Vibegron: a ß3-adrenergic agonist for the treatment of overactive bladder.

Overactive bladder (OAB) is an extremely common condition in adults of both sexes. It is characterized by an urgent need to micturate often accompanied by incontinence. The condition may also increase the number of micturitions in a 24-hour period as well as nocturia. The syndrome is not due to a urinary infection or other obvious pathology. In terms of drug treatment of OAB, there are two main approaches. One is the use of anticholinergic drugs that reduce the effect of the parasympathetic nervous system on the bladder. The other involves the use of drugs that are agonists at ß3-adrenergic receptors in the bladder. These drugs increase the capacity of the bladder and cause reductions in the number of daily micturitions and nocturia and also importantly reduce the frequency of urinary urgency and urinary urgency incontinence. Vibegron is the second ß3-adrenergic agonist to be approved for the treatment of OAB.

Selection and use of reference panels: a case study highlighting current gaps in the materials available for foot and mouth disease.

The World Organisation for Animal Health (OIE) Manual of Diagnostic Tests and Vaccines for Terrestrial Animals describes a diverse array of assays that can be used to detect, characterise and monitor the presence of infectious agents of farmed livestock. These methods have been developed in different laboratories, at different times, and often include tests or kits provided by the commercial sector. Reference panels are essential tools that can be used during assay development and in validation exercises to compare the performance of these varied (and sometimes competing) diagnostic technologies. World Organisation for Animal Health Reference Laboratories already provide approved international standard reagents to help calibrate diagnostic tests for a range of diseases, but there remain important gaps in their availability for comparative purposes and the calibration of test results across different laboratories. Using foot and mouth disease (FMD) as an example, this review highlights four specific areas where new reference reagents are required. These are to: reduce bias in estimates of the diagnostic sensitivity and inter-serotypic specificity of tests used to detect diverse strains of FMD virus (FMDV), provide bio-safe positive controls for new point-of-care test formats that can be deployed outside high containment, harmonise FMDV antigens for post-vaccination serology, and address inter-laboratory differences in serological assays used to measure virus-specific FMD antibody responses. Since there are often limited resources to prepare and distribute these materials, sustainable progress in this arena will only be achievable if there is consensus and coordination of these activities among OIE Reference Laboratories.

Le Manuel des tests de diagnostic et des vaccins pour les animaux terrestres de l'Organisation mondiale de la santé animale (OIE) décrit une vaste panoplie d'essais utilisables pour la détection, la caractérisation et la surveillance des agents pathogènes affectant les animaux d'élevage. Ces méthodes ont été mises au point par des laboratoires différents à diverses périodes et intègrent souvent des tests ou des kits fournis par le secteur privé. Les panels de référence sont des outils essentiels aussi bien lors de la conception d'un essai que lors d'exercices de validation, leur but étant alors de comparer les performances de technologies diagnostiques variées (et parfois concurrentes). Les Laboratoires de référence de l'OIE fournissent des réactifs de référence internationaux validés afin d'aider à calibrer les tests de diagnostic pour un certain nombre de maladies animales ; toutefois, on constate que nombre de ces réactifs ne sont pas disponibles pour la comparaison et le calibrage interlaboratoires des résultats de tests. À partir de l'exemple de la fièvre aphteuse, les auteurs soulignent quatre domaines spécifiques pour lesquels il conviendrait de disposer de nouveaux réactifs de référence. Il s'agit des réactifs nécessaires pour : (1) réduire les biais dans l'estimation de la sensibilité diagnostique et de la spécificité pour différents sérotypes des tests utilisés pour détecter diverses souches du virus de la fièvre aphteuse ; (2) fournir des contrôles positifs sûrs au plan biologique pour les nouveaux formats de tests utilisables sur le lieu d'intervention et non plus dans des laboratoires de confinement à haute sécurité ; (3) harmoniser les antigènes du virus de la fièvre aphteuse pour la sérologie post-vaccinale ; (4) résoudre le problème des différences obtenues entre laboratoires lors d'essais sérologiques visant à mesurer la réponse en anticorps spécifiques du virus de la fièvre aphteuse. Compte tenu des ressources souvent limitées consacrées à la préparation et à la distribution de ces réactifs, des progrès durables ne seront obtenus que s'il existe un consensus en la matière et une coordination de ces activités parmi les Laboratoires de référence de l'OIE.

