Hinman Syndrome: A Rare Entity With Neurogenic Bladder-Like Symptoms.

Hinman syndrome, as is the case with many other rare conditions, is a disease very commonly under-considered or missed in the diagnosis of patients with the presenting symptoms. Clinical and radiographic manifestations of the condition are easily confused with neurogenic bladder without proper history collection and neurological examination. Patients typically present with symptoms including enuresis, urinary retention, reoccurring urinary tract infections, and encopresis. Imaging often shows hydroureteronephrosis and marked bladder wall thickening. While these signs are characteristic of neurogenic bladder, routine neurologic examinations and MRIs of patients with Hinman syndrome often show normal results, and their condition is currently thought to be an acquired behavioral and psychological disorder, often associated with abnormal family dynamics. We present the case of a 14-year-old boy, who presented to the emergency department with nausea, bilateral flank pain, and urinary retention. The patient had an over seven-year history of recurrent urinary tract infections (UTI) and intermittent encopresis and followed up with different providers. Due to the patient's extensive history and the failure of previous treatments, he was evaluated for causes of neurogenic bladder, but the MRI of the lumbar spine was normal. Fluoroscopic voiding cystourethrogram (VCUG) was ordered and demonstrated abnormal and trabeculated contour of the urinary bladder with bilateral vesicoureteral reflux consistent with the diagnosis of Hinman syndrome.

The Lifetime Health and Economic Burden of Smokeless Tobacco use in Bangladesh, India, and Pakistan: Results From ASTRAMOD.

INTRODUCTION: Under the current policy landscapes, the lifetime health and economic burden of smokeless tobacco (ST) products, consumed by over 297 million ST users in South Asia, is unknown. The aim of this study was to estimate the lifetime health effects and costs attributable to current and future ST use in Bangladesh, India, and Pakistan where the majority of ST users live. AIMS AND METHODS: We developed a Markov-based state-transition model (ASTRAMOD) to predict the lifetime costs of treatment of four diseases (oral, pharyngeal, esophageal cancers, and stroke) and disability-adjusted life years (DALYs), attributable to the current and future use of ST under existing ST policy scenario. Country-specific Global Adult Tobacco Surveys, life tables, and meta-analyses of South Asian and South East Asian studies were used to populate the model. A probabilistic sensitivity analysis evaluated the uncertainty in model predictions. RESULTS: If there were no change in the current ST policies, the lifetime ST-attributable treatment costs would be over US$19 billion in India, over US$1.5 billion in Bangladesh, and over US$3 billion in Pakistan. For all countries, the attributable costs are higher for younger cohorts with costs declining with increasing age for those over 50. The model predicted that a typical 15-year-old male adoloscent would gain 0.07-0.18 life years, avert 0.07-0.19 DALYs, and generate a cost-savings of US$7-21 on healthcare spending if ST policies were changed to eliminate ST use. CONCLUSIONS: Policy interventions aimed at decreasing the uptake of ST and increasing quitting success have the potential to substantially decrease the economic and health burden of ST. IMPLICATIONS: This study provides the most comprehensive estimates of the lifetime health and economic burden of ST by 5-year age and sex cohorts. This is also the first study that highlights the scale of health and economic burden of ST in Bangladesh, India, and Pakistan if there were no changes in the current ST policies. Policymakers and practitioners can use the reported data to justify their decisions to improve current ST policies and practices in their country. Researchers can use the ASTRAMOD methodology to estimate the impact of future ST policy changes.

Emotion detection from handwriting and drawing samples using an attention-based transformer model.

Emotion detection (ED) involves the identification and understanding of an individual's emotional state through various cues such as facial expressions, voice tones, physiological changes, and behavioral patterns. In this context, behavioral analysis is employed to observe actions and behaviors for emotional interpretation. This work specifically employs behavioral metrics like drawing and handwriting to determine a person's emotional state, recognizing these actions as physical functions integrating motor and cognitive processes. The study proposes an attention-based transformer model as an innovative approach to identify emotions from handwriting and drawing samples, thereby advancing the capabilities of ED into the domains of fine motor skills and artistic expression. The initial data obtained provides a set of points that correspond to the handwriting or drawing strokes. Each stroke point is subsequently delivered to the attention-based transformer model, which embeds it into a high-dimensional vector space. The model builds a prediction about the emotional state of the person who generated the sample by integrating the most important components and patterns in the input sequence using self-attentional processes. The proposed approach possesses a distinct advantage in its enhanced capacity to capture long-range correlations compared to conventional recurrent neural networks (RNN). This characteristic makes it particularly well-suited for the precise identification of emotions from samples of handwriting and drawings, signifying a notable advancement in the field of emotion detection. The proposed method produced cutting-edge outcomes of 92.64% on the benchmark dataset known as EMOTHAW (Emotion Recognition via Handwriting and Drawing).

