug Administration (FDA) Medical Device Reporting Events Database, ITT has resulted in serious injuries including spinal cord injury, fractures, lacerations, and death. The FDA has regulated ITT for only manufacturers that indicated medical use; however, most manufacturers have not made such medical claims and were exempt from FDA regulation. This article discusses the risks of ITT, the current regulatory process for ITT, and the need for a better understanding of the role of ITT in the treatment of spinal pain while optimizing consumer safety.Implications for rehabilitationInversion table therapy (ITT) is a form of spinal traction which is thought to have a role in relieving low back pain due to the gravity-facilitated traction of the spine which distracts the lumbar vertebrae.According to the Food and Drug Administration (FDA) statistics, injuries due to non-powered traction from various medical devices have been rising since 2011.The FDA has regulated ITT for only manufacturers that indicated medical use; however, most manufacturers have not made such medical claims and were exempt from FDA regulation.This article discusses the risks of ITT, the current regulatory process for ITT, and the need for a better understanding of the role of ITT in the treatment of spinal pain while optimizing consumer safety.

Production of biodiesel from Caulerpa racemosa oil using recombinant Pichia pastoris whole cell biocatalyst with double displayed over expression of Candida antartica lipase.

In this study, Caulerpa racemosa oil was used to produce biodiesel by recombinant Pichia pastoris displaying bound (rPp-BL) and secretory lipase (rPp-SL). Collected algae was pre-treated using ultrasonication, microwave and solvent extraction. Defatted C. racemosa was subjected to dilute acid treatment to obtain algal biomass hydrolysate. Both rPp-BL and rPp-SL were cultivated in algal biomass hydrolysate and glycerol. Surfactant treatment was performed on rPp-BL. Screening and optimization of variables were performed for biodiesel production using Plackett Burman design and central composite design, respectively. About 10.64 % (w/w) of algal oil was extracted from C. racemosa. Both rPp-BL and rPp-SL effectively utilized C. racemosa biomass hydrolysate and glycerol. rPp-SL combined with triton X (1.0 % w/v) treated rPp-BL for 3 min improved lipase activity. Methanol to oil ratio, combined whole cell biocatalyst and temperature were significant factors. Under optimum conditions, biodiesel yield reached about 93.64 % after 30 h using developed whole cell biocatalyst.

Intrinsic Folding Properties of the HLA-B27 Heavy Chain Revealed by Single Chain Trimer Versions of Peptide-Loaded Class I Major Histocompatibility Complex Molecules.

Peptide-loaded Major Histocompatibility Complex (pMHC) class I molecules can be expressed in a single chain trimeric (SCT) format, composed of a specific peptide fused to the light chain beta-2 microglobulin (ß2m) and MHC class I heavy chain (HC) by flexible linker peptides. pMHC SCTs have been used as effective molecular tools to investigate cellular immunity and represent a promising vaccine platform technology, due to their intracellular folding and assembly which is apparently independent of host cell folding pathways and chaperones. However, certain MHC class I HC molecules, such as the Human Leukocyte Antigen B27 (HLA-B27) allele, present a challenge due to their tendency to form HC aggregates. We constructed a series of single chain trimeric molecules to determine the behaviour of the HLA-B27 HC in a scenario that usually allows for efficient MHC class I molecule folding. When stably expressed, a pMHC SCT incorporating HLA-B27 HC formed chaperone-bound homodimers within the endoplasmic reticulum (ER). A series of HLA-B27 SCT substitution mutations revealed that the F pocket and antigen binding groove regions of the HLA-B27 HC defined the folding and dimerisation of the single chain complex, independently of the peptide sequence. Furthermore, pMHC SCTs can demonstrate variability in their association with the intracellular antigen processing machinery.

Biopolymeric superabsorbent hydrogels enhance crop and water productivity of soybean-wheat system in Indo-Gangetic plains of India.

