Immune microenvironment modulation following neoadjuvant therapy for oesophageal adenocarcinoma: a translational analysis of the DEBIOC clinical trial.

BACKGROUND: The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant oxaliplatin and capecitabine (Xelox) ± AZD8931 in oesophageal adenocarcinoma (OAC) but limited efficacy. We evaluated the impact of neoadjuvant Xelox ± AZD8931, a novel small-molecule inhibitor with equipotent activity against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2 and HER3, on biological pathways using a unique software-driven solution. PATIENTS AND METHODS: Transcriptomic profiles from 25 pre-treatment formalin-fixed paraffin-embedded OAC biopsies and 18 matched resection specimens, treated with Xelox + AZD8931 (n = 16) and Xelox alone (n = 9), were analysed using the Almac claraT total mRNA report analysing 92 gene signatures, 100 unique single-gene drug targets and 7337 single genes across 10 hallmarks of cancer. Gene-set enrichment analysis (GSEA) was utilised to investigate pathways governing pathological response. Tumour-infiltrating lymphocytes (TILs) were assessed digitally using the QuPath software. RESULTS: Hierarchical clustering identified three molecular subgroups classified by activation of innate immune signalling. The immune-high subgroup was associated with HER2 positivity, increased pathological response and a marked reduction in immune signalling and TILs following neoadjuvant therapy. The immune-low cluster was predominantly HER2/EGFR-negative, and EGFR positivity was associated with the immune-mixed subgroup. Treatment with neoadjuvant therapy induced common resistance mechanisms, such as angiogenesis and epithelial-mesenchymal transition signalling, and a reduction in DNA repair signatures. Addition of AZD8931 was associated with reduction of expression of EGFR, HER2 and AKT pathways and also promoted an immunosuppressive microenvironment. GSEA showed that patients with a pathological response to treatment had increased immune signalling, whereas non-responders to neoadjuvant therapy were enriched for nucleotide repair and cellular growth through the action of E2F transcription factors. CONCLUSION: OAC may be subdivided into three immune-related subgroups which undergo modulation in response to neoadjuvant therapy with marked suppression of the immune microenvironment in HER2-positive/immune-high tumours.

More isn't always better: antibiotic duration after surgical decortication in pleural empyema.

Background: While ample high-level evidence supports the limited use of antibiotics post-source control in intraabdominal infections, there is a paucity of available data in guiding antibiotic duration for intrathoracic infections. This study aims to analyze patient outcomes among those who have undergone surgical decortication for parapneumonic pleural empyema, comparing cases managed with infectious disease (ID) specialists against those without, and to identify predictive factors influencing antibiotic duration post-source control. We hypothesized that antibiotic duration would vary depending on the involvement of ID specialists. Methods: A retrospective chart review was completed on patients with parapneumonic pleural empyemas who underwent surgical decortication at a single tertiary center from January 2011 to March 2021. Differences in patient characteristics and outcomes for those whose antibiotics were managed by ID or not were compared with Wilcoxon two-sample tests and Fisher's exact tests. Linear regression was used to evaluate for significant factors predictive of antibiotic duration. Results: A total of 116 patients underwent surgical decortication for pleural empyema of parapneumonic etiology. ID specialists were involved with antibiotic management in 62 (53.4%) cases, while the remaining cases were not managed by ID. Demographics and patient comorbidities were similar between both groups. Growth of preoperative fluid cultures was higher in patients managed by ID (40.3% vs. 20.4%, P=0.03). Postoperatively, patients managed by ID had longer durations of antibiotics (28.7 vs. 20.9 days, P<0.001) and were more likely to be on IV antibiotics than patients not managed by ID (59.7% vs. 38.9%, P=0.04). However, postoperative outcomes were similar, including rates of disease recurrence, readmission, and 30-day mortality. Linear regression revealed length of antibiotics was significantly dependent on preoperative ventilator status [estimate: 16.346; 95% confidence interval (CI): 6.365-26.326; P=0.002], growth of preoperative pleural fluid cultures (estimate: 10.203; 95% CI: 2.502-17.904; P=0.01), and ID involvement (estimate: 8.097; 95% CI: 1.003-15.191; P=0.03). Conclusions: Antibiotic duration for pleural empyema managed with surgical decortication is significantly dependent on ID involvement, preoperative growth of cultures, and preoperative ventilator status. However, outcomes, including disease recurrence and 30-day mortality, were similar between patients regardless of ID involvement and longer length of antibiotics, raising the question of what the adequate duration of antibiotics is for patients who receive appropriate source control for pleural empyema. Further study with randomized control trials should be conducted to provide high-level evidence regarding length of antibiotics in this patient population.