Right-to-Left Intra-cardiac Shunt in a COVID-19 Patient Leading to Stroke and Poor Prognosis: A Case Report and Review of the Literature.

Coronavirus disease 2019 (COVID-19) often presents with a wide range of complications, including respiratory distress, acute respiratory distress syndrome (ARDS), and hypercoagulable states with resultant cerebrovascular incidents. Intra- and extra-pulmonological shunts can further complicate patient courses, leading to persistent hypoxemia and paradoxical emboli, resulting in potentially life-threatening consequences, necessitating a comprehensive, multidisciplinary approach to patient care. Here we present the case of a 73-year-old male who experienced severe persistent hypoxemic respiratory failure, superimposed methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, and stroke with a previously undiagnosed patent foramen ovale (PFO) contributing to his clinical presentation.

Renal Infarction as the First Manifestation of Undiagnosed Atrial Fibrillation With Coexisting Left Atrial Thrombus: A Case Report and Review of the Literature.

Acute renal infarction, presenting with nonspecific symptoms, such as abdominal pain, nausea, vomiting, and hematuria, can lead to delayed diagnosis due to similarities with other medical conditions. Computed tomography with IV contrast is used to diagnose renal parenchymal infarction, treated through surgical, percutaneous interventions, and anticoagulation therapy. Investigation for the infarction source is crucial, particularly in the absence of prior cardiac issues, necessitating heart rhythm monitoring and an echocardiogram to evaluate paroxysmal atrial fibrillation (PAF) and intracardiac thrombus, respectively. Renal infarction may elevate blood pressure due to renin release, recommending medications like angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. We present a case of renal infarction due to PAF with a concomitant intracardiac thrombus.

Smokeless Tobacco Cessation Support in Dental Hospitals in Pakistan: Dentists and Dental Patients' Perspectives on Current Practices, Support Needed, and Opportunities Available.

INTRODUCTION: Despite evidence on the effectiveness of tobacco cessation interventions in dental settings, the implementation remains low, especially for smokeless tobacco (ST). The purpose of this study was to develop an understanding of the influences governing the implementation of ST cessation support in dental hospitals. AIMS AND METHODS: A multicenter qualitative study was conducted at two tertiary-care dental hospitals, in Pakistan. Semi-structured interview guide, guided by the Capability-Opportunity-Motivation-Behavior (COM-B) model, were used to capture the views of dentists (n = 12) and dental patients (n = 12), regarding ST cessation support in dental hospitals. Framework approach was used to thematically analyze the data. RESULTS: Screening of ST users in routine dental practice was seldom practiced and the cessation support offered was brief advice. Barriers identified by dentists included: Fear of offending and stereotyping patients; lack of knowledge and skills; lack of privacy; lack of belief in the effectiveness of behavioral support; lack of time and workload pressure; ST use amongst dentists; lack of referral systems and; the absence of a mandatory requirement of offering ST cessation support. Facilitators included: Delivering support through junior dentists and the length of interaction between the dentist and the patient. Naswar was the most common ST product used by dental patients. Patients reported receiving negligible cessation support from any healthcare provider. CONCLUSIONS: A range of influences governing the implementation of ST cessation support in dental hospitals were identified. These findings can inform the implementation of behavioral interventions for ST cessation in dental and other clinical settings, in low and middle-income countries. IMPLICATIONS: Smokeless tobacco control considerably lags, in comparison to the control of combustible tobacco. This is the first study that qualitatively explores the implementation of ST cessation support in dental settings in Pakistan. Utilizing the "Capability-Opportunity-Motivation-Behavior" model, it provides an in-depth understanding of the inability of dentists in implementing effective behavioral interventions for ST cessation support in routine dental practice. Highlighting the striking discrepancy between the patient's need for and receptivity towards cessation support and the dentists' concerns over their patients' receptivity towards cessation support, it calls for the need for effective implementation strategies to optimize dentist-led tobacco cessation interventions in low-resource settings.