Environmental crises, declining factor productivity, and shrinking natural resource is a threat to global agricultural sustainability. The task is much more daunting in the Indo-Gangetic northern plains of India, where depletion of the underground water table and erratic rains due to the changing climate pose a major challenge to agriculture. To address these challenges a field investigation was carried out during 2016-2018 to test the efficacy of biopolymeric superabsorbent hydrogels namely Pusa Hydrogel (P-hydrogel: a semi-synthetic cellulose derivative-based product) and kaolin derivative of Pusa Hydrogel (K-hydrogel: semi-synthetic cellulose derivative) to assess their effect on crop and water productivity, soil moisture, root dynamics, and economics of soybean (Glycine max L.)-wheat (Triticum aestivum L.) system under three irrigation regimes namely full irrigation, limited irrigation and rainfed. The results revealed that the full irrigation along with P-hydrogel led to enhanced grain yield, biomass yield, and water productivity (WP) of soybean (1.61-10.5%, 2.2-9.5%, and 2.15-21.8%, respectively) and wheat (11.1-18.3%, 12-54% and 11.1-13.1%, respectively) over control plots. Likewise, under water stressed plots of rainfed conditions with P-hydrogel exhibited 52.7 and 20.6% higher system yields (in terms of wheat equivalent yield) over control and other combinations during the respective study years. Whereas the magnitude of increase in system yield under limited irrigation with P-hydrogel was ~ 15.1% and under full irrigation with P-hydrogel was 8.0-19.4%. Plots treated with P-hydrogel retained 3.0-5.0% higher soil moisture compared to no-hydrogel plots, while K-hydrogel treated plots held the lower moisture (4.0-6.0%) than the control. In terms of profitability, full irrigation along with P-hydrogel plots registered 12.97% higher economic returns over control. The results suggested that P-hydrogel (2.5 kg ha-1) reduces runoff water loss in full irrigation applied plots and retained more water, where loss of water is more thus reduces number of irrigations. Hence P-hydrogel with irrigation water is a viable option for sustainable production of soybean-wheat systems in the Indo-Gangetic plains of India and other similar eco-regions of the world.

B Cell Mobilization, Dissemination, Fine Tuning of Local Antigen Specificity and Isotype Selection in Asthma.

In order to better understand how the immune system interacts with environmental triggers to produce organ-specific disease, we here address the hypothesis that B and plasma cells are free to migrate through the mucosal surfaces of the upper and lower respiratory tracts, and that their total antibody repertoire is modified in a common respiratory tract disease, in this case atopic asthma. Using Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) we have catalogued the antibody repertoires of B cell clones retrieved near contemporaneously from multiple sites in the upper and lower respiratory tract mucosa of adult volunteers with atopic asthma and non-atopic controls and traced their migration. We show that the lower and upper respiratory tracts are immunologically connected, with trafficking of B cells directionally biased from the upper to the lower respiratory tract and points of selection when migrating from the nasal mucosa and into the bronchial mucosa. The repertoires are characterized by both IgD-only B cells and others undergoing class switch recombination, with restriction of the antibody repertoire distinct in asthmatics compared with controls. We conclude that B cells and plasma cells migrate freely throughout the respiratory tract and exhibit distinct antibody repertoires in health and disease.

Virtual learning during the COVID-19 pandemic: a turning point in neurosurgical education.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has caused dramatic changes in medical education. Social distancing policies have resulted in the rapid adoption of virtual learning (VL) by neurosurgeons as a method to exchange knowledge, but it has been met with variable acceptance. The authors surveyed neurosurgeons from around the world regarding their opinions about VL and how they see the future of neurosurgical conferences. METHODS: The authors conducted a global online survey assessing the experience of neurosurgeons and trainees with VL activities. They also questioned respondents about how they see the future of on-site conferences and scientific meetings. They analyzed responses against demographic data, regions in which the respondents practice, and socioeconomic factors by using frequency histograms and multivariate logistic regression models. RESULTS: Eight hundred ninety-one responses from 96 countries were received. There has been an increase in VL activities since the start of the COVID-19 pandemic. Most respondents perceive this type of learning as positive. Respondents from lower-income nations and regions such as Europe and Central Asia were more receptive to these changes and wanted to see further movement of educational activities (conferences and scientific meetings) into a VL format. The latter desire may be driven by financial savings from not traveling. Most queried neurosurgeons indicated that virtual events are likely to partially replace on-site events. CONCLUSIONS: The pandemic has improved perceptions of VL, and despite its limitations, VL has been well received by the majority of neurosurgeons. Lower-income nations in particular are embracing this technology. VL is still evolving, but its integration with traditional in-person meetings seems inevitable.