Sublobar Resection of Non-Small-Cell Lung Cancer: Wedge Resection vs. Segmentectomy.

Lung cancer is the most common cause of cancer death. The mainstay treatment for non-small-cell lung cancer (NSCLC), particularly in the early stages, is surgical resection. Traditionally, lobectomy has been considered the gold-standard technique. Sublobar resection includes segmentectomy and wedge resection. Compared to lobectomy, these procedures have been viewed as a compromise procedure, reserved for those with poor cardiopulmonary function or who are poor surgical candidates for other reasons. However, with the advances in imaging and surgical techniques, the subject of sublobar resection as a curative treatment is being revisited. Many studies have now shown segmentectomy to be equivalent to lobectomy in patients with small (<2.0 cm), peripheral NSCLC. However, there is a mix of evidence when it comes to wedge resection and its suitability as a curative procedure. At this time, until more data can be found, segmentectomy should be considered before wedge resection for patients with early-stage NSCLC.

Emergent Esophagectomy in Patients with Esophageal Malignancy Is Associated with Higher Rates of Perioperative Complications but No Independent Impact on Short-Term Mortality.

Background: Data on perioperative outcomes of emergent versus elective resection in esophageal cancer patients requiring esophagectomy are lacking. We investigated whether emergent resection was associated with increased risks of morbidity and mortality. Methods: Data on patients with esophageal malignancy who underwent esophagectomy from 2005 to 2020 were retrospectively analyzed from the American College of Surgeons National Surgical Quality Improvement Program database. Thirty-day complication and mortality rates were compared between emergent esophagectomy (EE) and non-emergent esophagectomy. Logistic regression assessed factors associated with complications and mortality. Results: Of 10,067 patients with malignancy who underwent esophagectomy, 181 (1.8%) had EE, 64% had preoperative systemic inflammatory response syndrome, sepsis, or septic shock, and 44% had bleeding requiring transfusion. The EE group had higher American Society of Anesthesiologists (ASA) class and functional dependency. More transhiatal esophagectomies and diversions were performed in the EE group. After EE, the rates of 30-day mortality (6.1% vs. 2.8%), overall complications (65.2% vs. 44.2%), bleeding, pneumonia, prolonged intubation, and positive margin (17.7% vs. 7.4%) were higher, while that of anastomotic leak was similar. On adjusted logistic regression, older age, lower albumin, higher ASA class, and fragility were associated with increased complications and mortality. McKeown esophagectomy and esophageal diversion were associated with a higher risk of postoperative complications. EE was associated with 30-day postoperative complications (odds ratio, 2.39; 95% confidence interval, 1.66-3.43; p<0.0001). Conclusion: EE was associated with a more than 2-fold increase in complications compared to elective procedures, but no independent increase in short-term mortality. These findings may help guide data-driven critical decision-making for surgery in select cases of complicated esophageal malignancy.

Rotator cuff outcomes and mental health indices: Correlation or causation?

Background: Psychological factors such as catastrophizing, anxiety, and depression influence clinical outcomes in many conditions. Our purpose was to examine trends and associations between these and outcomes of rotator cuff surgery. Methods: 148 patients (76 W:72 M, 55.1 ± 8.2 years) with unilateral symptomatic rotator cuff syndrome were followed for 1 year after surgery. The Western Ontario Rotator Cuff Score (WORC), the Pain Catastrophizing Score (PCS), and the Hospital Anxiety and Depression Score (HADS) were administered. Evolution and associations of WORC, HADS and PCS scores were examined using uni- and multivariate analyzes. Results: At 1 year, PCS, HADS-A, and HADS-D scores negatively correlated with WORC score (R = -0.6, -0.61, -0.69). The strength of correlation was lower between baseline PCS, HADS-A, and HADS-D scores and 1-year WORC score (R = -0.38, -0.43, -0.42). Prior anxiety diagnosis was associated with higher HADS-A scores at 2- and 6- weeks post-op (p = 0.013, 0.011). 106 participants experienced an improving HADS-D over the year of follow-up. Worse pre-op pain, WORC, PCS, HADS-A, HADS-D, cardiovascular disease and current smoking were associated with non-improving HADS-D. Discussion: Patient-reported outcomes of rotator cuff surgery are associated with patient-reported anxiety, depression, and pain catastrophizing. In many, all outcome scores improved over time suggesting a two-way association between shoulder condition and psychological parameters. Level of evidence: II.