En el Manual de pruebas de diagnóstico y vacunas para los animales terrestres de la Organización Mundial de Sanidad Animal (OIE) se describe todo un conjunto de ensayos que se pueden emplear para detectar y caracterizar agentes infecciosos del ganado doméstico y hacer así controles sistemáticos de su eventual presencia. Estos métodos, concebidos en distintos laboratorios en distintos momentos, suelen acompañarse de pruebas o estuches analíticos que proporcionan empresas privadas. Los paneles de referencia son una herramienta esencial, que se puede emplear durante la concepción de ensayos y en los procesos de validación para comparar el funcionamiento de estas diferentes técnicas de diagnóstico, que a veces compiten unas con otras. Los laboratorios de referencia de la OIE ya facilitan reactivos de referencia internacional aprobados que ayudan a calibrar las pruebas de diagnóstico de una serie de enfermedades, pero todavía hay importantes carencias por lo que respecta a la posibilidad de procurárselos con fines de comparación y a la calibración de los resultados que obtienen diferentes laboratorios. Sirviéndose del ejemplo de la fiebre aftosa, los autores destacan cuatro aspectos específicos para los que hacen falta nuevos reactivos de referencia. Se trata de los siguientes: reducir el sesgo a la hora de calcular la sensibilidad de diagnóstico y la especificidad interserotípica de las pruebas empleadas para detectar diversas cepas del virus de la fiebre aftosa; proporcionar controles positivos que ofrezcan seguridad biológica para nuevos modalidades de ensayo utilizables en el lugar de consulta, esto es, en condiciones que no sean de alta contención; armonizar los antígenos víricos para la práctica de análisis serológicos tras la vacunación; y solventar las diferencias entre laboratorios por lo que respecta a los ensayos serológicos empleados para medir la respuesta de anticuerpos específicos contra el virus de la fiebre aftosa. Dado que suele haber escasos recursos para preparar y distribuir este tipo de material, solo será posible avanzar duraderamente en la materia si los laboratorios de referencia de la OIE consensúan y coordinan estas actividades.

The Cheshire & Merseyside Collaborative trainee-led on-call service: a review of safety and efficiency.

AIM: To assess safety and efficiency of the Cheshire & Merseyside Collaborative, the largest trainee led on-call service in the UK, based on discrepancy rates and time taken to issue reports. MATERIALS & METHODS: All studies reported by the collaborative in a 4-week period were evaluated for discrepancy and the time taken to issue a report. These figures were compared against the Royal College of Radiologists (RCR) guidelines and a recent national audit of discrepancy rates. The time taken to report was measured against the National Institute of Health and Clinical Excellence (NICE) and Trauma Audit Research Network (TARN) guidelines. RESULTS: The overall discrepancy rates for the collaborative were 2.5% for minor discrepancies and 2% for major discrepancies, which is within the RCR standard. The median time taken to issue a report was 30 min, which is within the NICE and TARN 1-h targets. CONCLUSIONS: The Cheshire & Merseyside Collaborative can be deemed a safe and efficient way of delivering an out-of-hours radiology service.

Remimazolam: a short-acting benzodiazepine for procedural sedation.

The ultra-short-acting opioid analgesic remifentanil provided the approach that was used in the synthesis of remimazolam. A carboxylic ester was incorporated into the benzodiazepine structure providing a resultant compound that is rapidly broken down in the body into a breakdown product that is inactive, thus ensuring a very short-acting benzodiazepine. Remimazolam is highly selective in its action, only having activity at the GABAA receptor. It has been shown to be highly effective in providing sedation for bronchoscopy and colonoscopy without having a prolonged duration of action, therefore having a short effect until patients are fully awake and ready for discharge.