The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial.

PURPOSE: Without supporting evidence, clinicians commonly recommend that warfarin be taken in the evening. We conducted a randomized controlled trial to evaluate the effect of administration time (morning vs evening) on the stability of warfarin's anticoagulant effect. METHODS: A total of 236 primary care physicians serving 54 western Canadian communities mailed letters of invitation to all their warfarin-using patients. Eligible patients were community-dwelling warfarin users (any indication) with at least 3 months of evening warfarin use and no plans for discontinuation. Participants were randomized (by web-based allocation) to morning vs continued evening warfarin ingestion. We used the Rosendaal method to determine the proportion of time within therapeutic range (TTR) of the international normalized ratio (INR) blood test month 2 to 7 postrandomization vs the 6 months prerandomization. The primary outcome was the percent change in proportion of time outside target INR range (with an a priori minimum clinically important difference of ±20%). All analyses were intention to treat. RESULTS: Between March 8, 2015 and September 30, 2016, we randomized 109 participants to morning and 108 to evening warfarin use. TTR rose from 71.8% to 74.7% in the morning group, and from 72.6% to 75.6% in the evening group, for a change in TTR of 2.9% in the former vs 3.0% in the latter (difference, -0.1%; P = .97; 95% CI for the difference, -6.1% to 5.9%). The difference in percent change in proportion of time outside the therapeutic INR range (obtained via Hodges-Lehmann estimation of the difference in medians) was 4.4% (P = .62; 95% CI for the difference, -17.6% to 27.3%). CONCLUSIONS: Administration time has no statistically significant nor clinically important impact on the stability of warfarin's anticoagulant effect. Patients should take warfarin whenever regular compliance would be easiest.

Quality of warfarin management in primary care: Determining the stability of international normalized ratios using a nationally representative prospective cohort.

OBJECTIVE: To determine the stability of warfarin anticoagulation using a nationally representative sample of Canadian primary care patients and providers. DESIGN: Prospective cohort study. SETTING: Primary care practices associated with the Canadian Primary Care Sentinel Surveillance Network. PARTICIPANTS: Adult warfarin users with 7 or more evaluable international normalized ratio (INR) readings. MAIN OUTCOMES MEASURES: International normalized ratio time in therapeutic range (TTR) determined using the Rosendaal method; TTR above 75% was considered good INR control and TTR below 60% was considered poor INR control. The primary outcome was the proportion of all warfarin users (using an INR target range of 2.0 to 3.5) with good INR control during their first year taking warfarin who have poor INR control the following year. Secondary outcomes included the TTR using an INR target of 2.0 to 3.0 when restricted to patients with known atrial fibrillation (AF) or venous thromboembolism (VTE); and the proportion of INR values below the target of 2.0 and above the targets of 3.0 and 3.5 in the year before the availability of other oral anticoagulants. RESULTS: Among 18 303 adult warfarin users (mean age of 71.0 years, 46.6% female), the median TTR (INR target range of 2.0 to 3.5) was 77.4% (interquartile range of 64.6% to 86.4%). The TTR was above 75% in 56.0% of patients and below 60% in 19.3% of patients. Of those exhibiting good INR control in year 1 of anticoagulation therapy, only 10.2% had poor control the following year. When restricted to patients with known AF or VTE (89.7% with AF and 13.5% with VTE), and assuming an INR target range of 2.0 to 3.0, the TTR was 67.8% (interquartile range of 54.8% to 77.9%). Of these patients, 27.9% had INR values below 2.0, and 19.4% and 8.6% had values above 3.0 and 3.5, respectively. CONCLUSION: Primary care warfarin management produces a TTR comparable to that in randomized trials, with out-of-range INR values 3 times more likely to predispose to thrombosis (INR of < 2.0) than to hemorrhage (INR of > 3.5). A history of good INR control does predict future INR stability and meaningfully informs decisions to switch established warfarin users onto newer agents.

Minimally Invasive Unilateral Percutaneous Transfracture Fixation of a Hangman's Fracture Using Neuronavigation and Intraoperative Fluoroscopy.

