Litigation claims in Urology in the UK National Health Service: an analysis of the trends, costs and causes over a 16-year period.

OBJECTIVE: To analyse the litigation trends and the reasons for claims within the specialty of Urology, within the UK National Health Service (NHS), over a 16-year period. MATERIALS AND METHODS: Data were requested from NHS Resolution under the Freedom of Information Act 2000. This included the total number of claims in Urology, the number of these that were successful (settled or closed), and the costs in damages paid out per financial year between 2006 and 2022. A breakdown of the successful claims by their primary cause was also collected. These were coded into the categories: 'non-operative', 'intraoperative', 'postoperative', and 'other'. RESULTS: A total of 4124 litigation claims were made between 2006 and 2022 and 60.9% (2511/4124) of these claims were successful. In all, £145 million (British pounds) was paid out in damages. The number of successful claims increased 2.9-fold from the start to end of this 16-year period, and the costs in damages paid out increased 10-fold. Regarding primary causes for the successful claims, failure or delay in treatment (20.9%, 525/2511), failure or delay in diagnosis (14.5%, 364/2511), and intraoperative problems (9.1%, 229/2511) accounted for the highest proportion. Overall, non-operative causes for successful claims accounted for 73.3% (1840/2511), intraoperative for 20.1% (504/2511), and postoperative for 3.9% (98/2511). CONCLUSIONS: The number of successful urological litigation claims, and their associated costs is rising. The majority are due to non-operative causes, which may be partially explained by NHS waiting lists alongside the effects of the coronavirus disease 2019 (COVID-19) pandemic.

Impact of PD1 and PDL1 immunotherapy on non-small cell lung cancer outcomes: a systematic review.

INTRODUCTION: Despite comprising many cancer diagnoses, few treatments are suitable for patients with advanced non-small cell lung cancer (aNSCLC). Trials suggest blockade of programmed death 1 (PD1) or its ligand (PDL1) may be effective for these patients. However, this therapy's impact on outcomes other than survival, and outcomes of patients not in trials, remains largely unknown. Therefore, we compared the effectiveness of PD1 and PDL1 immunotherapy to chemotherapy and placebo across multiple clinical outcomes. METHODS: Six databases were searched on 12-13 October 2019 for randomised controlled trials (RCTs) and observational studies investigating nivolumab, pembrolizumab, atezolizumab or durvalumab. Study selection was performed independently by two reviewers. Data for overall survival, progression-free survival, adverse effects (AEs) and quality of life (QoL) were descriptively and meta-analysed. Factors impacting treatment outcomes, including PDL1 expression, were explored. The similarity between RCT and observational data was assessed. RESULTS: From 5423 search results, 139 full texts and abstracts were included. Immunotherapy was associated with a lower risk of death than both comparators. In RCTs, the incidence of treatment-related AEs was approximately 20% lower among patients using immunotherapy compared with chemotherapy. However, no other consistent benefits were observed. Progression-free survival results were inconsistent. Improvements to QoL varied according to the instrument used; however, QoL was not recorded widely. Survival results were similar between study designs; however, AEs incidence was lower in observational studies. DISCUSSION: Among patients with aNSCLC, immunotherapy improved overall survival and incidence of treatment-related AEs compared with chemotherapy. Benefits to progression-free survival and QoL were less consistent. PROSPERO REGISTRATION NUMBER: CRD42019153345.

Comparative laboratory efficacy of novel botanical extracts against Tribolium castaneum.

BACKGROUND: Citrus sinensis, Allium sativum, Ocimum basilicum, Mentha spicata, Curcuma longa, Carica papaya, Andrographis paniculata, Azadirachta indica, Cymbopogon citratus and Acorus calamus were compared in the form of extracts of chloroform, hexane and aqueous media for their effectiveness in repelling Tribolium castaneum. Filter paper of 9 cm in diameter was cut into halves. Using a micro-pipette, each extract was applied to one half of the filter paper. The volume applied was kept constant at 0.6 mL per 30 cm2 . The filter paper was dried and reattached leaving a 0.5 cm gap between, in a Petri-plate. Ten adults of T. castaneum were introduced and the repellency was observed after 30, 60 and 180 min. RESULTS: The aqueous extract of C. papaya exhibited the highest repellency (82-97%) followed by that of garlic bulbs (aqueous extract) with 86.67% repellency. Further, gunny bags were sprayed separately using bottle sprayers with the two most effective extracts at a constant volume of 42 mL per 575 cm2 . These treated gunny bags were compared with malathion-treated gunny bags in the insect management unit. The observations were taken after 2, 8 and 24 h. Papaya leaf extract-treated gunny bags showed relative repellent activity similar to that of malathion-treated gunny bags after 24 h of treatment. Thus, gas chromatography-mass spectrometry analysis of aqueous extract of papaya leaves was performed. CONCLUSIONS: It can be concluded that extract of papaya leaves containing 2-methoxy-4-vinylphenol (8.47% peak area) can be used as a repellent biopesticide. © 2019 Society of Chemical Industry.