Chest vs. neck anastomotic leak post esophagectomy for malignancy: rate, predictors, and outcomes.

Background: Anastomotic leak is a major contributor to comorbidity and mortality following esophagectomy. We sought to assess rate and predictors of leak after esophagectomy and compare outcomes of chest versus neck anastomotic leaks. Methods: A retrospective review was performed utilizing National-Surgical-Quality-Improvement-Program data from 2016-2019 for patients undergoing esophagectomy for malignancy. Preoperative characteristics and postoperative outcomes were compared. Patients were classified into two groups: Ivor Lewis esophagectomy [ILE, chest leak (CL)] and transhiatal esophagectomy (THE)/McKeown esophagectomy [ME, neck leak (NL)]. Multivariable regression models were constructed to determine predictors of each type of leak and postoperative complications. Results: A total of 1,665 patients underwent esophagectomy with 14.1% reported post-operative leak, 61% of patients underwent ILE while 39% underwent THE or ME. Of patients who underwent ILE, 13.8% had CL with complications including significantly higher length of stay and mortality compared to patients without leak. Independent predictors of CL included: diabetes, hypertension, advanced disease stage, chronic steroid use, and operative time. Ninety-five patients (14.6%) who underwent either THE or ME had NL with similar complications. Diabetes, pre-operative white blood cell (WBC), and operative time were independent predictors for NL. On multivariable regression, CL was associated with greater odds of requiring intervention compared with NL. Conclusions: Post-esophagectomy CL and NL are associated with higher morbidity and mortality. Diabetes and operative time were independent predictors for both leaks while steroid use, hypertension, and advanced disease stage predicted CL. CL was associated with greater odds of needing an intervention, but contrary to conventional wisdom, was not associated with higher morbidity or mortality.

Holistic profiling of the venom from the Brazilian wandering spider Phoneutria nigriventer by combining high-throughput ion channel screens with venomics.

Introduction: Spider venoms are a unique source of bioactive peptides, many of which display remarkable biological stability and neuroactivity. Phoneutria nigriventer, often referred to as the Brazilian wandering spider, banana spider or "armed" spider, is endemic to South America and amongst the most dangerous venomous spiders in the world. There are 4,000 envenomation accidents with P. nigriventer each year in Brazil, which can lead to symptoms including priapism, hypertension, blurred vision, sweating, and vomiting. In addition to its clinical relevance, P. nigriventer venom contains peptides that provide therapeutic effects in a range of disease models. Methods: In this study, we explored the neuroactivity and molecular diversity of P. nigriventer venom using fractionation-guided high-throughput cellular assays coupled to proteomics and multi-pharmacology activity to broaden the knowledge about this venom and its therapeutic potential and provide a proof-of-concept for an investigative pipeline to study spider-venom derived neuroactive peptides. We coupled proteomics with ion channel assays using a neuroblastoma cell line to identify venom compounds that modulate the activity of voltage-gated sodium and calcium channels, as well as the nicotinic acetylcholine receptor. Results: Our data revealed that P. nigriventer venom is highly complex compared to other neurotoxin-rich venoms and contains potent modulators of voltage-gated ion channels which were classified into four families of neuroactive peptides based on their activity and structures. In addition to the reported P. nigriventer neuroactive peptides, we identified at least 27 novel cysteine-rich venom peptides for which their activity and molecular target remains to be determined. Discussion: Our findings provide a platform for studying the bioactivity of known and novel neuroactive components in the venom of P. nigriventer and other spiders and suggest that our discovery pipeline can be used to identify ion channel-targeting venom peptides with potential as pharmacological tools and to drug leads.

Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study.

OBJECTIVE: To estimate associations between covid-19 vaccination and long covid symptoms in adults with SARS-CoV-2 infection before vaccination. DESIGN: Observational cohort study. SETTING: Community dwelling population, UK. PARTICIPANTS: 28 356 participants in the Office for National Statistics COVID-19 Infection Survey aged 18-69 years who received at least one dose of an adenovirus vector or mRNA covid-19 vaccine after testing positive for SARS-CoV-2 infection. MAIN OUTCOME MEASURE: Presence of long covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021. RESULTS: Mean age of participants was 46 years, 55.6% (n=15 760) were women, and 88.7% (n=25 141) were of white ethnicity. Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (83.8% of participants). 6729 participants (23.7%) reported long covid symptoms of any severity at least once during follow-up. A first vaccine dose was associated with an initial 12.8% decrease (95% confidence interval -18.6% to -6.6%, P<0.001) in the odds of long covid, with subsequent data compatible with both increases and decreases in the trajectory (0.3% per week, 95% confidence interval -0.6% to 1.2% per week, P=0.51). A second dose was associated with an initial 8.8% decrease (95% confidence interval -14.1% to -3.1%, P=0.003) in the odds of long covid, with a subsequent decrease by 0.8% per week (-1.2% to -0.4% per week, P<0.001). Heterogeneity was not found in associations between vaccination and long covid by sociodemographic characteristics, health status, hospital admission with acute covid-19, vaccine type (adenovirus vector or mRNA), or duration from SARS-CoV-2 infection to vaccination. CONCLUSIONS: The likelihood of long covid symptoms was observed to decrease after covid-19 vaccination and evidence suggested sustained improvement after a second dose, at least over the median follow-up of 67 days. Vaccination may contribute to a reduction in the population health burden of long covid, although longer follow-up is needed.

Interstitial Granulomatous Drug Reaction to Ustekinumab.

Interstitial granulomatous drug reaction (IGDR) is a distinct inflammatory process that often presents as annular, violaceous plaques distributed on the extremities, proximal trunk, and intertriginous areas. The list of drugs implicated for inciting IGDR is growing, but most prominently includes ACE inhibitors, antihistamines, beta-blockers, antidepressants, and anticonvulsants. Ustekinumab is a human monoclonal antibody that targets inflammatory cytokines IL-12 and IL-23 and has been have shown to be effective in treating IGDR. However, we present a case that suggests ustekinumab can also act as an inciting agent for IGDR.

Disseminated protothecosis with central nervous system involvement in a dog in New Zealand.

CASE HISTORY: A 1-year-old Border Terrier presented with acute onset of neurological signs and neck pain. CLINICAL FINDINGS: Severe generalised ataxia, muscle tremors and cranial nerve deficits were noted. Multifocal brain lesions were suspected based on neurological examination. Computed tomography revealed an abdominal mass and cerebellar herniation through the foramen magnum. LABORATORY AND PATHOLOGICAL FINDINGS: Cytological and histopathological analysis of the abdominal mass revealed necrotising and granulomatous lymphadenitis with intralesional algal elements most consistent with Prototheca spp.. Culture of a sample from the mesenteric lymph node confirmed the presence of Prototheca spp. which was identified as P. bovis based on sequencing of a DNA fragment amplified by PCR. Following inadequate response to symptomatic therapy and poor prognosis, the dog was subjected to euthanasia. Histopathological evaluation of the central nervous system lesions, identified granulomatous meningitis and ventriculitis with the presence of intralesional algae. DIAGNOSIS: Disseminated protothecosis with granulomatous meningitis and ventriculitis caused by Prototheca bovis (formerly P. zopfii gen. 2). CLINICAL RELEVANCE: This is the first case report of disseminated protothecosis with central nervous system involvement in a dog in New Zealand.

Bochdalek Hernia With Gastric Necrosis Requiring Roux-en-Y Esophagojejunostomy.