BACKGROUND: Traumatic spondylolisthesis or hangman's fracture is a common cervical spine fracture. Most cases of traumatic spondylolisthesis are treated nonoperatively with external immobilization. The indications for surgery have generally included fracture instability or failed nonoperative management. Operative stabilization can be performed through either anterior or posterior approaches and has generally required instrumentation using open methods. We propose a technique for surgical repair of hangman's fracture that is minimally invasive and motion preserving using recent advances in 3-dimensional image-guidance technology. We believe this method represents another option in the treatment of hangman's fractures, because it allows for immediate stabilization, prompt recovery, and quick mobilization. CASE DESCRIPTION: We present the case of 2 patients with hangman's fractures who had undergone surgical unilateral transfixation with minimally invasive percutaneous screw placement. In both cases, we used 3-dimensional neuronavigation and bidirectional intraoperative fluoroscopy. The operative time from incision to closure was <30 minutes. Preparation and positioning after intubation varied from 40 to 150 minutes. No intraoperative complications occurred. Both patients were discharged within 48 hours postoperatively. The follow-up examinations at 3 months, 12 months, and 5 years revealed healthy bony fusion on computed tomography imaging and an excellent clinical recovery. CONCLUSION: We have provided 2 examples in which minimally invasive unilateral fixation of hangman's fractures proved to be safe and effective. In both cases, the patients were immediately relieved of their pain, quickly mobilized, and promptly discharged. The achievement of successful fusion confirmed at the follow-up examinations.

End-of-Life Care: Consensus Statement by Indian Academy of Pediatrics.

JUSTIFICATION: The right to life has been accepted as one of the fundamental rights in our constitution. Resuscitation is a procedure performed for all patients suffering from cardiac or respiratory arrest irrespective of the clinical condition. There are no legal guidelines defining process to be adopted in situations where resuscitation is unlikely to be useful. There are no guidelines on withdrawal of care or end of life (EOL) decisions, accepted by the Government, judiciary, professionals, academicians or the community. PROCESS: A National Consultative meet was organized by Indian Medico-Legal and Ethics Association and the Medico-legal group of Indian Academy of Pediatrics (IAP) to formulate the guidelines on 'Do Not Resuscitate' (DNR), and 'End of Life Support'. The meeting was organized on 30th May, 2014 at Ram Manohar Lohia Hospital, New Delhi. The meeting involved professionals from legal and various medical fields as well as administrators, and members from Medical Council of India. OBJECTIVES: To frame the guidelines related to EOL care issues and withdrawal or with-holding treatment in situations where outcome of continued treatment is expected to be poor in terms of ultimate survival or quality of life. RECOMMENDATIONS: (i) DNR or end of life care should not be activated till consensus is achieved between treating team and the next of kin; (ii) Consensus within health care team (including nurses) needs to be achieved before discussion with family members; (iii) Discussion should involve the family members - next of kin and other persons who can influence decisions; (iv) If family members want to include their family physician or a prominent person from the community, it should be encouraged. Similarly if family members want a particular member of treating team, he/she should be included; (v) Treating doctors should have all the facts of the case including investigations available with them before discussion; (vi) Unit in-charge or treating doctor should be responsible for achieving consensus and should initiate the discussion; (vii) After presenting the facts of the cases, family members should be encouraged to ask questions and clear doubts (if any); (viii) At the end of discussion, a summary of the discussion should be prepared and signed by the next of kin and the unit in-charge or treating doctors; (ix) DNR orders should be reviewed in the event of unexpected improvement or on request of next of kin. Same should be documented; (x) DNR orders remain valid during transport.

Blood pressure targets for hypertension in older adults.