Smoke veil prior regularized surgical field desmoking without paired in-vivo data.

Though deep learning-based surgical smoke removal methods have shown significant improvements in effectiveness and efficiency, the lack of paired smoke and smoke-free images in real surgical scenarios limits the performance of these methods. Therefore, methods that can achieve good generalization performance without paired in-vivo data are in high demand. In this work, we propose a smoke veil prior regularized two-stage smoke removal framework based on the physical model of smoke image formation. More precisely, in the first stage, we leverage a reconstruction loss, a consistency loss and a smoke veil prior-based regularization term to perform fully supervised training on a synthetic paired image dataset. Then a self-supervised training stage is deployed on the real smoke images, where only the consistency loss and the smoke veil prior-based loss are minimized. Experiments show that the proposed method outperforms the state-of-the-art ones on synthetic dataset. The average PSNR, SSIM and RMSE values are 21.99±2.34, 0.9001±0.0252 and 0.2151±0.0643, respectively. The qualitative visual inspection on real dataset further demonstrates the effectiveness of the proposed method.

Behaviour Change Intervention for Smokeless Tobacco (ST) Cessation Delivered through Dentists in Dental Settings: A pragmatic pilot trial.

INTRODUCTION: Evidence on smokeless tobacco (ST) cessation interventions is scarce. The South Asian (SA) region which shares more than 90% of the burden of ST use, is grossly underrepresented in research on ST cessation. This study aimed to assess the feasibility of delivering and investigating a behavioural support intervention for ST cessation in dental settings in Pakistan. METHODS: A multi-centre, pilot, 2-armed parallel group, individually randomised control trial, with a 1:1 allocation ratio, was conducted at two dental hospitals. Eligibility criteria included: being a ST user; seeking dental treatment and; not currently accessing cessation support. All participants were provided written self-help, ST cessation material. The intervention group also received a dentist-delivered, bespoke behavioural support intervention for ST cessation developed for users of SA origin. Participants were followed up telephonically at three and six months. Self-reported six month abstinence was verified by salivary cotinine. Analysis was descriptive, with 95% confidence intervals presented where appropriate. RESULTS: 100 participants were successfully recruited from the selected hospitals. Of these 78% continued to engage throughout the study duration and provided primary outcome data, whereas, 63% completed all hospital visits. The outcome measures were successfully collected. Biochemically verified six-month abstinence in the intervention and control group was 10% and 4%. CONCLUSIONS: It was feasible to deliver and evaluate a dentist-delivered behavioural support intervention for ST cessation in Pakistan. The data suggested that the intervention may improve ST quit rates. The findings of this study will be useful in informing the design of future definitive studies. IMPLICATIONS: To our knowledge this is the first pragmatic pilot trial on ST cessation in dental settings in Pakistan and the first trial on dentist-delivered structured behavioural support intervention for ST cessation. It adds to the scarce, trial evidence base on ST cessation interventions. Findings suggest behavioural support intervention for ST cessation may improve quit rates. The trial was conducted in a country with poor ST control measures, where ST products are not taxed, the products are sold openly to and by minors and the users are offered negligible cessation support. The findings may therefore be generalisable to LMICs and particularly South Asian countries, with similar policy backgrounds.

A dilemma of patients: poor quality administration of tertiary care hospitals: a cross-sectional study.

