Opportunities and Challenges in Building a Spatiotemporal Multi-scale Model of the Human Pancreatic ß Cell.

The construction of a predictive model of an entire eukaryotic cell that describes its dynamic structure from atomic to cellular scales is a grand challenge at the intersection of biology, chemistry, physics, and computer science. Having such a model will open new dimensions in biological research and accelerate healthcare advancements. Developing the necessary experimental and modeling methods presents abundant opportunities for a community effort to realize this goal. Here, we present a vision for creation of a spatiotemporal multi-scale model of the pancreatic ß-cell, a relevant target for understanding and modulating the pathogenesis of diabetes.

Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2A Adenosine Receptor.

Signaling across cellular membranes, the 826 human G protein-coupled receptors (GPCRs) govern a wide range of vital physiological processes, making GPCRs prominent drug targets. X-ray crystallography provided GPCR molecular architectures, which also revealed the need for additional structural dynamics data to support drug development. Here, nuclear magnetic resonance (NMR) spectroscopy with the wild-type-like A2A adenosine receptor (A2AAR) in solution provides a comprehensive characterization of signaling-related structural dynamics. All six tryptophan indole and eight glycine backbone 15N-1H NMR signals in A2AAR were individually assigned. These NMR probes provided insight into the role of Asp522.50 as an allosteric link between the orthosteric drug binding site and the intracellular signaling surface, revealing strong interactions with the toggle switch Trp 2466.48, and delineated the structural response to variable efficacy of bound drugs across A2AAR. The present data support GPCR signaling based on dynamic interactions between two semi-independent subdomains connected by an allosteric switch at Asp522.50.

Evaluating a shared care pathway intervention for people receiving chemotherapy to reduce post-treatment unplanned hospital presentations: a randomised controlled trial.

PURPOSE: The aim of this randomised controlled trial (RCT) was to explore whether a community nursing intervention for outpatients receiving systemic therapy reduced unplanned hospital presentations and improved physical and psychosocial health outcomes over the first three cycles of treatment compared to a control group receiving standard care. METHODS: The number of and reasons for unplanned presentations were obtained for 170 intervention and 176 control group adult patients with solid tumours starting outpatient chemotherapy. Poisson regression was used to compare the number of presentations between the intervention and control groups. Patients self-completed the Hospital Anxiety and Depression Scale, the Cancer Behavior Inventory and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ-C30) at the start of the first four cycles. Linear regression techniques were used to compare quality of life outcomes. RESULTS: The reduction in unplanned presentations in the intervention group relative to the control group was 12% (95% CI, - 25%, 37%; P = 0.48). At the start of cycle 4, there was no difference in anxiety (difference = 0.47 (95% CI, - 0.28, 1.22; P = 0.22)), depression (difference = 0.57 (95% CI, - 0.18, 1.31; P = 0.13)) or EORTC QLQ-C30 summary score (difference = 0.16 (95% CI, - 2.67, 3.00; P = 0.91)). Scores for self-efficacy as measured by the Cancer Behavior Inventory were higher in the intervention group (difference = 4.3 (95% CI, 0.7, 7.9; P = 0.02)). CONCLUSION: This RCT did not demonstrate a benefit in reducing unplanned presentations to hospital. The trial identified improved cancer-based self-efficacy in patients receiving the intervention. TRIAL REGISTRATION: Registered at Australian and New Zealand Clinical Trials Registry: ACTRN12614001113640, registered 21/10/2014.

Bayesian metamodeling of complex biological systems across varying representations.

Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide and conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are 1) converted to a standardized statistical representation relying on probabilistic graphical models, 2) coupled by modeling their mutual relations with the physical world, and 3) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic ß-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic ß-Cell Consortium.

Impact of an evidence-based bundle on incontinence-associated dermatitis prevalence in hospital patients: A quasi-experimental translational study.