Impact of Personal Alcohol Consumption on Aspects of Medical Student Alcohol-Related Competencies.

AIM: As part of the prevention and management of alcohol-related harms, health professionals need to be competent to assess the level of alcohol use in patients. In this study, we explored how medical students' own alcohol consumption impacts on their familiarity with alcohol brands, strengths and alcohol-related harms. METHODS: As part of a wider study investigating the concept of 'alcohol health literacy', this study combined an anonymous online survey, linked to an electronic alcohol 'brand' recognition game. Participants were medical students in their first clinical year. The survey recorded demographics, self-reported alcohol consumption (using the AUDIT-C), a visual test of relative alcohol concentrations of wine, beer and spirits, and a free-text response asking them to list alcohol-related harms. Participants then completed the brand recognition game recording accuracy and reaction time for identifying alcohol drink brands. RESULTS: One hundred and fifty students participated. There was a significant effect of ethnicity on drinking status, with 48% of non-white participants scoring zero on the AUDIT-C. Students who reported any alcohol consumption were more likely to correctly assess relative alcohol concentrations and were faster and more accurate at recognizing alcohol brands, which was dose dependent. Overall, only 45% correctly recognized relative alcohol strengths of drinks presented. CONCLUSIONS: Among third-year medical students, ability to correctly identify relative strengths of alcoholic drinks is low. As might be expected, students who drink alcohol tend to identify brands and strengths more accurately. This has implications for how best to tailor the delivery of teaching and training about alcohol to ensure similar levels of clinical confidence in dealing with future patients regardless of personal experience.

Role of Autoregulation and Relative Synthesis of Operon Partners in Alternative Sigma Factor Networks.

Despite the central role of alternative sigma factors in bacterial stress response and virulence their regulation remains incompletely understood. Here we investigate one of the best-studied examples of alternative sigma factors: the σB network that controls the general stress response of Bacillus subtilis to uncover widely relevant general design principles that describe the structure-function relationship of alternative sigma factor regulatory networks. We show that the relative stoichiometry of the synthesis rates of σB, its anti-sigma factor RsbW and the anti-anti-sigma factor RsbV plays a critical role in shaping the network behavior by forcing the σB network to function as an ultrasensitive negative feedback loop. We further demonstrate how this negative feedback regulation insulates alternative sigma factor activity from competition with the housekeeping sigma factor for RNA polymerase and allows multiple stress sigma factors to function simultaneously with little competitive interference.

Diagnosis of Pseudomyxoma peritonei via endoscopic ultrasound guided fine needle aspiration: a case report and review of literature.

INTRODUCTION: Pseudomyxoma peritonei (PMP) is a rare condition caused by mucinous adenocarcinoma cancerous cells that produce abundance of mucin or gelatinous ascites. This cancer can cause tissue fibrosis and can impair normal organ function. Diagnosis can involve multiple imaging modalities including CT scan. There have been few cases of endoscopic ultrasound (EUS) being used as a means for diagnosis of this condition. Here we report a second case of PMP with a previous history of appendectomy diagnosed with EUS guided fine needle aspiration (FNA) biopsy. CASE STUDY: A 66-year-old male with a history of an appendectomy presented with intermittent abdominal pain for two years and weight loss of 40 pounds over two months. EGD and colonoscopy performed at an outside hospital was unremarkable. CT abdomen revealed perigastric ascities and lesions of the liver. ESR was elevated at 75. At our facility, EUS was performed revealing a peri-gastric and omental mass measuring 36.6 mm × 25.5 mm. FNA performed of both mass and ascetic fluid revealed low grade mucinous adenocarcinoma with mucinous deposits in the peritoneum consistent with PMP. CONCLUSIONS: Endoscopic ultrasound guided FNA, although very rarely used, can be a reliable and safe technique in diagnosis of PMP.