Bochdalek hernias are the most common congenital diaphragmatic hernias and are usually diagnosed during childhood. They can present in adulthood and, in uncommon circumstances, result in gastric herniation with strangulation. We present a case of an adult Bochdalek hernia resulting in total gastric necrosis necessitating Roux-en-Y esophagojejunostomy in an otherwise healthy 39-year-old man. This case highlights the potential morbidity associated with unrepaired congenital diaphragmatic hernias and the need for appropriate referral.

Changes in paediatric respiratory infections at a UK teaching hospital 2016-2021; impact of the SARS-CoV-2 pandemic.

Objective To describe the impact of the SARS-CoV-2 pandemic on the incidence of paediatric viral respiratory tract infection in Oxfordshire, UK. Methods Data on paediatric Emergency Department (ED) attendances (0-15 years inclusive), respiratory virus testing, vital signs and mortality at Oxford University Hospitals were summarised using descriptive statistics. Results Between 1-March-2016 and 30-July-2021, 155,056 ED attendances occurred and 7,195 respiratory virus PCRs were performed. Detection of all pathogens was suppressed during the first national lockdown. Rhinovirus and adenovirus rates increased when schools reopened September-December 2020, then fell, before rising in March-May 2021. The usual winter RSV peak did not occur in 2020/21, with an inter-seasonal rise (32/1,000 attendances in 0-3 yr olds) in July 2021. Influenza remained suppressed throughout. A higher paediatric early warning score (PEWS) was seen for attendees with adenovirus during the pandemic compared to pre-pandemic (p = 0.04, Mann-Witney U test), no other differences in PEWS were seen. Conclusions SARS-CoV-2 caused major changes in the incidence of paediatric respiratory viral infection in Oxfordshire, with implications for clinical service demand, testing strategies, timing of palivizumab RSV prophylaxis, and highlighting the need to understand which public health interventions are most effective for preventing respiratory virus infections.

EPOS 4 Patients.

EPOS2020 is the 4th and most recent version of the European Position Paper on Rhinosinusitis and Nasal Polyps which was first published in 2005. It aims to provide the most up to date scientifically robust information on the topic published in the literature which has been critically analysed by an international group of clinicians drawn from all disciplines dealing with these problems together with patients. The guidelines offer evidence-based recommendations and care pathways for acute and chronic rhinosinusitis in both adults and children. Management of these diseases from the patients' perspective is an important part of EPOS2020. Not only is this included in the main document but, for the first time, we have produced a separate supplement dedicated to and in collaboration with patients, EPOS4Patients, which aims to provide information in an accessible format, to answer frequently asked questions about these diseases and their treatment options as well as including useful patient resources and websites. It has never been more important for patients to be actively involved in their care. Being well informed helps you to make the best decisions together with your doctor.

Epidemiology of Mycobacterium abscessus in England: an observational study.

BACKGROUND: Mycobacterium abscessus has emerged as a significant clinical concern following reports that it is readily transmissible in health-care settings between patients with cystic fibrosis. We linked routinely collected whole-genome sequencing and health-care usage data with the aim of investigating the extent to which such transmission explains acquisition in patients with and without cystic fibrosis in England. METHODS: In this retrospective observational study, we analysed consecutive M abscessus whole-genome sequencing data from England (beginning of February, 2015, to Nov 14, 2019) to identify genomically similar isolates. Linkage to a national health-care usage database was used to investigate possible contacts between patients. Multivariable regression analysis was done to investigate factors associated with acquisition of a genomically clustered strain (genomic distance <25 single nucleotide polymorphisms [SNPs]). FINDINGS: 2297 isolates from 906 patients underwent whole-genome sequencing as part of the routine Public Health England diagnostic service. Of 14 genomic clusters containing isolates from ten or more patients, all but one contained patients with cystic fibrosis and patients without cystic fibrosis. Patients with cystic fibrosis were equally likely to have clustered isolates (258 [60%] of 431 patients) as those without cystic fibrosis (322 [63%] of 513 patients; p=0·38). High-density phylogenetic clusters were randomly distributed over a wide geographical area. Most isolates with a closest genetic neighbour consistent with potential transmission had no identifiable relevant epidemiological contacts. Having a clustered isolate was independently associated with increasing age (adjusted odds ratio 1·14 per 10 years, 95% CI 1·04-1·26), but not time spent as an hospital inpatient or outpatient. We identified two sibling pairs with cystic fibrosis with genetically highly divergent isolates and one pair with closely related isolates, and 25 uninfected presumed household contacts with cystic fibrosis. INTERPRETATION: Previously identified widely disseminated dominant clones of M abscessus are not restricted to patients with cystic fibrosis and occur in other chronic respiratory diseases. Although our analysis showed a small number of cases where person-to-person transmission could not be excluded, it did not support this being a major mechanism for M abscessus dissemination at a national level in England. Overall, these data should reassure patients and clinicians that the risk of acquisition from other patients in health-care settings is relatively low and motivate future research efforts to focus on identifying routes of acquisition outside of the cystic fibrosis health-care-associated niche. FUNDING: The National Institute for Health Research, Health Data Research UK, The Wellcome Trust, The Medical Research Council, and Public Health England.