The study aimed to evaluate the effect of an intervention on the prevalence and severity of incontinence-associated dermatitis (IAD) in six hospitals in one state in Australia. This quasi-experimental pre-and post-study, conducted in 18 wards, was part of a larger implementation science study on incontinence-associated dermatitis. Skin and incontinence assessments were conducted on patients during February and March 2020 (pre-intervention) and July and August 2021 (post-intervention). The intervention comprised continence assessment and management, an education brochure for patients, family and caregivers on IAD, the Ghent Global IAD Categorisation Tool (GLOBIAD) and a skin care regime with patient skin protection measures (three-in-one barrier cream cloths, minimisation of bed protection layers, use of appropriate continence aid). A total of 1897 patients were assessed (pre-intervention = 964, post-intervention = 933). A total of 343 (35.6%) pre-intervention patients and 351 (37.6%) post-intervention patients had incontinence. The prevalence of hospital-acquired IAD was 6.71% in the pre-intervention group and 4.27% in the post-intervention group; a reduction of 36.3% (p = 0.159) despite higher patient acuity, prevalence of double incontinence and the COVID-19 pandemic in the post-intervention group compared with the pre-intervention group. Our multisite best practice IAD prevention and treatment intervention was able to reduce the prevalence and severity of hospital-acquired IAD, suggesting enduring effectiveness of the intervention.

Kinetic and data-driven modeling of pancreatic ß-cell central carbon metabolism and insulin secretion.

Pancreatic ß-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic ß-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell's fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between ß-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure in vitro. In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.

Structural basis for selectivity and diversity in angiotensin II receptors.

The angiotensin II receptors AT1R and AT2R serve as key components of the renin-angiotensin-aldosterone system. AT1R has a central role in the regulation of blood pressure, but the function of AT2R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT2R bound to an AT2R-selective ligand and to an AT1R/AT2R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or ß-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.

How consequences of colorectal cancer treatment are managed: a qualitative study of stakeholder experiences about supportive care and current practices.

PURPOSE: Colorectal cancer (CRC) survivors experience treatment-effects such as symptoms and functional impairments. There is limited evidence about how these are managed and what services or supports are available in the community. We aimed to identify current practice and available supports for managing consequences of treatment from clinician and CRC survivor perspectives. METHODS: This qualitative study, informed by an interpretivist constructionist paradigm, included semi-structured interviews. Clinicians with experience of treating CRC patients and adult CRC survivors were recruited across Australia. Interviews explored experiences about problems experienced after CRC treatment and how these were managed. Data collection and analysis, using thematic analysis, was iterative whereby emergent themes during analysis were incorporated into subsequent interviews. RESULTS: We interviewed 16 clinicians and 18 survivors. Survivors experienced a range of consequences of treatment amendable to support including allied health, information, and self-management. Barriers to support access included clinicians' worry about patient out-of-pocket expenses, long waitlists, lack of awareness about existing supports, and perception no therapeutic options were available. Healthcare professionals with expertise in CRC were often difficult to identify outside of cancer settings. Survivorship care could be improved with individualised timely information and identification of pathways to access healthcare providers with expertise in managing consequences of CRC treatment within primary care. CONCLUSIONS: To improve CRC survivor lives posttreatment, routine assessment of consequences of treatment, individualised care planning involving relevant healthcare professionals, access to supportive care when needed, and improved information provision and engagement of a range of health professionals in follow-up care are needed.

Resilience in adults with colorectal cancer: Refining a conceptual model using a descriptive qualitative approach.

AIMS: To examine and refine a conceptual model of resilience in adult cancer care based on the perspectives and experiences of resilience in adults with colorectal cancer. DESIGN: A descriptive qualitative study was performed. METHODS: Twelve participants diagnosed with colorectal cancer that had completed cancer treatment with curative intent were recruited from a tertiary hospital in Australia from July to December 2019. The meaning of individual resilience was explored using in-depth individual interviews. Data were analysed using inductive thematic analysis. Following data analysis, the elements of the conceptual model of resilience were mapped against the themes and subthemes to refine the model. RESULTS: Five themes were identified as key elements of individual resilience in adults with colorectal cancer: (1) seeking motivations to move forward; (2) striving for normality; (3) adapting and managing self; (4) drawing on external supports; (5) redefining self. A refined conceptual model of individual resilience in adults with colorectal cancer was developed based on the integration of the themes and the elements of the conceptual model of individual resilience. CONCLUSIONS: Our refined conceptual model of individual resilience in adults with colorectal cancer could facilitate nurses' and other health professionals' understanding of the process of how resilient individuals with colorectal cancer overcome their illness-related adversity. This refined model may be used to further develop and test cancer-specific resilience measures and develop interventions to facilitate resilience in people living with colorectal cancer. IMPACT: This research identified five features of resilience in adults with colorectal cancer and refined a conceptual model of resilience in adults with colorectal cancer. The findings could help nurses and other health professionals with identifying individuals who are at risk of adaptation difficulties and contribute to an early referral to psychosocial support services.

Using email interviews to reflect on women's careers at a regional university.

The article investigates asynchronous narrative research via email as a flexible and agentic method of collecting data that may empower female participants. A case study was used that focused on the challenges for academic and professional women at an Australian regional university. Twenty-one women responded by email to a range of questions about working conditions and career progression. The data demonstrated that participants found this methodology empowering, encouraging agentic behaviour as they could respond at a time that suited them and in as much detail as they desired. They could also leave their narratives and return to them after some reflection. While lacking the non-verbal markers that often add to meanings in face-to-face interviews, the participants' writing gave voice and form to their lived experience that has been missing from academic literature. This research method may be vital in the continuing COVID-19 environment where it can be difficult to access geographically dispersed participants.

Women with gynaecological cancer awaiting radiotherapy: Self-reported wellbeing, general psychological distress, symptom distress, sexual function, and supportive care needs.

OBJECTIVE: To better serve women with gynaecological cancers, we need a sound understanding of their health, wellbeing and needs. This study sought to explore these issues in a sample of Australian women before commencing curative radiotherapy. METHODS: We undertook a secondary analysis of baseline data from a supportive care trial (n = 311). Descriptive statistics were used to summarise responses to measures of wellbeing, general psychological distress, symptom distress, sexual function and vaginal changes, and supportive care needs. Pre-specified regression models were used to examine sources of variation in wellbeing and sexual function. RESULTS: Women reported lower emotional, functional and physical wellbeing than population norms (all p < 0.001). The prevalence of general psychological distress was 31% (95% CI 26-36%). Distress caused by physical symptoms was typically low. Health system and information needs comprised eight of the top ten moderate-to-high supportive care needs. Most women reported no change in interest for physical contact or sex compared to pre-diagnosis, but some sexually active women (16-24%) reported smaller vaginal size, increased dryness, and more pain on intercourse. General psychological distress was a robust marker of poorer wellbeing and sexual function. CONCLUSIONS: Before radiotherapy, a substantial minority of women with gynaecological cancers experience general psychological distress, reduced wellbeing and moderate-to-high health system and information needs. A model of comprehensive care incorporating assessment of unmet needs, general psychological distress, and sexual issues is recommended. Healthcare providers may require training to elicit and respond to a constellation of interrelated issues and access relevant services for women requiring additional support.

Psychosocial well-being and supportive care needs of cancer patients and survivors living in rural or regional areas: a systematic review from 2010 to 2021.

PURPOSE: To summarise what is currently known about the psychosocial morbidity, experiences, and needs of people with cancer and their informal caregivers, who live in rural or regional areas of developed countries. METHODS: Eligible studies dating from August 2010 until May 2021 were identified through several online databases, including MEDLINE, EMBASE, PsychINFO, and RURAL (Rural and Remote Health Database). Results were reported according to the PRISMA guidelines and the protocol was registered on PROSPERO (CRD42020171764). RESULTS: Sixty-five studies were included in this review, including 20 qualitative studies, 41 quantitative studies, and 4 mixed methods studies. Qualitative research demonstrated that many unique psychosocial needs of rural people remain unmet, particularly relating to finances, travel, and accessing care. However, most (9/19) quantitative studies that compared rural and urban groups reported no significant differences in psychosocial needs, morbidity, or quality of life (QOL). Five quantitative studies reported poorer psychosocial outcomes (social and emotional functioning) in urban cancer survivors, while three highlighted poorer outcomes (physical functioning, role functioning, and self-reported mental health outcomes) in the rural group. CONCLUSION: Recent research shows that rural people affected by cancer have unique unmet psychosocial needs relating to rurality. However, there was little evidence that rural cancer survivors report greater unmet needs than their urban counterparts. This contrasts to the findings from a 2011 systematic review that found rural survivors consistently reported worse psychosocial outcomes. More population-based research is needed to establish whether uniquely rural unmet needs are due to general or cancer-specific factors.

A qualitative investigation of the supportive care experiences of people living with pancreatic and oesophagogastric cancer.

BACKGROUND: Pancreatic and oesophagogastric (OG) cancers have a dismal prognosis and high symptom burden, with supportive care forming an integral component of the care provided to patients. This study aimed to explore the supportive care experiences of patients and caregivers living with pancreatic and OG cancers in order to identify perceived opportunities for improvement. METHODS: Semi-structured individual interviews were conducted with people living with pancreatic and OG cancers, and their caregivers, across Victoria, Australia during 2020. Interviews were thematically analysed to identify common themes. RESULTS: Forty-one participants were interviewed, including 30 patients and 11 caregivers. Three overarching themes, each with multiple sub-themes, were identified: (i) inadequate support for symptoms and issues across the cancer journey (ii) caregiver's desire for greater support, and (iii) a multidisciplinary care team is the hallmark of a positive supportive care experience. Generally, those who had access to a cancer care coordinator and/or a palliative care team recounted more positive supportive care experiences. CONCLUSION: Unmet needs are prevalent across the pancreatic and OG cancer journey, with supportive care provided to varying levels of satisfaction. Greater awareness of and access to high-quality multidisciplinary support services is greatly desired by both patients with pancreatic and OG cancer and their caregivers.

Clinician Knowledge of Incontinence-Associated Dermatitis: A Multisite Survey of Healthcare Professionals in Acute and Subacute Settings.

PURPOSE: This study examined clinicians' knowledge of incontinence-associated dermatitis (IAD) using the Barakat-Johnson Incontinence-Associated Dermatitis Knowledge Tool (Know-IAD). DESIGN: A cross-sectional multicenter survey. SUBJECTS AND SETTING: The setting was 6 hospitals across 5 health districts in New South Wales, Australia. The participants were nurses (registered nurses and enrolled nurses), physicians, allied health (occupational therapists, dietitians, and physiotherapists), and students (nursing and allied health). METHODS: Data about IAD knowledge were collected from November 2019 to January 2020. The Know-IAD, an 18-item validated instrument that measures knowledge of IAD in 3 domains (etiology and risk, classification and diagnosis, and prevention and management), was administered to a cross section of eligible clinicians. The participants anonymously completed hard copy surveys. Descriptive and exploratory analyses were conducted to quantify clinicians' knowledge about the etiology and risk, classification and diagnosis, and prevention and management of IAD. A mean knowledge score of 70% was considered to be satisfactory. RESULTS: Four hundred twelve respondents completed the survey. One hundred twenty nine respondents (31.3%) achieved 70% correct responses and greater for the entire set of items. For the etiology and risk domain, 348 respondents (84.5%) obtained a score of 70% correct responses and greater, 67 respondents (16.3%) achieved 70% correct responses and greater for the classification and diagnosis domain, and 84 respondents (20.4%) achieved 70% correct responses and greater for the prevention and management domain. CONCLUSION: Clinicians tend to have low knowledge and recognition of IAD, particularly in the areas of classification and diagnosis along with prevention and management. They tend to have higher knowledge of how IAD is caused and the risk factors. This study has identified knowledge gaps for further education that can improve assessment, prevention, and management of IAD.

The viability and acceptability of a Virtual Wound Care Command Centre in Australia.

The objective of this study was to assess the viability and acceptability of an innovative Virtual Wound Care Command Centre where patients in the community, and their treating clinicians, have access to an expert wound specialist service that comprises a digitally enabled application for wound analysis, decision-making, remote consultation, and monitoring. Fifty-one patients with chronic wounds from 9 centres, encompassing hospital services, outpatient clinics, and community nurses in one metropolitan and rural state in Australia, were enrolled and a total of 61 wounds were analysed over 7 months. Patients received, on average, an occasion of service every 4.4 days, with direct queries responded to in a median time of 1.5 hours. During the study period, 26 (42.6%) wounds were healed, with a median time to healing of 66 (95% CI: 56-88) days. All patients reported high satisfaction with their wound care, 86.4% of patients recommended the Virtual Wound Care Command Centre with 84.1% of patients reporting the digital wound application as easy to use. Potential mean travel savings of $99.65 for rural patients per visit were recognised. The data revealed that the Virtual Wound Care Command Centre was a viable and acceptable patient-centred expert wound consultation service for chronic wound patients in the community.

Assessing the Educational Value of a Zoo Placement for Veterinary Students: A Report on Student Feedback and Perceptions.

Zoological medicine is an expanding field with limited practical training opportunities for veterinary students. Those training programs that do exist require significant financial and resource investment by both veterinary schools and the zoological organizations involved. This article summarizes the findings of a retrospective survey of students carried out to ascertain the educational value of a compulsory 5-day-long zoo clinical placement for final-year veterinary students. We aimed to explore the placement's potential impact on students' knowledge and attitudes toward zoological medicine and the role of modern zoos and conservation. Data were collected by means of an end-of-placement questionnaire (N = 200) and statistically analyzed for pre- versus post-placement changes and the effect of pre-placement interest and experience on student responses. Despite the placement's short time frame and lack of opportunity for in-depth comprehensive training in zoological medicine, students reported that the placement had a positive educational impact. More than 90% of students stated that their understanding about modern zoos was good or excellent at the end of the placement (compared with 35.0% before the placement), and 43.0% reported that the placement had a positive impact on their attitudes toward zoos. Students self-reported an increased understanding of the work of zoo clinicians, and there was a highly significant positive change in the students' reported opinions regarding wildlife conservation in general. We provide preliminary evidence to suggest that even short-duration but immersive zoo-based practical training has positive educational value for veterinary students.

Prognostic models to predict survival in patients with pancreatic cancer: a systematic review.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has poor survival. Current treatments offer little likelihood of cure or long-term survival. This systematic review evaluates prognostic models predicting overall survival in patients diagnosed with PDAC. METHODS: We conducted a comprehensive search of eight electronic databases from their date of inception through to December 2019. Studies that published models predicting survival in patients with PDAC were identified. RESULTS: 3297 studies were identified; 187 full-text articles were retrieved and 54 studies of 49 unique prognostic models were included. Of these, 28 (57.1%) were conducted in patients with advanced disease, 17 (34.7%) with resectable disease, and four (8.2%) in all patients. 34 (69.4%) models were validated, and 35 (71.4%) reported model discrimination, with only five models reporting values >0.70 in both derivation and validation cohorts. Many (n = 27) had a moderate to high risk of bias and most (n = 33) were developed using retrospective data. No variables were unanimously found to be predictive of survival when included in more than one study. CONCLUSION: Most prognostic models were developed using retrospective data and performed poorly. Future research should validate instruments performing well locally in international cohorts and investigate other potential predictors of survival.

The association between quality care and outcomes for a real-world population of Australian patients diagnosed with pancreatic cancer.

BACKGROUND: This study: (i) assessed compliance with a consensus set of quality indicators (QIs) in pancreatic cancer (PC); and (ii) evaluated the association between compliance with these QIs and survival. METHODS: Four years of data were collected for patients diagnosed with PC. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A multivariable analysis tested the relationship between significant patient and hospital characteristics, patient cluster effects within hospitals and survival. RESULTS: 1061 patients were eligible for this study. Significant association with improved survival were: (i) in the potentially resectable group having adjuvant chemotherapy administered following surgery or a reason documented (HR, 0.29; 95 CI, 0.19-0.46); (ii) in the locally advanced group included having chemotherapy ± chemoradiation, or a reason documented for not undergoing treatment (HR, 0.38; 95 CI, 0.25-0.58); and (iii) in the metastatic disease group included having documented performance status at presentation (HR, 0.65; 95 CI, 0.47-0.89), being seen by an oncologist in the absence of treatment (HR, 0.48; 95 CI, 0.31-0.77), and disease management discussed at a multidisciplinary team meeting (HR, 0.79; 95 CI, 0.64-0.96). CONCLUSION: Capture of a concise data set has enabled quality of care to be assessed.

Assessment of scoring functions to rank the quality of 3D subtomogram clusters from cryo-electron tomography.

Cryo-electron tomography provides the opportunity for unsupervised discovery of endogenous complexes in situ. This process usually requires particle picking, clustering and alignment of subtomograms to produce an average structure of the complex. When applied to heterogeneous samples, template-free clustering and alignment of subtomograms can potentially lead to the discovery of structures for unknown endogenous complexes. However, such methods require scoring functions to measure and accurately rank the quality of aligned subtomogram clusters, which can be compromised by contaminations from misclassified complexes and alignment errors. Here, we provide the first study to assess the effectiveness of more than 15 scoring functions for evaluating the quality of subtomogram clusters, which differ in the amount of structural misalignments and contaminations due to misclassified complexes. We assessed both experimental and simulated subtomograms as ground truth data sets. Our analysis showed that the robustness of scoring functions varies largely. Most scores were sensitive to the signal-to-noise ratio of subtomograms and often required Gaussian filtering as preprocessing for improved performance. Two scoring functions, Spectral SNR-based Fourier Shell Correlation and Pearson Correlation in the Fourier domain with missing wedge correction, showed a robust ranking of subtomogram clusters without any preprocessing and irrespective of SNR levels of subtomograms. Of these two scoring functions, Spectral SNR-based Fourier Shell Correlation was fastest to compute and is a better choice for handling large numbers of subtomograms. Our results provide a guidance for choosing an accurate scoring function for template-free approaches to detect complexes from heterogeneous samples.

Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox's Bazar, Bangladesh, 2017 to 2019: A retrospective study.

BACKGROUND: Unrest in Myanmar in August 2017 resulted in the movement of over 700,000 Rohingya refugees to overcrowded camps in Cox's Bazar, Bangladesh. A large outbreak of diphtheria subsequently began in this population. METHODS AND FINDINGS: Data were collected during mass vaccination campaigns (MVCs), contact tracing activities, and from 9 Diphtheria Treatment Centers (DTCs) operated by national and international organizations. These data were used to describe the epidemiological and clinical features and the control measures to prevent transmission, during the first 2 years of the outbreak. Between November 10, 2017 and November 9, 2019, 7,064 cases were reported: 285 (4.0%) laboratory-confirmed, 3,610 (51.1%) probable, and 3,169 (44.9%) suspected cases. The crude attack rate was 51.5 cases per 10,000 person-years, and epidemic doubling time was 4.4 days (95% confidence interval [CI] 4.2-4.7) during the exponential growth phase. The median age was 10 years (range 0-85), and 3,126 (44.3%) were male. The typical symptoms were sore throat (93.5%), fever (86.0%), pseudomembrane (34.7%), and gross cervical lymphadenopathy (GCL; 30.6%). Diphtheria antitoxin (DAT) was administered to 1,062 (89.0%) out of 1,193 eligible patients, with adverse reactions following among 229 (21.6%). There were 45 deaths (case fatality ratio [CFR] 0.6%). Household contacts for 5,702 (80.7%) of 7,064 cases were successfully traced. A total of 41,452 contacts were identified, of whom 40,364 (97.4%) consented to begin chemoprophylaxis; adherence was 55.0% (N = 22,218) at 3-day follow-up. Unvaccinated household contacts were vaccinated with 3 doses (with 4-week interval), while a booster dose was administered if the primary vaccination schedule had been completed. The proportion of contacts vaccinated was 64.7% overall. Three MVC rounds were conducted, with administrative coverage varying between 88.5% and 110.4%. Pentavalent vaccine was administered to those aged 6 weeks to 6 years, while tetanus and diphtheria (Td) vaccine was administered to those aged 7 years and older. Lack of adequate diagnostic capacity to confirm cases was the main limitation, with a majority of cases unconfirmed and the proportion of true diphtheria cases unknown. CONCLUSIONS: To our knowledge, this is the largest reported diphtheria outbreak in refugee settings. We observed that high population density, poor living conditions, and fast growth rate were associated with explosive expansion of the outbreak during the initial exponential growth phase. Three rounds of mass vaccinations targeting those aged 6 weeks to 14 years were associated with only modestly reduced transmission, and additional public health measures were necessary to end the outbreak. This outbreak has a long-lasting tail, with Rt oscillating at around 1 for an extended period. An adequate global DAT stockpile needs to be maintained. All populations must have access to health services and routine vaccination, and this access must be maintained during humanitarian crises.