Introduction: The study focuses on healthcare delivery standards in Pakistan's tertiary care hospitals. Poor accountability and a lack of financial and human resources are the main contributing factors to a hospital's substandard performance and low patient satisfaction rates. Feedback surveillance forms are the Achilles tendon in the quality improvement of a facility, and this practice is, unfortunately, not widely practiced in the hospitals of Pakistan. Through this paper and experience, the authors hope to shed light on the need for regular feedback surveys and implementing their results to improve healthcare quality. Settings and Design: A prospective, observational study of seven tertiary care hospitals in Pakistan. Materials and Methods: The data was collected using a survey form. Each survey form was filled out by a team comprising three public health professionals who observed the hospital and its functioning without interfering with its workings. The questionnaire was developed with the help of Tools for Assessing the Operationality of District Health Systems: Health Facility Questionnaire designated in the respective facilities. The analysis was then draughted as a qualitative narrative review. Finally, the review was broken down into an assessment of the hospital's outpatient clinic setting, inpatient department, emergency department and other departments. Results: The survey was conducted at seven public sector hospitals in three major cities of Pakistan. The survey focused on administrative and nonmedical parameters of healthcare facilities. Overall, the hospitals of Lahore and Islamabad lacked mass casualty apparatus and cleanliness, and staff behaviour can be improved. The hospitals in Rawalpindi have mass casualty apparatuses in place. However, they need improvement in accessibility services and hygiene and staff attitude. Conclusions: The survey showed that all the hospitals had good access and accessibility, and the directions were clearly marked for the visitors. The hospital staff is knowledgeable about the hospital, but their behaviour needs to be improved. Also, the quality of the cleanliness and waiting areas is fair but needs improvements. Finally, regular cheques via regular feedback and quality assessments can improve healthcare delivery.

Delayed Metastatic Cholangiocarcinoma to the Stomach With Imaging Characteristics Resembling Gastrointestinal Stromal Tumor: A Case Report and Review of the Literature.

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare subtype of cholangiocarcinoma, and there has been an increasing incidence of ICC in Western countries in recent years. Surgical resection is the most effective treatment for ICC. However, overall outcomes are extremely poor given that most patients are diagnosed at an advanced stage, and postoperative ICC recurrence is still very high despite hepatic resection. We report a case of metastatic ICC to the stomach presenting after resection of the original tumor, with imaging characteristics highly resembling gastrointestinal stromal tumor (GIST) on imaging. Reported cases of metastatic ICC to the liver are sparse. Given that there is a significant difference in the survival rate between metastatic cholangiocarcinoma and other tumors arising from the gastrointestinal tract, including GISTs, it is important to delineate the differences via imaging features. We further discuss the imaging characteristics of intrahepatic ICC, comparing and contrasting it to other gastric tumors.

The global impact of tobacco control policies on smokeless tobacco use: a systematic review.

BACKGROUND: Smokeless tobacco, used by more than 300 million people globally, results in substantial morbidity and mortality. For smokeless tobacco control, many countries have adopted policies beyond the WHO Framework Convention on Tobacco Control, which has been instrumental in reducing smoking prevalence. The impact of these policies (within and outside the Framework Convention on Tobacco Control) on smokeless tobacco use remains unclear. We aimed to systematically review policies that are relevant to smokeless tobacco and its context and investigate their impact on smokeless tobacco use. METHODS: In this systematic review, we searched 11 electronic databases and grey literature between Jan 1, 2005, and Sept 20, 2021, in English and key south Asian languages, to summarise smokeless tobacco policies and their impact. Inclusion criteria were all types of studies on smokeless tobacco users that mentioned any smokeless tobacco relevant policies since 2005, except systematic reviews. Policies issued by organisations or private institutions were excluded as well as studies on e-cigarettes and Electronic Nicotine Delivery System except where harm reduction or switching were evaluated as a tobacco cessation strategy. Two reviewers independently screened articles, and data were extracted after standardisation. Quality of studies was appraised using the Effective Public Health Practice Project's Quality Assessment Tool. Outcomes for impact assessment included smokeless tobacco prevalence, uptake, cessation, and health effects. Due to substantial heterogeneity in the descriptions of policies and outcomes, data were descriptively and narratively synthesised. This systematic review was registered in PROSPERO (CRD42020191946). FINDINGS: 14 317 records were identified, of which 252 eligible studies were included as describing smokeless tobacco policies. 57 countries had policies targeting smokeless tobacco, of which 17 had policies outside the Framework Convention on Tobacco Control for smokeless tobacco (eg, spitting bans). 18 studies evaluated the impact, which were of variable quality (six strong, seven moderate, and five weak) and reported mainly on prevalence of smokeless tobacco use. The body of work evaluating policy initiatives based on the Framework Convention on Tobacco Control found that these initiatives were associated with reductions in smokeless tobacco prevalence of between 4·4% and 30·3% for taxation and 22·2% and 70·9% for multifaceted policies. Two studies evaluating the non-Framework policy of sales bans reported significant reductions in smokeless tobacco sale (6·4%) and use (combined sex 17·6%); one study, however, reported an increased trend in smokeless tobacco use in the youth after a total sales ban, likely due to cross-border smuggling. The one study reporting on cessation found a 13·3% increase in quit attempts in individuals exposed (47·5%) to Framework Convention on Tobacco Control policy: education, communication, training, and public awareness, compared with non-exposed (34·2%). INTERPRETATION: Many countries have implemented smokeless tobacco control policies, including those that extend beyond the Framework Convention on Tobacco Control. The available evidence suggests that taxation and multifaceted policy initiatives are associated with meaningful reductions in smokeless tobacco use. FUNDING: UK National Institute for Health Research.

