FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Hepatobiliary Disposition of Atovaquone: A Case of Mechanistically Unusual Biliary Clearance.

Atovaquone, an antiprotozoal and antipneumocystic agent, is predominantly cleared by biliary excretion of unchanged parent drug. Atovaquone is ≥10,000-fold concentrated in human bile relative to unbound plasma. Even after correcting for apparent nonspecific binding and incomplete solubility in bile, atovaquone is still concentrated ≥100-fold in bile, consistent with active biliary excretion. Mechanisms of atovaquone hepatobiliary disposition were studied using a multiexperimental in vitro and in vivo approach. Atovaquone uptake was not elevated in HEK293 cells singly overexpressing OATP1B1, OATP1B3, OATP2B1, OCT1, NTCP, or OAT2. Hepatocyte uptake of atovaquone was not impaired by OATP and OCT inhibitor cocktail (rifamycin and imipramine). Atovaquone liver-to-blood ratio at distributional equilibrium was not reduced in Oatp1a/1b and Oct1/2 knockout mice. Atovaquone exhibited efflux ratios of approximately unity in P-gp and BCRP overexpressing MDCK cell monolayers and did not display enhanced uptake in MRP2 vesicles. Biliary and canalicular clearance were not decreased in P-gp, Bcrp, Mrp2, and Bsep knockout rats. In the present study, we rule out the involvement of major known basolateral uptake and bile canalicular efflux transporters in the hepatic uptake and biliary excretion of atovaquone. This is the first known example of a drug cleared by biliary excretion in humans, with extensive biliary concentration, which is not transported by the mechanisms investigated herein.

Enhanced Accuracy of CMOS Smart Temperature Sensors by Nonlinear Curvature Correction.

In this paper, we demonstrate an improvement in the accuracy of a low-cost smart temperature sensor, by measurement of the nonlinear curvature correction at multiple temperature references. The sensors were positioned inside a climate chamber and connected outside to a micro-controller via a network cable. The chamber temperature was increased systematically over a wide range from -20 °C to 55 °C. A set of calibration curves was produced from the best fitting second-order polynomial curves for the offset in temperature between the sensor and reference. An improvement in accuracy of ±0.15 °C is with respect to the mentioned temperature range, compared to the significantly higher value reported of ±0.5 °C by the manufacturer for similar conditions. In summary, we demonstrate a significant improvement in the calibration of a low-cost, smart sensor frequently used in research and academic projects over a useful range of temperatures.

Advanced multivariate data analysis to determine the root cause of trisulfide bond formation in a novel antibody-peptide fusion.

Product quality heterogeneities, such as a trisulfide bond (TSB) formation, can be influenced by multiple interacting process parameters. Identifying their root cause is a major challenge in biopharmaceutical production. To address this issue, this paper describes the novel application of advanced multivariate data analysis (MVDA) techniques to identify the process parameters influencing TSB formation in a novel recombinant antibody-peptide fusion expressed in mammalian cell culture. The screening dataset was generated with a high-throughput (HT) micro-bioreactor system (AmbrTM 15) using a design of experiments (DoE) approach. The complex dataset was firstly analyzed through the development of a multiple linear regression model focusing solely on the DoE inputs and identified the temperature, pH and initial nutrient feed day as important process parameters influencing this quality attribute. To further scrutinize the dataset, a partial least squares model was subsequently built incorporating both on-line and off-line process parameters and enabled accurate predictions of the TSB concentration at harvest. Process parameters identified by the models to promote and suppress TSB formation were implemented on five 7 L bioreactors and the resultant TSB concentrations were comparable to the model predictions. This study demonstrates the ability of MVDA to enable predictions of the key performance drivers influencing TSB formation that are valid also upon scale-up. Biotechnol. Bioeng. 2017;114: 2222-2234. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

Female perineal injuries in children and adolescents presenting to a paediatric emergency department.