BACKGROUND: Eight out of 10 major antihypertensive trials in older adults attempted to achieve a target systolic blood pressure (BP) less than 160 mmHg. Collectively these trials demonstrated benefit for treatment, as compared to no treatment, for an older adult with BP greater than 160 mmHg. However an even lower BP target of less than 140 mmHg is commonly applied to all age groups. At the present time it is not known whether a lower or higher BP target is associated with better cardiovascular outcomes in older adults. OBJECTIVES: To assess the effects of a higher (less than 150 to 160/95 to 105 mmHg) BP target compared to the lower BP target of less than 140/90 mmHg in hypertensive adults 65 years of age or older. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to February 2017: the Cochrane Hypertension Specialised Register, MEDLINE, Embase, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We also contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomised trials, of at least one year's duration, conducted on hypertensive adults aged 65 years or older, which report the effect on mortality and morbidity of a higher systolic or diastolic BP treatment target (whether ambulatory, home, or office measurements) in the range of systolic BP less than 150 to 160 mmHg or diastolic BP less than 95 to 105 mmHg as compared to a lower BP treatment target of less than 140/90 mmHg or lower. DATA COLLECTION AND ANALYSIS: Two authors independently screened and selected trials for inclusion, assessed risk of bias, and extracted data. We combined data for dichotomous outcomes using the risk ratio (RR) with 95% confidence interval (CI) and for continuous outcomes we used mean difference (MD). Primary outcomes were all-cause mortality, stroke, institutionalisation, and cardiovascular serious adverse events. Secondary outcomes included cardiovascular mortality, non-cardiovascular mortality, unplanned hospitalisation, each component of cardiovascular serious adverse events separately (including cerebrovascular disease, cardiac disease, vascular disease, and renal failure), total serious adverse events, total minor adverse events, withdrawals due to adverse effects, systolic BP achieved, and diastolic BP achieved. MAIN RESULTS: We found and included three unblinded randomised trials in 8221 older adults (mean age 74.8 years), in which higher BP targets of less than 150/90 mmHg (two trials) and less than 160/90 mmHg (one trial) were compared to a lower target of less than 140/90 mmHg. Treatment to the two different BP targets over two to four years failed to produce a difference in any of our primary outcomes, including all-cause mortality (RR 1.24 95% CI 0.99 to 1.54), stroke (RR 1.25 95% CI 0.94 to 1.67) and total cardiovascular serious adverse events (RR 1.19 95% CI 0.98 to 1.45). However, the 95% confidence intervals of these outcomes suggest the lower BP target is probably not worse, and might offer a clinically important benefit. We judged all comparisons to be based on low-quality evidence. Data on adverse effects were not available from all trials and not different, including total serious adverse events, total minor adverse events, and withdrawals due to adverse effects. AUTHORS' CONCLUSIONS: At the present time there is insufficient evidence to know whether a higher BP target (less than150 to 160/95 to 105 mmHg) or a lower BP target (less than 140/90 mmHg) is better for older adults with high BP. Additional good-quality trials assessing BP targets in this population are needed.

Intrapancreatic accessory spleen: An eluding diagnosis.

Intrapancreatic accessory spleen (IPAS) is a benign anomaly of splenic embryology and a rare cause of pancreatic pseudotumour. Here, we report a case of a 70-year-old Malay lady whose IPAS was discovered incidentally during her surveillance computed tomography for her underlying left lower lung fibrosis. Radiologically, the lesion mimicked a neuroendocrine pancreatic tumour and was only diagnosed pathologically as IPAS after surgery. In conclusion, recognising IPAS as a differential for enhancing pancreatic mass allows us to exhaust all non-invasive diagnostic means to diagnose this benign lesion. It will allow the patient to avoid unnecessary surgery and its accompanying complications.

Effect of medication timing on anticoagulation stability in users of warfarin (the INRange RCT): study protocol for a randomized controlled trial.

BACKGROUND: Warfarin is an oral anticoagulant medication that disrupts the liver's production of clotting factors. While this medication is highly effective for the prevention of thromboembolic events, it also has a narrow therapeutic range and a vulnerability to interactions with other drugs and vitamin K-containing foods. Warfarin is commonly ingested at dinnertime, the same time of day that dietary vitamin K consumption (found largely in green leafy vegetables) is most variable. While the long half-life of warfarin might make this irrelevant, the ultra short half-life of vitamin K and the possibility of a hepatic first-pass effect for warfarin make it worth evaluating whether morning ingestion of warfarin, when vitamin K levels are consistently low, leads to greater stability of its anticoagulant effect. An examination of the timing of administration on the effectiveness of warfarin has never before been conducted. METHODS/DESIGN: This is a 7-month Prospective Randomized Open Blinded End-point (PROBE) study in which established evening warfarin users (primary care managed Canadian outpatients in the provinces of British Columbia and Alberta) will be randomized to either switch to morning ingestion of warfarin (the intervention) or to continue with evening use (the control). The primary outcome is the percent change in the proportion of time spent outside the therapeutic range of the international normalized ratio (INR) blood test. Secondary outcomes include change in proportion of time spent within the therapeutic INR range (TTR), percentage of patients with TTR >75 %, percentage of patients with TTR <60 %, and major warfarin-related cardiovascular events (including all-cause mortality, hospitalization for stroke, hospitalization for GI bleeding, and deep venous thrombosis/pulmonary embolism). We will also compare whether day-to-day variability in the consumption of high vitamin K-containing foods at baseline affects the baseline TTR in this cohort of evening warfarin users. DISCUSSION: This study addresses whether the timing of warfarin ingestion influences the stability of its anticoagulant effect. Should morning ingestion prove superior, the safety and effectiveness of this medication, and hence the prevention of stroke, pulmonary embolus, and major hemorrhage, could potentially be improved with no added cost or inconvenience to the patient. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02376803 . Registered on 25 February 2015.