A neural network based framework for effective laparoscopic video quality assessment.

Video quality assessment is a challenging problem having a critical significance in the context of medical imaging. For instance, in laparoscopic surgery, the acquired video data suffers from different kinds of distortion that not only hinder surgery performance but also affect the execution of subsequent tasks in surgical navigation and robotic surgeries. For this reason, we propose in this paper neural network-based approaches for distortion classification as well as quality prediction. More precisely, a Residual Network (ResNet) based approach is firstly developed for simultaneous ranking and classification task. Then, this architecture is extended to make it appropriate for the quality prediction task by using an additional Fully Connected Neural Network (FCNN). To train the overall architecture (ResNet and FCNN models), transfer learning and end-to-end learning approaches are investigated. Experimental results, carried out on a new laparoscopic video quality database, have shown the efficiency of the proposed methods compared to recent conventional and deep learning based approaches.

Non-compliant packaging and illicit smokeless tobacco in Bangladesh, India and Pakistan: findings of a pack analysis.

INTRODUCTION: Illicit smokeless tobacco (ST) trade has seldom been documented despite ST use in at least 127 countries across the world. Based on non-compliance with packaging regulations, we report the proportion of illicit ST products from samples on sale in Bangladesh, India and Pakistan where 85% of global ST users reside. METHODS: We purchased unique ST products from tobacco sellers in two purposively selected administrative areas (division/district) in each of the three countries. The criteria to determine illicit ST products were based on country-specific legal requirements for ST packaging and labelling. These requirements included: 'market retail price disclosure', 'sale statement disclosure', 'pictorial health warning (PHW) pertinence', 'appropriate textual health warning' and 'using misleading descriptors (MDs)'. Non-compliance with even one of the legal requirements was considered to render the ST product illicit. RESULTS: Almost all ST products bought in Bangladesh and India were non-compliant with the local packaging requirements and hence potentially illicit, all products in Pakistan lacked desirable features. The most common feature missing was health warnings: 84% packs in Bangladesh, 93% in India, and 100% in Pakistan either did not have PHW or their sizes were too small. In Bangladesh, 61% packs carried MDs. In India and Pakistan, the proportions of such packs were 32% and 42%, respectively. CONCLUSIONS: Weak and poorly enforced ST control policies may be slowing the progress of tobacco control in South Asia. Standardised regulations are required for packaging and labelling ST. Improving compliance and reducing sale of cheap illicit products may require business licensing and market surveillance.

Experiences of Newly Diagnosed Oral Cancer Patients during the First Wave of the COVID-19 Pandemic: A Qualitative Study from Pakistan.

The COVID-19 pandemic has resulted in the scaling back or postponement of non-emergency hospital services, including care of cancer patients. The present qualitative study explored the experiences of newly diagnosed oral cancer patients during the first wave of the COVID-19 pandemic in Pakistan. Patients who attended the Department of Maxillofacial Surgery, Khyber College of Dentistry in July 2020 were selected using a maximum variation purposive sampling method. Seventeen semi-structured interviews were conducted in Pashto, the local language of Khyber Pakhtunkhwa. All interviews were audiotaped, transcribed verbatim, and translated into English. Thematic content analysis yielded eight major themes: pain and generalised physical weakness, shock at diagnosis, psychological distress of the COVID-19 pandemic, faith and religion, double hit loss of employment, social isolation, social support from caregivers, and lack of support from health care professionals. In conclusion, the COVID-19 pandemic has a clear impact on the life experiences of newly diagnosed oral cancer patients. Distress due to delay in accessing health care and lack of support from health care providers are a matter of great concern. Appropriate interventions should be introduced to ensure psychological and social support strategies are in place for patients during interruptions of health care services.

Clinical Characteristics, Comorbidities, and Outcome of Critically Sick Patients With COVID-19 Pneumonia Admitted in the Intensive Care Unit of a Tertiary Care Hospital in Lahore, Pakistan: A Retrospective Cohort Study.

Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a multisystem disease that primarily involves the respiratory tract. The first case of COVID-19 was identified in late 2019 in the province of Wuhan, China, which was followed by the rapid spread of the disease globally, becoming a present-day pandemic. Objectives The aim of this study is to describe the clinical characteristics, comorbidities, and outcomes of critically sick patients with COVID-19 pneumonia admitted to the intensive care unit (ICU) of Fatima Memorial Hospital, Lahore, from March 2021 to August 2021. A total of 133 patients were chosen for this retrospective cohort study. Results There was a total of 133 patients, out of which 65 (48.9%) were male and 68 (51.1%) were female. Of these 133 patients, 70 (52.6%) were discharged home after recovery and 63 (47.4%) died; 96 (72.2%) patients had diabetes mellitus and of these, 53 (55.2%) patients died and 43 (44.8%) were discharged, 94 (70.7%) patients had hypertension, out of which 53 (56.4%) died and 41 (43.6%) were discharged home, 40 (30.1%) patients had ischemic heart disease (IHD), out of which 28 (70%) died and 12 (30%) were discharged. A total of 48 (36.1%) patients needed invasive positive pressure ventilation (IPPV) and 78 (58.6%) patients required noninvasive positive pressure ventilation (NIPPV). Conclusion Patients with one or more underlying co-morbidities had poor clinical outcomes compared to those with no co-morbidities, with the most vulnerable group being patients with Ischemic heart disease, chronic kidney disease, hypertension, and diabetes mellitus in descending order.

Behaviour change intervention for smokeless tobacco (ST) cessation delivered through dentists within a dental setting: a feasibility study protocol.

OBJECTIVES/AIM: To adapt a structured behavioural support intervention for smokeless tobacco (ST) cessation and to assess the feasibility and acceptability of delivering the intervention via dentists within dental settings in Pakistan. MATERIAL AND METHODS: The study will have 3 phases: (1) Adapt a previously developed intervention to make it suitable for delivery in a clinical/dental setting through qualitative interviews with dental patients and dentists; (2) A multi-centre, pilot randomised control trial in two teaching dental hospitals in Pakistan. Participants (dental patients) will be randomly assigned to intervention or control group in a 1:1 allocation ratio to receive either a structured behavioural support intervention involving face to face counselling or self-help material plus usual care. Each participant will be in the study for approximately 6 months and the overall study is expected to run for 12 months; (3) An embedded qualitative process evaluation. All trial participants will be followed up at 3 and 6 months to assess self-reported ST use. Outcome measures will include: rates of eligibility, recruitment and retention, randomisation group cross-over rates, the provision of data on ST use behaviour, fidelity to the intervention and qualitative assessment of acceptability and feasibility. DISCUSSION: Despite the high use of ST in Pakistan, users are offered negligible cessation support. The findings of this multi-centre, mixed-method feasibility study will inform the scope for a larger trial on ST cessation delivered through the existing dental health system.

Scaling up tobacco cessation within TB programmes: findings from a multi-country, mixed-methods implementation study.

BACKGROUND: Brief behavioural support can effectively help tuberculosis (TB) patients quit smoking and improve their outcomes. In collaboration with TB programmes in Bangladesh, Nepal and Pakistan, we evaluated the implementation and scale-up of cessation support using four strategies: (1) brief tobacco cessation intervention, (2) integration of tobacco cessation within routine training, (3) inclusion of tobacco indicators in routine records and (4) embedding research within TB programmes. METHODS: We used mixed methods of observation, interviews, questionnaires and routine data. We aimed to understand the extent and facilitators of vertical scale-up (institutionalization) within 59 health facility learning sites in Pakistan, 18 in Nepal and 15 in Bangladesh, and horizontal scale-up (increased coverage beyond learning sites). We observed training and surveyed all 169 TB health workers who were trained, in order to measure changes in their confidence in delivering cessation support. Routine TB data from the learning sites were analysed to assess intervention delivery and use of TB forms revised to report smoking status and cessation support provided. A purposive sample of TB health workers, managers and policy-makers were interviewed (Bangladesh n = 12; Nepal n = 13; Pakistan n = 19). Costs of scale-up were estimated using activity-based cost analysis. RESULTS: Routine data indicated that health workers in learning sites asked all TB patients about tobacco use and offered them cessation support. Qualitative data showed use of intervention materials, often with adaptation and partial implementation in busy clinics. Short (1-2 hours) training integrated within existing programmes increased mean confidence in delivering cessation support by 17% (95% CI: 14-20%). A focus on health system changes (reporting, training, supervision) facilitated vertical scale-up. Dissemination of materials beyond learning sites and changes to national reporting forms and training indicated a degree of horizontal scale-up. Embedding research within TB health systems was crucial for horizontal scale-up and required the dynamic use of tactics including alliance-building, engagement in the wider policy process, use of insider researchers and a deep understanding of health system actors and processes. CONCLUSIONS: System-level changes within TB programmes may facilitate routine delivery of cessation support to TB patients. These strategies are inexpensive, and with concerted efforts from TB programmes and donors, tobacco cessation can be institutionalized at scale.

Lung lymphatic thrombosis and dysfunction caused by cigarette smoke exposure precedes emphysema in mice.

The lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated the effect of CS on lung lymphatic function. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that all preceded the development of emphysema. Proteomic analysis demonstrated an increased abundance of coagulation factors in the lymph draining from the lungs of CS-exposed mice compared to control mice. In addition, in vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. These data show that CS exposure results in lung lymphatic dysfunction and a shift in thoracic lymph towards a prothrombic state. Furthermore, our data suggest that lymphatic dysfunction is due to effects of CS on the lymphatic vasculature that precede emphysema. These studies demonstrate a novel component of CS-induced lung injury that occurs early in the pathogenesis of emphysema.

Micro-RNA and Proteomic Profiles of Plasma-Derived Exosomes from Irradiated Mice Reveal Molecular Changes Preventing Apoptosis in Neonatal Cerebellum.

Cell communication via exosomes is capable of influencing cell fate in stress situations such as exposure to ionizing radiation. In vitro and in vivo studies have shown that exosomes might play a role in out-of-target radiation effects by carrying molecular signaling mediators of radiation damage, as well as opposite protective functions resulting in resistance to radiotherapy. However, a global understanding of exosomes and their radiation-induced regulation, especially within the context of an intact mammalian organism, has been lacking. In this in vivo study, we demonstrate that, compared to sham-irradiated (SI) mice, a distinct pattern of proteins and miRNAs is found packaged into circulating plasma exosomes after whole-body and partial-body irradiation (WBI and PBI) with 2 Gy X-rays. A high number of deregulated proteins (59% of WBI and 67% of PBI) was found in the exosomes of irradiated mice. In total, 57 and 13 miRNAs were deregulated in WBI and PBI groups, respectively, suggesting that the miRNA cargo is influenced by the tissue volume exposed to radiation. In addition, five miRNAs (miR-99b-3p, miR-200a-3p, miR-200a, miR-182-5p, miR-182) were commonly overexpressed in the exosomes from the WBI and PBI groups. In this study, particular emphasis was also given to the determination of the in vivo effect of exosome transfer by intracranial injection in the highly radiosensitive neonatal cerebellum at postnatal day 3. In accordance with a major overall anti-apoptotic function of the commonly deregulated miRNAs, here, we report that exosomes from the plasma of irradiated mice, especially in the case of WBI, prevent radiation-induced apoptosis, thus holding promise for exosome-based future therapeutic applications against radiation injury.