Unraveling the regulatory connections between two controllers of breast cancer cell fate.

Estrogen receptor alpha (ERα) expression is critical for breast cancer classification, high ERα expression being associated with better prognosis. ERα levels strongly correlate with that of GATA binding protein 3 (GATA3), a major regulator of ERα expression. However, the mechanistic details of ERα-GATA3 regulation remain incompletely understood. Here we combine mathematical modeling with perturbation experiments to unravel the nature of regulatory connections in the ERα-GATA3 network. Through cell population-average, single-cell and single-nucleus measurements, we show that the cross-regulation between ERα and GATA3 amounts to overall negative feedback. Further, mathematical modeling reveals that GATA3 positively regulates its own expression and that ERα autoregulation is most likely absent. Lastly, we show that the two cross-regulatory connections in the ERα-GATA3 negative feedback network decrease the noise in ERα or GATA3 expression. This may ensure robust cell fate maintenance in the face of intracellular and environmental fluctuations, contributing to tissue homeostasis in normal conditions, but also to the maintenance of pathogenic states during cancer progression.

Mathematical model of a gene regulatory network reconciles effects of genetic perturbations on hematopoietic stem cell emergence.

Interlinked gene regulatory networks (GRNs) are vital for the spatial and temporal control of gene expression during development. The hematopoietic transcription factors (TFs) Scl, Gata2 and Fli1 form one such densely connected GRN which acts as a master regulator of embryonic hematopoiesis. This triad has been shown to direct the specification of the hemogenic endothelium and emergence of hematopoietic stem cells (HSCs) in response to Notch1 and Bmp4-Smad signaling. Here we employ previously published data to construct a mathematical model of this GRN network and use this model to systematically investigate the network dynamical properties. Our model uses a statistical-thermodynamic framework to describe the combinatorial regulation of gene expression and reconciles, mechanistically, several previously published but unexplained results from different genetic perturbation experiments. In particular, our results demonstrate how the interactions of Runx1, an essential hematopoietic TF, with components of the Bmp4 signaling pathway allow it to affect triad activation and acts as a key regulator of HSC emergence. We also explain why heterozygous deletion of this essential TF, Runx1, speeds up the network dynamics leading to accelerated HSC emergence. Taken together our results demonstrate that the triad, a master-level controller of definitive hematopoiesis, is an irreversible bistable switch whose dynamical properties are modulated by Runx1 and components of the Bmp4 signaling pathway.

Lemierre's Syndrome in the 21st Century: A Literature Review.

Lemierre's syndrome is a rare, life-threatening complication of an acute oropharyngeal infection. It is generally characterised by pharyngitis secondary to Fusobacterium necrophorum, causing thrombophlebitis of the internal jugular vein and sepsis, with subsequent formation of septic emboli that can rapidly spread to different organ sites. The condition is associated with high mortality if treatment with antibiotics is delayed, and recent evidence suggests that patients are at significant risk of in-hospital morbidity and long-term neurological sequelae. Although it is agreed that antibiotics are the mainstay of treatment, there is currently no consensus on the use of anticoagulation in the condition. This review article aims to summarise our current understanding of Lemierre's syndrome with regard to its definition, epidemiology, microbiology, presentation, diagnosis, and treatment.

Role of Positron Emission Tomography/Computed Tomography in Epithelial Ovarian Cancer.

Ovarian cancer (OC) is the most lethal gynecological malignancy with majority of cases diagnosed in advanced stages and associated with high morbidity and mortality. Positron emission tomography/computed tomography (PET/CT) has emerged as an integral part of the management of several nongynecological cancers. We used PubMed search engine using MeSH words "ovarian cancer" and "PET/CT" and reviewed the current status of PET/CT in epithelial OC. Its application related to ovarian tumor including adnexal mass evaluation, baseline staging, as a triaging tool for upfront surgery or neoadjuvant chemotherapy, for response assessment and prognostication, and for relapse detection and treatment planning has been highlighted. we highlight the current guidelines and newer upcoming PET modalities and radiotracers.

Combinatorial encoding of odors in the mosquito antennal lobe.

Among the cues that a mosquito uses to find a host for blood-feeding, the smell of the host plays an important role. Previous studies have shown that host odors contain hundreds of chemical odorants, which are detected by different receptors on the peripheral sensory organs of mosquitoes. But how individual odorants are encoded by downstream neurons in the mosquito brain is not known. We developed an in vivo preparation for patch-clamp electrophysiology to record from projection neurons and local neurons in the antennal lobe of Aedes aegypti. Combining intracellular recordings with dye-fills, morphological reconstructions, and immunohistochemistry, we identify different sub-classes of antennal lobe neurons and their putative interactions. Our recordings show that an odorant can activate multiple neurons innervating different glomeruli, and that the stimulus identity and its behavioral preference are represented in the population activity of the projection neurons. Our results provide a detailed description of the second-order olfactory neurons in the central nervous system of mosquitoes and lay a foundation for understanding the neural basis of their olfactory behaviors.

Coupling between feedback loops in autoregulatory networks affects bistability range, open-loop gain and switching times.

Biochemical regulatory networks governing diverse cellular processes such as stress-response, differentiation and cell cycle often contain coupled feedback loops. We aim at understanding how features of feedback architecture, such as the number of loops, the sign of the loops and the type of their coupling, affect network dynamical performance. Specifically, we investigate how bistability range, maximum open-loop gain and switching times of a network with transcriptional positive feedback are affected by additive or multiplicative coupling with another positive- or negative-feedback loop. We show that a network's bistability range is positively correlated with its maximum open-loop gain and that both quantities depend on the sign of the feedback loops and the type of feedback coupling. Moreover, we find that the addition of positive feedback could decrease the bistability range if we control the basal level in the signal-response curves of the two systems. Furthermore, the addition of negative feedback has the capacity to increase the bistability range if its dissociation constant is much lower than that of the positive feedback. We also find that the addition of a positive feedback to a bistable network increases the robustness of its bistability range, whereas the addition of a negative feedback decreases it. Finally, we show that the switching time for a transition from a high to a low steady state increases with the effective fold change in gene regulation. In summary, we show that the effect of coupled feedback loops on the bistability range and switching times depends on the underlying mechanistic details.

Intractable Seizures and Limbic Encephalitis, Unaccounted Complications of Type 1 Diabetes Autoimmunity.

Glutamic acid decarboxylase 65kD autoantibody (GAD65Ab) is frequently detected in patients with refractory epilepsy and stiff person syndrome. In contrast to T1D, the pathological role of GAD65Ab in neurological disorders is still debatable. As a result, the implementation of possible immunotherapy is usually delayed. This report presents 2 cases of GAD65Ab-associated brain autoimmunity and their different management. We present clinical data and discuss management based on available evidence in the reviewed literature. Both cases presented with acute on chronic neurological symptoms and were GAD65Ab positive. Case 1, a 30-year-old man with a history of early-onset type 1 diabetes mellitus at 14 months, followed by cryptogenic temporal epilepsy at 11 years of age, presented with intractable seizures. Case 2, a 48-year-old woman, presented with a history of recurrent severe headaches, cognitive impairment, decreased memory, and behavioral symptoms. GAD65Ab was detected in both patients' sera. Cerebrospinal fluid GAD65Ab was only checked and positive in case 1. Case 2 was diagnosed with limbic encephalitis, treated with immunotherapy, and showed a remarkable clinical improvement. Case 1 with refractory epilepsy failed multiple antiepileptic drugs and responsive-stimulator system treatments. He was finally diagnosed with autoimmune epilepsy. The delay in diagnosis resulted in a lost opportunity for early immunotherapy. In conclusion, autoantibody screening and early initiation of immunotherapy should be considered to manage GAD65Ab-associated neurological disorders.

The interplay of multiple feedback loops with post-translational kinetics results in bistability of mycobacterial stress response.

Bacterial persistence is the phenomenon in which a genetically identical fraction of a bacterial population can survive exposure to stress by reduction or cessation of growth. Persistence in mycobacteria has been recently linked to a stress-response network, consisting of the MprA/MprB two-component system and alternative sigma factor sigma(E). This network contains multiple positive transcriptional feedback loops which may give rise to bistability, making it a good candidate for controlling the mycobacterial persistence switch. To analyze the possibility of bistability, we develop a method that involves decoupling of the network into transcriptional and post-translational interaction modules. As a result we reduce the dimensionality of the dynamical system and independently analyze input-output relations in the two modules to formulate a necessary condition for bistability in terms of their logarithmic gains. We show that neither the positive autoregulation in the MprA/MprB network nor the sigma(E)-mediated transcriptional feedback is sufficient to induce bistability in a biochemically realistic parameter range. Nonetheless, inclusion of the post-translational regulation of sigma(E) by RseA increases the effective cooperativity of the system, resulting in bistability that is robust to parameter variation. We predict that overexpression or deletion of RseA, the key element controlling the ultrasensitive response, can eliminate bistability.

Comparing Model Performance in Characterizing the PK/PD of the Anti-Myostatin Antibody Domagrozumab.

Modeling and simulation provides quantitative information on target coverage for dose selection. Optimal model selection often relies on fit criteria and is not necessarily mechanistically driven. One such case is discussed where healthy volunteer data of an anti-myostatin monoclonal antibody domagrozumab were used to develop different target-mediated drug disposition models; a quasi-steady state (QSS) rapid binding approximation model, a Michaelis-Menten (MM)-binding kinetics (MM-BK) model, and an MM-indirect response (MM-IDR) model. Whereas the MM-BK model was identified as optimal in fitting the data, with all parameters estimated with high precision, the QSS model also converged but was not able to capture the nonlinear decline. Although the least mechanistic model, MM-IDR, had the lowest objective function value, the MM-BK model was further developed as it provided a reasonable fit and allowed simulations regarding growth differentiation factor-8 target coverage for phase II dose selection with sufficient certainty to allow for testing of the underlying mechanistic assumptions.

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling.

The human adaptive immune system is a very complex network of different types of cells, cytokines, and signaling molecules. This complex network makes it difficult to understand the system level regulations. To properly explain the immune system, it is necessary to explicitly investigate the presence of different feedback and feedforward loops (FFLs) and their crosstalks. Considering that these loops increase the complexity of the system, the mathematical modeling has been proved to be an important tool to explain such complex biological systems. This review focuses on these regulatory loops and discusses their importance on systems modeling of the immune system.

ERCP-Related Duodenal Perforation Presenting as Pneumoscrotum.

Duodenal perforation is a rare but life-threatening complication of endoscopic retrograde cholangiopancreatography (ERCP). Duodenal perforation can cause air leak into the extraperitoneal space. In rare instances, the air in the extraperitoneal space could dissect along the fascial planes of the abdomen to reach scrotum, leading to pneumoscrotum. We present the case of a 35-year-old male patient who developed scrotal pain and swelling following ERCP. He was found to have extensive pneumoscrotum, pneumoretroperitoneum, pneumomediastinum, and subcutaneous emphysema. The patient was diagnosed with retroperitoneal duodenal perforation. He was managed conservatively with close monitoring and supportive care.

Posttransplant Tacrolimus-Induced Diabetic Ketoacidosis: Review of the Literature.

Diabetic ketoacidosis (DKA) in patients receiving tacrolimus as part of their immunosuppressive regimen is a rarely reported adverse event. We report a patient with autosomal dominant polycystic kidney disease (ADPKD) and no known history of diabetes mellitus who presented with DKA, 3 months after kidney transplantation.

Isolated Polycystic Liver Disease: An Unusual Cause of Recurrent Variceal Bleed.

Isolated polycystic liver disease is a rare disorder. Majority of the patients with isolated polycystic liver disease are asymptomatic with incidental detection of liver cysts on imaging studies done for other purposes. Minority of patients develop symptoms which are mostly secondary to enlarging cysts size and hepatomegaly. Rarely, these patients develop portal hypertension and can present with its clinical manifestations and consequences in the form acute variceal bleeding or recurrent ascites. We present a rare case of 67-year-old female patient with significant history of polycystic liver disease who presented to the hospital with recurrent hematemesis and melena. She underwent esophagogastroduodenoscopy which showed multiple large esophageal varices requiring banding.