This retrospective case series determined documentation quality and likelihood of safeguarding issues in girls  aged 0-15 years with perineal and genital injuries presenting to a paediatric emergency department (ED). During the period between 2002 and 2010, cases were identified and clinical information was recorded. Cases were cross-referenced against the hospital's safeguarding unit's records up to 2011. In total, 181 case notes were available for review with 76.2% of patients discharged home from the ED. Fewer than 50% of case notes contained clear anatomical description of the injuries. In 51 (28.2%) cases, child safeguarding issues were considered, with specific referrals made to safeguarding services in 20 of these (11.0%). Only one case involved subsequent child safeguarding proceedings. Clear documentation of injury patterns by medical staff was poor, but medical and nursing staff should not be anxious about dealing with this cohort of patients as they are no different from other incidental injuries needing diligent levels of child safeguarding awareness.

Timely diagnosis and treatment essential in glomerulonephritis.

Glomerulonephritis is an important cause of kidney disease and, in the UK, the most common diagnosis in patients receiving chronic dialysis or waiting for kidney transplantation. A key feature is the presence of urinary abnormalities (proteinuria ± haematuria). Patients with nephrotic syndrome typically present with peripheral oedema, massive urinary protein loss and associated low serum albumin levels. Blood pressure and renal function, as measured by eGFR, are usually normal initially. Patients presenting with nephritic syndrome tend to be hypertensive with dipstick-positive or visible haematuria. There may be rapidly progressive renal dysfunction and fall in eGFR. Many patients will have a background genetic susceptibility to glomerulonephritis which may be triggered by environmental, infective or autoimmune factors. Autoimmunity, in combination with genetic factors, is responsible for a significant proportion of cases of glomerulonephritis. Infective agents such as viruses can precipitate minimal change disease. NSAIDs, lithium, penicillamine and heroin can cause nephrotic syndrome. Timely diagnosis and treatment of glomerulonephritis can help to minimise both the occurrence and severity of complications. All patients with glomerulonephritis should be managed according to CKD guidelines with CKD stage-appropriate measurement of renal function, blood pressure, and proteinuria.

Risk factor control is key in diabetic nephropathy.

Prolonged duration of diabetes, poor glycaemic control and hypertension are major risk factors for both diabetic nephropathy and cardiovascular disease. Optimising blood sugar control together with excellent control of blood pressure can reduce the risk of developing diabetic nephropathy. Diabetic nephropathy should be considered in any patient with diabetes when persistent albuminuria develops. Microalbuminuria is the earliest clinically detectable indicator of diabetic nephropathy risk. The majority of patients with diabetic nephropathy are appropriately diagnosed based on elevated urinary albumin excretion and/or reduced 0032-6518 renal function. Patients with type 2 diabetes should have annual urinary ACR measurements from the time of diabetes diagnosis while those with type 1 diabetes should commence five years after diagnosis. Blood pressure lowering to 130/80mmHg and reduction of proteinuria to <1 g/day retards progression of diabetic nephropathy and reduces the number of cardiovascular events. Drugs that block the renin-angiotensin-aldosterone system (RAAS) are effective in reducing proteinuria, managing hypertension and reducing cardiovascular risk. Unless there are clear contraindications or intolerance all patients with diabetic nephropathy should be prescribed an ACEI or ARB. Stopping an ACEI or ARB during intercurrent illness or times of volume depletion is critically important. Patients with diabetic nephropathy should have at least yearly measurements of blood pressure, renal function and urinary ACR.

Two different presentations, one diagnosis.

Acute confusion and hyponatraemia are common presentations in acute medicine. We report two cases of anti-voltage gated potassium channel (VGKC) antibody-related limbic encephalitis highlighting the variable presentation of this condition. Both patients were thoroughly investigated with MRI scan of brain, lumbar puncture, EEG as well as infective and autoimmune screens for encephalitis. Anti-VGKC antibodies were positive for both patients and prompt treatment with immunotherapy yielded good recovery. Patients presenting with confusion and seizures who have no demonstrable infectious or metabolic cause should have investigation for an autoimmune cause expedited. In addition, psychiatric presentations with atypical features such as drowsiness should prompt similar investigations. The outcome of anti-VGKCrelated limbic encephalitis is improved with early treatment employing steroids or immunotherapy.

Physiologically-based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug-drug interactions.

Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin-only pill. Acceptance of COC drug-drug interaction (DDI) assessment using physiologically-based pharmacokinetic (PBPK) is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE's) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if an investigational drug is a weak or moderate inducer, or a moderate/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG, and NET, within Simcyp, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp PBPK to interrogate the regulatory decision-tree to contextualize the potential interaction by known perpetrators and NCEs, enabling model-informed decision making, clinical study designs, and delivering potential alternative COC options for women of childbearing potential.

Tracking down the cause of proteinuria in primary care.

Proteinuria originates from the kidney and occurs as a result of injury to either the glomerulus or the renal tubule or both. It is relatively common in the general population with reported point prevalence of up to 8% but the prevalence falls to around 2% on repeated testing. Chronic glomerular injury resulting in proteinuria may be secondary to prolonged duration of diabetes or hypertension. A tubular origin of proteinuria may be associated with inflammation of renal tubules triggered by prescribed drugs or ingested toxins. In the absence of obvious clues to the cause of persistent proteinuria on history or clinical examination it is worthwhile reviewing the patient's prescribed drugs to identify any potentially nephrotoxic agents e.g. NSAIDs. NICE guidelines recommend screening for proteinuria in individuals at higher risk for chronic kidney disease (CKD). These include patients with diabetes, hypertension, cardiovascular disease, connective tissue disorders, a family history of renal disease and those prescribed potentially nephrotoxic drugs. Patients with sudden onset of lower limb oedema and associated proteinuria should have a serum albumin level measured to exclude the nephrotic syndrome. Renal tract ultrasound will measure kidney size, and detect scarring associated with chronic pyelonephritis or prior renal stone disease which can cause proteinuria.

Differences in medical care usage between two mass-gathering sporting events.

BACKGROUND: Event planning for mass gatherings involves the utilization of methods that prospectively can predict medical resource use. However, there is growing recognition that historical data for a specific event can help to accurately forecast medical requirements. This study was designed to investigate the differences in medical usage rates between two popular mass-gathering sports events in the UK: rugby matches and horse races. METHODS: A retrospective study of all attendee consultations with the on-site medical teams at the Leicester Tigers Rugby Football Club and the Leicester Racecourse from September 2008 through August 2009 was undertaken. Patient demographics, medical usage rates, level of care, as well as professional input and the effects of alcohol use were recorded. RESULTS: Medical usage rates were higher at the Leicester Racecourse (P < .01), although the demographics of the patients were similar and included 24% children and 16% staff. There was no difference in level of care required between the two venues with the majority of cases being minor, although a higher proportion of casualties at the Leicester Tigers event were seen by a health care professional compared with the Leicester Racecourse (P < .001). Alcohol was a contributing factor in only 5% of consultations. CONCLUSIONS: These two major sporting venues had similar attendance requirements for medical treatment that are comparable to other mass-gathering sports events. High levels of staff and pediatric presentations may have an impact on human resource planning for events on a larger scale, and the separation of treatment areas may help to minimize the number of unnecessary or opportunistic reviews by the on-site health care professionals.

Early diagnosis improves survival in kidney cancer.

Kidney cancers account for 2-3% of all adult malignancies in the UK. Men are predominantly affected by renal cancer with an average age at diagnosis of 64 years. Renal (or clear) cell carcinoma (RCC) accounts for 90% of kidney cancers. Early diagnosis improves survival with five-year survival rates for renal cancer of 70-94% for localised tumours in the UK. RCC should be suspected in the presence of localising symptoms such as flank pain, a loin mass or haematuria; constitutional upset including weight loss, pyrexia and/or night sweats; or with unexplained laboratory tests. Smoking, obesity and hypertension are the most important and most common risk factors. Environmental exposure to asbestos, cadmium and trichloroethylene are less common risk factors. Patients on chronic dialysis and renal transplant recipients are at increased risk of RCC in their native kidneys. If kidney cancer is suspected on history, physical examination or initial screening tests then a red flag ultrasound examination of the renal tracts should be requested. Dipstick urinalysis is of great value as asymptomatic haematuria may be the only abnormal test in the presence of non-specific symptoms such as weight loss or loin pain. Visible or non-visible haematuria, in the absence of proteinuria, suggests an underlying structural abnormality is present in the kidneys, ureters or bladder. Surgical removal of RCCs, where feasible, may result in cure in up to 40-60% of cases. Individuals too frail for major surgery may benefit from thermal ablation and cryotherapy. Agents that target the VEGF and mTOR pathways are considered first line in the treatment of metastatic RCC. Sunitinib, recommended by NICE, is administered orally and acts by inhibiting the VEGF receptor.

Iatrogenic splenectomy during left nephrectomy: a single-institution experience of eight years.

INTRODUCTION: Iatrogenic injury to the spleen is not an uncommon complication. Left nephrectomy has been reported as the second commonest cause of iatrogenic splenectomy with a reported incidence between 1.3 and 24%. Iatrogenic splenectomy is associated with significant morbidity and mortality. AIMS: We reviewed the occurrence of iatrogenic splenectomy during left nephrectomy at our centre. Our aims were to determine the incidence of iatrogenic splenectomy within the Mid Yorkshire Hospitals NHS Trust in order to understand the nature of the splenic injury and the morbidity and mortality associated with it. METHODS: All splenectomy and nephrectomy histology reports from January 2000 to December 2007 were reviewed retrospectively. Indications for splenectomy and nephrectomy were identified. Patients' demographic data, tumour characteristics, operative details, length of hospital stay and any reported morbidity or mortality were collected. RESULTS: A total of 447 nephrectomies were identified which included 234 left nephrectomies. Within the same period 136 cases of splenectomy were performed. Thirty-four cases were iatrogenic splenectomies and 12 were caused by left nephrectomy. The incidence was 5.13%. The male to female ratio was 1:1 with an average age of 66 years. Grade 2 and stage pT2 renal cancer were the commonest tumour characteristics. All iatrogenic injuries occurred during mobilisation of the colon or division of adhesion. The average operative time was 4.7 h. Average length of hospital stay was 14 days. Five patients had postoperative complications and 1 died of respiratory failure and sepsis. CONCLUSION: Splenic injury during left nephrectomy is a morbid complication. A good understanding of anatomy and surgical approach may reduce the incidence, morbidity and mortality of iatrogenic splenectomy during left nephrectomy.

A novel technique to facilitate dacryocystectomy using viscoelastic substances.

The procedure of dacryocystectomy is described in a patient with Wegener's granulomatosis where bone preservation is essential for future reconstructive procedures. With the aid of canalicular clamps, viscoelastic substance is used to distend the lacrimal sac thereby facilitating easier dissection. We describe the use of canalicular clamping and injection of a viscoelastic substance into the lacrimal sac to facilitate easier dissection during dacryocystectomy.

The high-resolution structure of pig heart succinyl-CoA:3-oxoacid coenzyme A transferase.

The enzyme succinyl-CoA:3-oxoacid coenzyme A transferase (SCOT) participates in the metabolism of ketone bodies in extrahepatic tissues. It catalyses the transfer of coenzyme A (CoA) from succinyl-CoA to acetoacetate with a classical ping-pong mechanism. There is biochemical evidence that the enzyme undergoes conformational changes during the reaction, but no domain movements have been reported in the available crystal structures. Here, a structure of pig heart SCOT refined at 1.5 A resolution is presented, showing that one of the four enzyme subunits in the crystallographic asymmetric unit has a molecule of glycerol bound in the active site; the glycerol molecule is hydrogen bonded to the conserved catalytic glutamate residue and is likely to occupy the cosubstrate-binding site. The binding of glycerol is associated with a substantial relative movement (a 13 degrees rotation) of two previously undefined domains that close around the substrate-binding site. The binding orientation of one of the cosubstrates, acetoacetate, is suggested based on the glycerol binding and the possibility that this dynamic domain movement is of functional importance is discussed.

Non-traumatic thoracic aortic emergencies: imaging diagnosis and management.

The major component of non-traumatic thoracic aortic emergencies is the acute aortic syndromes. These include acute aortic dissection, intramural haematoma and penetrating atherosclerotic ulcer, grouped together because they are indistinguishable clinically and highly fatal. All three entities involve disruption to the tunica intima and media and may be complicated by rupture, end-organ ischaemia or aneurysmal transformation. Early diagnosis is vital to allow timely and appropriate management. Paired unenhanced and electrocardiogram-gated computed tomography angiography of the chest, extending more distally if required, is recommended for diagnosis. Specific computed tomography features of all three entities are reviewed, with a focus on morphological features associated with complications. Those with type A pathology are usually managed with open surgery because this has a high risk of complication. Patients with uncomplicated type B pathology are usually managed with best medical therapy whereas those with complicated type B pathology are usually offered either surgery or thoracic endovascular aortic repair. The limited evidence regarding the use of thoracic endovascular aortic repair in patients with subacute uncomplicated type B pathology is briefly discussed.

US database study: burden and healthcare resource utilization in adults with systemic endemic mycoses and aspergillosis.

Aim: This study evaluated burden of illness in immunocompromised patients with systemic mycoses (SM) eligible for itraconazole treatment, specifically, histoplasmosis, blastomycosis and aspergillosis. Methods: A cross-sectional study used an electronic medical record network integrating information from 30 US hospitals, including >34 million patients, to evaluate burden and healthcare resource utilization over 6 months following initiation of antifungal therapy. Results: Symptomatic burden experienced by each of the otherwise healthy or age >65 or immunosuppressed cohorts receiving antifungal therapy for SM was comparable but significantly greater in cancer or HIV patients and transplant recipients. Across groups, there was substantially higher healthcare resource utilization in patients with SM versus matched controls without SM. Conclusion: The total impact of SM is particularly severe in high-risk or vulnerable populations.

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro-drug of miridesap.

BACKGROUND AND PURPOSE: Miridesap, a depleter of serum amyloid P component (SAP), forms an essential component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates that it is given parenterally. We sought to identify and clinically characterise a pro-drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability. EXPERIMENTAL APPROACH: We utilised a preclinical screening cascade focused on appropriate physicochemical properties, physical and gut stability, and conversion to miridesap in liver microsomes and blood. GSK3039294 (GSK294) had the desired in vitro profile and progressed to preclinical in vivo pharmacokinetic and safety assessments. Based on a favourable profile, it was tested in healthy participants after single and repeat dosing. KEY RESULTS: GSK294 was highly soluble and stable in simulated gastric and intestinal fluids, stable in intestinal microsomes, and permeable in Madine Darby Canine Kidney type II cells. GSK294 was rapidly hydrolysed to miridesap and its mono pro-drug ester in blood and liver microsomes. GSK294 showed good oral bioavailability of miridesap in rats and dogs. Following administration of GSK294 600 mg QD for 7 days in humans, pharmacodynamically active concentrations of miridesap were achieved with substantial and sustained depletion of plasma SAP. The study was terminated due to observations of arrhythmia, the relation of which to GSK294 remains unclear. CONCLUSION AND IMPLICATIONS: Using a preclinical screening cascade, we identified a pro-drug for a palindromic molecule with unique pharmacology (miridesap). The pro-drug depleted circulating SAP with a time course and extent similar to that of parenterally administered miridesap.