Physiological, biochemical, and anatomical responses of Araucaria araucana seedlings to controlled water restriction.

Water stress triggers acclimation responses and can damage plants, which varies by species and stress levels. Ongoing climate change is projected to result in longer and more intense water stress conditions leading to an alarming increase in drought-induced forest decline. The aim of this study was to evaluate the physiological responses of leaves and stem wood anatomy from Araucaria araucana pot-grown three-year old seedlings, a conifer tree from northwestern Patagonia. Plants were subjected to moderate and severe water restriction regimes and compared to well-watered controls. Severe water stress reduced relative leaf water content and triggered an accumulation of free proline in leaves, regardless of age. Epicuticular wax extrusions increased in apical leaf stomata while photosynthetic pigments decreased, resulting in differential oxidative damage. The concentration of phenolic compounds was not affected by water restrictions. Plants exposed to restricted water regimes showed diminished middle leaf biomass and expansion (~60% of total leaves), increased stem wood density, and experienced 7% and 30% mortality rates under moderate and severe water stress, respectively. Our findings suggest that under moderate water stress, analogous to short-term droughts, A. araucana seedlings activate physiological mechanisms that allow them to withstand short periods of drought, while more severe water stress and longer droughts can be severely harmful.

Satralizumab: an interleukin-6 (IL-6) receptor antagonist for the treatment of neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) consist of a rare autoimmune disorder in which patients suffer from relapses that affect the optic nerve, spinal cord or brainstem. Few have a full recovery. NMOSD is more common in women, the age of onset being around 30-40 years of age depending on race. The prevalence of the condition varies from 0.5-4.4 per 100,000 population. About 80% of patients have antibodies directed against the aquaporin-4 (AQP4) protein that form membrane-bound water transporters in the central nervous system (CNS). This protein is highly expressed in those areas of the CNS often targeted in NMOSD relapses. Satralizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) receptor and thus inhibits IL-6 signaling. Two recent phase III studies have demonstrated that satralizumab significantly reduced the relapse rate in NMOSD by 76-79%. This beneficial effect was apparently confined to patients who have anti-AQP4 antibodies and satralizumab did not reduce the rate of pain or fatigue in NMOSD patients.

Apomorphine hydrochloride: a sublingual tablet for the OFF episodes in Parkinson's disease.

Parkinson's disease is one of the commonest neurodegenerative disorders, particularly in those over 60 years of age. Although the introduction of levodopa was a tremendous advance in its treatment, the condition is a progressive one. It has been found that the longer patients have the condition and are treated with levodopa, the more likely they are to develop OFF episodes in which their ability to do things becomes increasingly limited. The development of a sublingual apomorphine hydrochloride film (APL-130277, Kynmobi) was designed to alleviate this OFF condition by allowing the patients to experience rapid relief of their OFF episodes up to 5 times a day.

Osilodrostat: 11ß-hydroxylase inhibitor for treatment of Cushing's disease.

Osilodrostat was synthesized in a search for a drug that would inhibit the synthesis of aldosterone, with the aim to discover a new approach for treating hypertension. However, early clinical trials revealed that the doses that could be used for this purpose were limited because osilodrostat was also inhibiting the synthesis of cortisol. Osilodrostat is in fact an inhibitor of both the cytochrome P450 (CYP) enzymes 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) and thus inhibits the synthesis of both cortisol and aldosterone. Subsequent clinical trials have established that it can be used very effectively in Cushing's disease caused by a functioning tumor of the pituitary gland in patients whose condition has not been adequately treated by surgery or who are not candidates for such surgery.

Bempedoic acid: effect of ATP-citrate lyase inhibition on low-density lipoprotein cholesterol and other lipids.

Bempedoic acid is a new, first-in-class oral ATP-citrate lyase (ACLY) inhibitor that has to be converted to its CoA thioester before it inhibits ACLY. This conversion only occurs in the liver and not in skeletal muscle. This may explain why, unlike the statins, bempedoic acid does not cause myalgia. Bempedoic acid given at a dosage of 180 mg orally once daily produces a highly significant reduction in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and importantly also in high-sensitivity C-reactive protein. It has recently been approved by both the Food and Drug Administration (FDA) and the European Commission for use in adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional lowering of LDL-C, and for the treatment of adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia, respectively.

Nurses working in healthcare facilities during natural disasters: a qualitative enquiry.

AIM: To explore the ability of nurses to be adequately ready for and to respond to a disaster caused by a natural hazard. BACKGROUND: During a disaster involving a healthcare facility, nurses are commonly the largest group of healthcare workers impacted. The range of problems facing nurses working in healthcare facilities in Australia and New Zealand at the time of disasters triggered by earthquakes and bushfires have been underexamined. METHODS: A qualitative enquiry was used to explore matters facing nurses working in residential healthcare facilities during a natural disaster. Inductive thematic analysis was used to identify the key themes from fifteen in-depth interviews with nurses. FINDINGS: Participants preserved a robust sense of professional duty, personal obligation and responsibility to their family, patients and the facility, demonstrating the ability to adapt, cope and respond despite experiencing diverse personal, structural and organizational barriers. DISCUSSION: Support was provided for using interactive systems and socio-ecological frameworks to better understand the contributions that individuals, teams and organizations make to facilitate the development and maintenance of adaptive capacity and resilience in a nursing workforce. An ecological model of adaptive capacity can be operationalized to guide education, training for nurses and the development of organizational systems and strategies. CONCLUSION: This study identified factors that help and hinder a nursing workforce's ability to prepared for, adapt to and learn from natural hazard disasters. IMPLICATIONS FOR NURSING POLICY: This understanding of disaster preparedness and how this may be applied to enable the growth of adaptive nurses provides an insight for a global audience which also adds to nurse education, service delivery, organizational and policy development.

Drospirenone: a novel progestogen used as an oral contraceptive without an estrogen component.

Drospirenone (DRSP) was synthesized as an analogue of spironolactone with the aim of producing a fourth-generation progestogen that differed from earlier progestogens in that it had antiandrogenic and little or no androgenic activity and lacked estrogenic effects while retaining some antimineralocorticoid activity. Since then, DRSP has been included in several oral contraceptive preparations together with an estrogen. However, increasing evidence has demonstrated that DRSP 4 mg on its own inhibits ovulation. It was thus a logical development to determine the efficacy of a tablet that only included DRSP 4 mg as an oral contraceptive. This proved successful and this product has now been approved by the Food and Drug Administration (FDA).

Istradefylline: adenosine A2A receptor antagonist to reduce "OFF" time in Parkinson's disease.

Parkinson's disease (PD) is an extremely common degenerative disease with a progressive course. Unfortunately, the longer patients are treated with levodopa, the more likely they are to suffer from increasingly long periods of immobility or "OFF" time. For over 30 years Kyowa Kirin Co., Ltd. (formerly Kyowa Hakko Kirin Co., Ltd.) has been researching the possibility of finding drugs that affect adenosine receptors and that can be used successfully as additional drugs in the treatment of PD. Istradefylline is an adenosine A2A receptor antagonist that significantly reduces the "OFF" time and improves the motor function of patients with PD, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) Part III, while increasing the time without troublesome dyskinesia. It was approved for use in PD in Japan in 2013 and in the United States in 2019.

Risankizumab.rzaa: an interleukin monoclonal antibody antagonist binding to the p19 subunit of human IL-23 cytokine.

Plaque psoriasis is the commonest form of psoriasis affecting about 85% of those patients with the condition. Risankizumab was developed as a high-affinity humanized monoclonal antibody specific for the p19 subunit of interleukin-23 (IL-23p19). Clinical trials demonstrated that risankizumab was very effective in patients with moderate to severe plaque psoriasis causing total clearing of the condition as evidenced by Psoriasis Scalp Severity Index (PSSI100) and static Physician's Global Assessment (sPGA) of 0 in more than 50% of patients after 52 weeks of treatment. Risankizumab has been approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy as a dose of 150 mg administered by subcutaneous injection at week 0, week 4 and every 12 weeks thereafter.

Estimating the protection afforded by foot-and-mouth disease vaccines in the laboratory.

Foot-and-mouth disease (FMD) vaccines must be carefully selected and their application closely monitored to optimise their effectiveness. This review covers serological techniques for FMD vaccine quality control, including potency testing, vaccine matching and post-vaccination monitoring. It also discusses alternative laboratory procedures, such as antigen quantification and nucleotide sequencing, and briefly compares the approaches for FMD with those for measuring protection against influenza virus, where humoral immunity is also important. Serology is widely used to predict the protection afforded by vaccines and has great practical utility but also limitations. Animals differ in their responses to vaccines and in the protective mechanisms that they develop. Antibodies have a variety of properties and tests differ in what they measure. Antibody-virus interactions may vary between virus serotypes and strains and protection may be affected by the vaccination regime and the nature and timing of field virus challenge. Finally, tests employing biological reagents are difficult to standardise, whilst cross-protection data needed for test calibration and validation are scarce. All of this is difficult to reconcile with the desire for simple and universal criteria and thresholds for evaluating vaccines and vaccination responses and means that oversimplification of test procedures and their interpretation can lead to poor predictions. A holistic approach is therefore recommended, considering multiple sources of field, experimental and laboratory data. New antibody avidity and isotype tests seem promising alternatives to evaluate cross-protective, post-vaccination serological responses, taking account of vaccine potency as well as match. After choosing appropriate serological tests or test combinations and cut-offs, results should be interpreted cautiously and in context. Since opportunities for experimental challenge studies of cross-protection are limited and the approaches incompletely reflect real life, more field studies are needed to quantify cross-protection and its correlation to in vitro measurements.

Contraceptive vaginal ring containing segesterone acetate and ethinyl estradiol: long-acting, patient-controlled, procedure-free, reversible prescription birth control.

The Food and Drug Administration (FDA) approved on August 10, 2018, a soft, reusable, flexible silicone ring (56 mm diameter) containing segesterone acetate and ethinyl estradiol as the first contraceptive vaginal ring (CVR) that can be used for a year and that is totally under the control of the woman using it. The vaginal ring releases segesterone and ethinyl estradiol at estimated rates of 150 mcg/day and 13 mcg/day, respectively. The CVR is inserted into the upper two-thirds of the vagina and left in place for 21 days, then removed for 7 days. The same ring can be used for 13 cycles for a total of a year's contraception. The CVR was found to be 97.5% effective in preventing pregnancy with a Pearl Index of 2.98. The adverse effects in women using the ring were similar in nature and frequency to those reported during the use of other hormonal contraceptives. The one exception was the occurrence of venous thromboembolism, which was reported more often than expected. Because of this, the FDA has required a postmarketing study to determine the true incidence of this adverse effect. The CVR was developed by the Population Council, is known as Annovera, and will be marketed by TherapeuticsMD in the U.S.

Current imaging practice for suspected scaphoid fracture in patients with normal initial radiographs: UK-wide national audit.

AIM: To assess the current practice of scaphoid fracture imaging (where initial scaphoid radiographs are normal) in the UK. MATERIALS AND METHODS: A survey monkey questionnaire was sent to 140 eligible NHS trusts derived from the NHS England database following exclusion of all non-acute and specialist centres. Four questions were asked regarding the provision of magnetic resonance imaging (MRI) for radiographically occult scaphoid fractures, time to MRI, number of departmental MRI scanners, and alternative imaging offered. RESULTS: Responses were received from 74 trusts (53%). Thirty-eight offered MRI as a first-line test in plain-film occult scaphoid injury, 25 preferred computed tomography (CT), and 11 opted for repeat plain radiographs. Of the 38 trusts who offered MRI, 26 provided this within 1 week; the rest within 2 weeks. No trends were identified based on the size of the hospital or its geographical location. Statistical analysis of the data revealed no significant relationship between the number of MRI scanners and the provision of MRI, nor between the numbers of MRI scanners and the time to MRI. CONCLUSIONS: MRI has been recognised in the literature as a highly specific, highly sensitive, and cost-effective tool, yet only 51% of trusts provide this service in the UK. For those who cannot offer MRI first-line, CT remains a very accurate and reliable alternative.

Tafamidis: a selective transthyretin stabilizer to treat wild-type ATTR amyloidosis and hereditary ATTR amyloidosis with cardiomyopathy.

Plasma protein transthyretin (TTR) can undergo conformational change resulting in the formation of amyloid fibrils that can then cause amyloidosis. This can occur spontaneously in individuals over the age of 70-80 resulting in wild-type transthyretin amyloidosis (ATTR) (with cardiomyopathy). This then progresses to fatal cardiac failure. TTR can also undergo conformational change in individuals who have a genetic abnormality in the structure of TTR resulting in hereditary ATTR amyloidosis. This is usually first manifested as polyneuropathy but can progress to cardiomyopathy with time. Until recently, there has been no specific treatment for these conditions. However, a detailed search for compounds that stabilize TTR resulted in the discovery of tafamidis. This compound stabilizes TTR and has been found to significantly reduce the progression of both wild-type ATTR amyloidosis and hereditary ATTR amyloidosis.

Estradiol vaginal inserts (Imvexxy): effective in genitourinary syndrome of menopause without increasing systemic estrogen levels.

Many women suffer from the genitourinary syndrome of the menopause (GSM), in particular pathological changes that occur in the vagina due to the reduction in their production of estrogens. TherapeuticsMD has developed Imvexxy, small softgel capsules that contain solubilized estradiol and that are inserted vaginally by women twice a week, every 3 to 4 days. These vaginal inserts have been found to readily supply estradiol to the vagina and to result in significant improvement in the GSM signs and symptoms these women had been experiencing. At the same time, pharmacokinetic studies have demonstrated that the small doses of estradiol used do not increase systemic blood levels of estrogens above baseline values, thus greatly reducing the likelihood of unwanted systemic effects of estradiol. The placebo used in clinical trials, which only contained the 'inactive' ingredients in Imvexxy, had partial efficacy, the result either of a placebo effect or of the use of MIGLYOL 812 N to keep the estradiol in solution.

Humpback whale migrations to Antarctic summer foraging grounds through the southwest Pacific Ocean.

Humpback whale (Megaptera novaeangliae) populations typically undertake seasonal migrations, spending winters in low latitude breeding grounds and summers foraging in high latitude feeding grounds. Until recently, a broad scale understanding of whale movement has been derived from whaling records, Discovery marks, photo identification and genetic analyses. However, with advances in satellite tagging technology and concurrent development of analytical methodologies we can now detail finer scale humpback whale movement, infer behavioural context and examine how these animals interact with their physical environment. Here we describe the temporal and spatial characteristics of migration along the east Australian seaboard and into the Southern Ocean by 30 humpback whales satellite tagged over three consecutive austral summers. We characterise the putative Antarctic feeding grounds and identify supplemental foraging within temperate, migratory corridors. We demonstrate that Antarctic foraging habitat is associated with the marginal ice zone, with key predictors of inferred foraging behaviour including distance from the ice edge, ice melt rate and variability in ice concentration two months prior to arrival. We discuss the highly variable ice season within the putative foraging habitat and the implications that this and other environmental factors may have on the continued strong recovery of this humpback whale population.