Persistent Sexual Dysfunction and Suicidal Ideation in Young Men Treated with Low-Dose Finasteride: A Pharmacovigilance Study.

STUDY OBJECTIVE: Finasteride, a 5α-reductase inhibitor, is marketed in a low dose (1 mg) as a popular therapy for androgenic alopecia in young men. As case reports and small surveys have suggested a link between persistent sexual dysfunction (SD) and suicidal ideation (SI) with low-dose finasteride, the aim of this study was to detect signals of SD and SI secondary to low-dose finasteride use in young men. DESIGN: Retrospective pharmacovigilance disproportionality analysis. DATA SOURCE: United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. MEASUREMENTS AND MAIN RESULTS: Low-dose finasteride-related adverse event reports for men aged 18-45 years that were submitted to the FAERS between 1998 and 2013 were retrieved. Multi-item Gamma Poisson Shrinker disproportionality analysis was applied to calculate the empirical Bayes geometric mean (EBGM) and corresponding 95% confidence interval (CI) as an association metric between low-dose finasteride and the events of interest. Signals were defined as associations with thresholds of a CI lower limit of 2.0 or greater. Medical Dictionary for Regulatory Activities Preferred Terms denoting to SD and SI were identified to reflect the outcome of interest. In total, of 4910 reports, 577 persistent SD and 39 SI adverse event reports (11.8% and 7.9%, respectively) were identified for young men using low-dose finasteride; 34 (87.2%) of the 39 men with SI also experienced SD. The majority of these events were serious (e.g., contributed to the patient's death, hospitalization, or disability). Low-dose finasteride was associated with more than expected reporting of SD in young men compared with reporting of these events with all other drugs within the database (EBGM 28.0, 95% CI 26.1-30.0). Disproportional reporting in SI events was noted, although it did not reach signal threshold (EBGM 1.72; 95% CI 1.31-2.23). Among serious SD events, 43% led to disability; 28% required medical intervention, including hospitalization; and 5% were life-threatening. Six fatal SD reports were identified. CONCLUSION: Persistent SD might be a potential risk of low-dose finasteride for androgenic alopecia therapy in young men, and this risk might contribute to SI. Our findings provide a strong hypothesis for pharmacoepidemiologic studies to further examine this association.

Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are widely prescribed for primary hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg). However, while ACE inhibitors have been shown to reduce mortality and morbidity in placebo-controlled trials, ARBs have not. Therefore, a comparison of the efficacies of these two drug classes in primary hypertension for preventing total mortality and cardiovascular events is important. OBJECTIVES: To compare the effects of ACE inhibitors and ARBs on total mortality and cardiovascular events, and their rates of withdrawals due to adverse effects (WDAEs), in people with primary hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization (WHO) International Clinical Trials Registry Platform, and the ISI Web of Science up to July 2014. We contacted study authors for missing and unpublished information, and also searched the reference lists of relevant reviews for eligible studies. SELECTION CRITERIA: We included randomized controlled trials enrolling people with uncontrolled or controlled primary hypertension with or without other risk factors. Included trials must have compared an ACE inhibitor and an ARB in a head-to-head manner, and lasted for a duration of at least one year. If background blood pressure lowering agents were continued or added during the study, the protocol to do so must have been the same in both study arms. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Nine studies with 11,007 participants were included. Of the included studies, five reported data on total mortality, three reported data on total cardiovascular events, and four reported data on cardiovascular mortality. No study separately reported cardiovascular morbidity. In contrast, eight studies contributed data on WDAE. Included studies were of good to moderate quality. There was no evidence of a difference between ACE inhibitors and ARBs for total mortality (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.88 to 1.10), total cardiovascular events (RR 1.07; 95% CI 0.96 to 1.19), or cardiovascular mortality (RR 0.98; 95% CI 0.85 to 1.13). Conversely, a high level of evidence indicated a slightly lower incidence of WDAE for ARBs as compared with ACE inhibitors (RR 0.83; 95% CI 0.74 to 0.93; absolute risk reduction (ARR) 1.8%, number needed to treat for an additional beneficial outcome (NNTB) 55 over 4.1 years), mainly attributable to a higher incidence of dry cough with ACE inhibitors. The quality of the evidence for mortality and cardiovascular outcomes was limited by possible publication bias, in that several studies were initially eligible for inclusion in this review, but had no extractable data available for the hypertension subgroup. To this end, the evidence for total mortality was judged to be moderate, while the evidence for total cardiovascular events was judged to be low by the GRADE approach. AUTHORS' CONCLUSIONS: Our analyses found no evidence of a difference in total mortality or cardiovascular outcomes for ARBs as compared with ACE inhibitors, while ARBs caused slightly fewer WDAEs than ACE inhibitors. Although ACE inhibitors have shown efficacy in these outcomes over placebo, our results cannot be used to extrapolate the same conclusion for ARBs directly, which have not been studied in placebo-controlled trials for hypertension. Thus, the substitution of an ARB for an ACE inhibitor, while supported by evidence on grounds of tolerability, must be made in consideration of the weaker evidence for the efficacy of ARBs regarding mortality and morbidity outcomes compared with ACE inhibitors. Additionally, our data mostly derives from participants with existing clinical sequelae of hypertension, and it would be useful to have data from asymptomatic people to increase the generalizability of this review. Unpublished subgroup data of hypertensive participants in existing trials comparing ACE inhibitors and ARBs needs to be made available for this purpose.

Blood pressure lowering efficacy of potassium-sparing diuretics (that block the epithelial sodium channel) for primary hypertension.

BACKGROUND: Potassium-sparing diuretics, which block the epithelial sodium channel (ENaC), are widely prescribed for hypertension as a second-line drug in patients taking other diuretics (e.g. thiazide diuretics) and much less commonly prescribed as monotherapy. Therefore, it is essential to determine the effects of ENaC blockers on blood pressure (BP), heart rate and withdrawals due to adverse effects (WDAEs) when given as a first-line or second-line therapy. OBJECTIVES: To quantify the dose-related reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of ENaC blocker therapy as a first-line or second-line drug in patients with primary hypertension. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2012), MEDLINE (1950 to August 2012), EMBASE (1980 to August 2012) and reference lists of articles. SELECTION CRITERIA: Double-blind, randomized, controlled trials in patients with primary hypertension that evaluate, for a duration of 3 to 12 weeks, the BP lowering efficacy of: 1) fixed-dose monotherapy with an ENaC blocker compared with placebo; or 2) an ENaC blocker in combination with another class of anti-hypertensive drugs compared with the respective monotherapy (without an ENaC blocker). DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Study authors were contacted for additional information. WDAE information was also collected from the trials. MAIN RESULTS: No trials evaluating the BP lowering efficacy of ENaC blockers as monotherapy in patients with primary hypertension were identified. Only 6 trials evaluated the BP lowering efficacy of low doses of amiloride and triamterene as a second drug in 496 participants with a baseline BP of 151/102 mm Hg. The additional BP reduction caused by the ENaC blocker as a second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. The addition of low doses of amiloride and triamterene in these trials did not reduce BP. An estimate of the dose-related BP lowering efficacy for ENaC blockers was not possible because of a lack of trial data at higher doses. AUTHORS' CONCLUSIONS: ENaC blockers do not have a statistically or clinically significant BP lowering effect at low doses but trials at higher doses are not available. The review did not provide a good estimate of the incidence of harms associated with ENaC blockers.