The impact of viraemia on inflammatory biomarkers and CD4+ cell subpopulations in HIV-infected children in sub-Saharan Africa.

OBJECTIVE: To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa. DESIGN: Longitudinal cohort study. METHODS: In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events. RESULTS: Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression. CONCLUSIONS: As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.

Transfusion management of severe anaemia in African children: a consensus algorithm.

The phase III Transfusion and Treatment of severe anaemia in African Children Trial (TRACT) found that conservative management of uncomplicated severe anaemia [haemoglobin (Hb) 40-60 g/l] was safe, and that transfusion volume (20 vs. 30 ml/kg whole blood equivalent) for children with severe anaemia (Hb <60 g/l) had strong but opposing effects on mortality, depending on fever status (>37·5°C). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all 3196 children receiving an initial transfusion there was no evidence that nutritional status, presence of shock, malaria parasite burden or sickle cell disease status influenced outcomes or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating three additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practice.

Characterization of Electronic Cigarette Warning Statements Portrayed in YouTube Videos.

INTRODUCTION: In 2018, the United States Food and Drug Administration (FDA) required that electronic cigarette (e-cigarette) manufacturers, packagers, importers, distributors, and retailers display an addictive or alternate warning statement on e-cigarette visual advertisements. Few studies have investigated the FDA-mandated and other warnings on social media. This study examined the prevalence and content of warning statements in e-cigarette-related YouTube videos. METHODS: In 2019, The Virginia Commonwealth University Center for the Study of Tobacco Products conducted bi-monthly (February-June) YouTube searches by relevance and view count to identify e-cigarette-related videos. Overall, 178 videos met the inclusion criteria. Staff coded each video for the presence of a visual/verbal warning statement, warning statement type (eg, FDA-mandated, addiction/tobacco, safety/toxic exposure, health effects), sponsorship, and tobacco product characteristics. A data extraction tool collected the video URL, title, upload date, and number of views, likes/dislikes, and comments. RESULTS: Only 5.1% of videos contained FDA-mandated and 21.9% contained non-mandated warnings. All videos with FDA-mandated and 46.2% of non-mandated warnings were represented visually. Only 13.1% of industry-sponsored videos uploaded after the mandate effective date had an FDA-mandated warning statement and videos with FDA-mandated and non-mandated (v. no) warnings had significantly fewer views, likes, dislikes, and comments. Among all non-mandated warnings, 31.3% featured an addiction/tobacco, 18.8% a safety/toxic exposure, and 37.5% a health effects warning. CONCLUSIONS: The prevalence of FDA-mandated warning statements in e-cigarette related YouTube videos was low. FDA enforcement of the warning statement mandate on YouTube could increase the public's understanding of the addictive nature of nicotine in e-cigarettes. IMPLICATIONS: The FDA has the authority to regulate the advertisement and promotion of e-cigarettes on the Internet. These data can inform future FDA requirements related to the language content and visual representation of addiction/tobacco, safety/exposure, and health effects warning statements that appear in YouTube videos and other visual social media popular among young people. Such data would help consumers make informed decisions about purchasing e-cigarette products, using e-cigarettes, and avoiding unintentional harm related to e-cigarettes. In addition, these data may help social media platforms make decisions on whether they will prohibit advertisements that promote or facilitate the sale of tobacco products.

Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy.

BACKGROUND: The impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear. METHODS: In the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications. RESULTS: In simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction. DISCUSSION: This study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures.