Human cytomegalovirus modulates mTORC1 to redirect mRNA translation within quiescently infected monocytes.

Human cytomegalovirus (HCMV) utilizes peripheral blood monocytes as a means to systemically disseminate throughout the host. Following viral entry, HCMV stimulates non-canonical Akt signaling leading to the activation of mTORC1 and the subsequent translation of select antiapoptotic proteins within infected monocytes. However, the full extent to which the HCMV-initiated Akt/mTORC1 signaling axis reshapes the monocyte translatome is unclear. We found HCMV entry alone was able to stimulate widescale changes to mRNA translation levels and that inhibition of mTOR, a component of mTORC1, dramatically attenuated HCMV-induced protein synthesis. Although monocytes treated with normal myeloid growth factors also exhibited increased levels of translation, mTOR inhibition had no effect, suggesting HCMV activation of mTOR stimulates the acquisition of a unique translatome within infected monocytes. Indeed, polyribosomal profiling of HCMV-infected monocytes identified distinct prosurvival transcripts that were preferentially loaded with ribosomes when compared to growth factor-treated cells. Sirtuin 1 (SIRT1), a deacetylase that exerts prosurvival effects through regulation of the PI3K/Akt pathway, was found to be highly enriched following HCMV infection in an mTOR-dependent manner. Importantly, SIRT1 inhibition led to the death of HCMV-infected monocytes while having minimal effect on uninfected cells. SIRT1 also supported a positive feedback loop to sustain Akt/mTORC1 signaling following viral entry. Taken together, HCMV profoundly reshapes mRNA translation in an mTOR-dependent manner to enhance the synthesis of select factors necessary for the survival of infected monocytes.IMPORTANCEHuman cytomegalovirus (HCMV) infection is a significant cause of morbidity and mortality among the immunonaïve and immunocompromised. Peripheral blood monocytes are a major cell type responsible for disseminating the virus from the initial site of infection. In order for monocytes to mediate viral spread within the host, HCMV must subvert the naturally short lifespan of these cells. In this study, we performed polysomal profiling analysis, which demonstrated HCMV to globally redirect mRNA translation toward the synthesis of cellular prosurvival factors within infected monocytes. Specifically, HCMV entry into monocytes induced the translation of cellular SIRT1 to generate an antiapoptotic state. Defining the precise mechanisms through which HCMV stimulates survival will provide insight into novel anti-HCMV drugs able to target infected monocytes.

Virology-the path forward.

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.

Virology under the Microscope-a Call for Rational Discourse.

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.

Abrocitinib efficacy and safety in moderate-to-severe atopic dermatitis by race, ethnicity, and Fitzpatrick skin type.

BACKGROUND: Response to abrocitinib treatment for moderate-to-severe atopic dermatitis (AD) has not been evaluated across racial and ethnic subpopulations. OBJECTIVE: To assess the efficacy and safety of abrocitinib on the basis of patient race, ethnicity, and Fitzpatrick skin type (FST). METHODS: Data were pooled post hoc from patients treated with abrocitinib 200 mg, 100 mg, or placebo in 3 monotherapy trials (NCT02780167, NCT03349060, and NCT03575871). Race and ethnicity were self-reported; FST was determined by study investigators. Evaluations through Week 12 include the following: (1) Investigator's Global Assessment of clear or almost-clear skin; (2) greater than or equal to 75% improvement in Eczema Area and Severity Index or SCORing AD; (3) a greater-than-or-equal-to 4-point improvement in Peak Pruritus Numerical Rating Scale score; (4) least squares mean changes in Dermatology Life Quality Index and Patient-Oriented Eczema Measure scores; and (5) treatment-emergent adverse events. RESULTS: The sample comprised 628 White, 204 Asian, and 83 Black patients; 37 were Hispanic or Latino; 624 had FST I to III and 320 had FST IV to VI. Treatment with either abrocitinib dose was associated with greater proportions of patients achieving Investigator's Global Assessment of clear or almost-clear skin, ≥ 75% improvement in Eczema Area and Severity Index, ≥ 75% improvement in SCORing AD, and a ≥ 4-point improvement in Peak Pruritus Numerical Rating Scale, or greater score changes from baseline in Dermatology Life Quality Index and Patient-Oriented Eczema Measure vs placebo regardless of race, ethnicity, or FST. Dose-response was most prominent in White patients. In Black patients, the effects of the 2 doses were similar. Treatment-emergent adverse events were more common in White and Black than in Asian patients. CONCLUSION: Abrocitinib was more efficacious than placebo across the racial and ethnic groups and ranges of phototypes analyzed. Studies with increased representation of populations of color are warranted to elucidate potential variations in response across diverse populations. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02780167 (phase 2b), NCT03349060 (phase 3 MONO-1), and NCT03575871 (phase 3 MONO-2).

Regional and Country Prevalence Estimates of Unsafe Sex Among Adolescents in 68 Low-Income and Middle-Income Countries.

Prioritizing adolescent health is a public health priority to achieve the sustainable development goals, including reducing the risk of unsafe sex. Data on unsafe sex have remained scarce among adolescents in low-and middle-income countries (LMICs). To estimate the prevalence of unsafe sex in LMICs, we conducted secondary data analysis on the Global School-based Student Health Surveys among 244,863 students aged 13-17 years from 68 countries across five World Health Organization regions. The overall prevalence of ever had sex was 16.2%. The highest to lowest regional prevalence estimation of ever had sex was 30.5% (28.9-32.1) in the Americas, 28.6% (26.8-30.4) in Africa, 10.9% (9.2-12.6) in the Eastern Mediterranean, 9.6% (8.8-10.5) in South-East Asia, and 8.0% (6.8-9.1) in the Western Pacific. The highest prevalence of sexual intercourse before age 14 and practicing sexual intercourse without condom use were 36.5% (34.5-38.5) and 32.2% (30.1-34.3) in Africa, respectively. Findings suggest that current interventions are inadequate in promoting the uptake of safe sexual behaviors and an urgent intervention is needed.

Abrocitinib Provides Rapid and Sustained Improvement in Skin Pain and Is Associated with Improved Quality of Life Outcomes in Adult and Adolescent Patients with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Skin pain in atopic dermatitis (AD) increases with disease severity and is associated with substantial quality of life (QoL) burden. OBJECTIVES: The aim of the study was to evaluate abrocitinib efficacy on skin pain and QoL in adults and adolescents with moderate-to-severe AD. METHODS: This post hoc analysis included data with abrocitinib administered as monotherapy (pooled phase 2b [NCT02780167] and phase 3 JADE MONO-1 [NCT03349060] and JADE MONO-2 [NCT03575871]) or in combination with topical therapy (phase 3 JADE COMPARE [NCT03720470] and JADE TEEN [NCT03796676]). Patients received oral, once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 or 16 weeks (JADE COMPARE). Skin pain was rated using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) skin pain Numerical Rating Scale (NRS) item ("How painful was your skin over the past 24 h?") on a scale from 0 (not painful) to 10 (extremely painful). Itch (Peak Pruritus NRS) and QoL (Dermatology Life Quality Index or Children's Dermatology Life Quality Index) were assessed. Least squares mean (LSM) change from baseline was analyzed using mixed-effects repeated measures modeling. RESULTS: A total of 1,822 patients (monotherapy pool, n = 942; JADE COMPARE, n = 595; and JADE TEEN, n = 285) were analyzed. LSM change from baseline in PSAAD skin pain score was significantly greater with abrocitinib versus placebo from week 2 through week 12 or 16 across all 3 study populations and occurred in a dose-dependent manner. A greater proportion of patients achieved a ≥4-point improvement from baseline in PSAAD skin pain score with abrocitinib (200 mg and 100 mg) versus placebo in the monotherapy pool (56% and 38% vs. 12%; week 12), JADE COMPARE (72% and 52% vs. 26%; week 16), and JADE TEEN (51% and 60% vs. 31%; week 12). Additionally, a greater proportion of patients achieved a stringent threshold of skin pain improvement (PSAAD skin pain score <2) with abrocitinib versus placebo. Adults and adolescents who achieved a ≥4-point improvement in skin pain reported greater QoL improvement than those who did not achieve a ≥4-point improvement. A positive correlation (≥0.3) was observed between skin pain and QoL and separately between skin pain and itch across the 3 study populations. CONCLUSION: Abrocitinib as monotherapy or in combination with topical therapy improved skin pain and was associated with improved QoL in both adults and adolescents with moderate-to-severe AD across all evaluated studies.

Systematic review and meta-analysis of text messaging interventions to support tobacco cessation.

OBJECTIVE: To review randomised controlled trials (RCTs) investigating the effectiveness of text message-based interventions for smoking cessation, including the effects of dose (number of text messages) and concomitant use of behavioural or pharmacological interventions. DATA SOURCES: We searched seven databases (PubMed, CINAHL, PsycINFO, Scopus, EMBASE, Cochrane Library and Web of Science), Google Scholar and the reference lists of relevant publications for RCTs. Eligible studies included participants aged ≥15 years who smoked tobacco at enrolment. STUDY SELECTION: One reviewer screened titles and abstracts and two reviewers independently screened full texts of articles. DATA EXTRACTION: One of three reviewers independently extracted data on study and intervention characteristics and smoking abstinence rates using Qualtrics software. DATA SYNTHESIS: 30 of the 40 included studies reported higher rates of smoking cessation among those receiving text messaging interventions compared with comparators, but only 10 were statistically significant. A meta-analysis of seven RCTs found that participants receiving text messages were significantly more likely to quit smoking compared with participants in no/minimal intervention or 'usual care' conditions (risk ratio 1.87, 95% CI 1.52 to 2.29, p <0.001). Three trials found no benefit from a higher dose of text messages on smoking cessation. Two trials that tested the added benefit of text messaging to pharmacotherapy reported outcomes in favour of adding text messaging. CONCLUSIONS: Findings suggest that text messaging-based interventions are effective at promoting smoking cessation. Further research is required to establish if any additional benefit is gained from an increased number of text messages or concurrent pharmacotherapy or behavioural counselling.

A systematic review of second-hand smoking mass media campaigns (2002-2022).

BACKGROUND: Second-hand smoking (SHS) increases the risk of chronic disease in adults and poses a serious health threat to children. Mass media campaigns are instrumental in raising awareness and reducing SHS exposure. There is a need to identify recent SHS mass media campaigns and assess their sustainability in terms of knowledge, attitudes, and behavioural changes. This systematic review summarises the characteristics and outcomes of mass media campaigns on SHS prevention. METHODS: PubMed, Embase, Web of Science, and grey literature were searched in November 2022 for SHS campaigns implemented between 2016 and 2022. The eligibility criteria included campaigns on the dangers or effects of SHS with any target group, dissemination medium, study design, or language. The database search identified 1,413 peer-reviewed titles, of which 82 full-texts were screened, with 14 meeting the eligibility criteria. The grey literature search identified 9,807 sources, of which 61 were included. We extracted data on the campaign characteristics, metrics, and smoking-related outcomes. The JBI critical appraisal tool was used to assess the risk of bias of the included studies. RESULTS: We found 73 SHS campaigns conducted between 2002 and 2022, across 50 countries. The campaigns reached 378 million people. The reported recall rates range from 8 to 76%. Of the 11 studies that reported smoking-related outcomes, 10 reported increased knowledge in understanding SHS risks (73-85%), five reported an increased prevalence of smoke-free homes, and two reported an increase in number of participants persuading others to quit smoking. Two studies reported a decrease in overall smoking, whereas three studies observed a reduction in smoking in the presence of children. CONCLUSION: The available data provide some support for the effectiveness of SHS campaigns in reducing smoking behaviours in homes and around children. However, the certainty of evidence was low due to the lack of a control group and the substantial heterogeneity in the outcomes assessed. Future campaigns need comprehensive evaluation and reporting to reduce publication bias.

The underbelly of E-cigarette advertising: regulating online markets on social media platforms.

Australia prohibits the sale of nicotine-vaping products unless prescribed by medical practitioners. Significant policy reforms were announced on the 28th of November 2023 including a ban on single-use disposable vapes with and without nicotine, and the removal of the personal importation scheme. Despite stringent regulations, loopholes exist such that e-cigarette vendors are getting around it, and online markets provide a route to do so. We discuss strategies used by vendors to covertly market e-cigarettes online through social media. In this perspective, we highlight three proposed policies to strengthen social media regulations that may be feasible to implement. Our proposed strategies to regulate e-cigarette product listings on social media involve implementing robust age verification measures, enhancing the system for flagging and reporting prohibited content, and developing a more effective system to identify and flag content related to e-cigarettes.

Motivations to Change Smoking Behaviors Between 2007 and 2019 in Australia: A Repeated Cross-sectional Study.

INTRODUCTION: In 2010, Australian tobacco excise (administered federally) increased by 25%, and by 12.5% annually from 2013 to 2020, with additional increases on roll-your-own (RYO) tobacco between 2017 and 2020. We estimated past year changes in smoking behavior among Australian adults who smoked (daily and non-daily) in the past year, and the association between consumer characteristics and stated motivations to change/attempt to change smoking behavior between 2007 and 2019. METHODS: Logistic regression analysis of combined data from national representative triennial cross-sectional surveys in Australia (N = 22 977). RESULTS: The main motivation cited for changing smoking behavior switched from health-related from 2007 to 2010 to cost-related from 2013 to 2019. Among those who quit between one and 12 months ago, living in a lower socioeconomic area (odds ratio (OR) = 1.61, 95% CI = 1.18% to -2.18%), was associated with reporting the cost of smoking motivated them to quit. Among those who reduced their smoking, smoking daily and >20 cigarettes/day vs. non-daily smoking (OR = 2.11, 95% CI = 1.60% to 2.78%), having high/very high psychological distress (OR = 1.33, 95% CI = 1.12% to 1.59%), and alcohol consumption (ORdaily drinking = 1.38, 95% CI = 1.05% to 1.81%) was associated with cost as a motivation. Exclusive (OR = 0.65, 95% CI = 0.53% to 0.80%) and non-exclusive (OR = 0.77, 95% CI = 0.65% to 0.91%) RYO use was associated with being less likely to report the cost of tobacco as motivation for cutting down. CONCLUSIONS: The cost of smoking became the most cited motivator to change smoking behavior (eg, quitting and cutting down), particularly for those who lived in low socioeconomic areas, smoked more cigarettes per day, drank alcohol, and had high/very high psychological distress. IMPLICATIONS: A change in the main federal tobacco control intervention implemented in Australia from mass-media campaigns to tobacco tax increases has likely led to cost, rather than health, being the main motivation cited for changing smoking behavior in Australia since 2013. Further monitoring is needed to ensure the harmonization in tax rates for RYO and factory-made cigarettes has effectively reduced the price difference between these products because the lower cost of RYO may have reduced the effectiveness of tax increases as a motivator to change smoking behavior.

Impact of Concomitant Corticosteroids on Tofacitinib Induction Efficacy and Infection Rates in Ulcerative Colitis.

BACKGROUND: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. AIM: To report efficacy and infection rates in patients receiving tofacitinib induction treatment, by baseline corticosteroid status. METHODS: We evaluated efficacy and safety data from OCTAVE Induction 1&2 in patients with moderately-to-severely active ulcerative colitis who received tofacitinib 10 mg twice daily or placebo for 8 weeks, based on induction baseline oral corticosteroid use (Corticosteroid-Yes/No) and dose (< 20/ ≥ 20 mg/day). Infections of interest included serious infections, herpes zoster (HZ), and adjudicated opportunistic infections (OIs). RESULTS: At OCTAVE Induction 1&2 baseline, 478/1092 (43.8%) patients were receiving corticosteroids. Tofacitinib demonstrated significant induction efficacy versus placebo for both Corticosteroid-Yes and Corticosteroid-No. With adjustment for prior tumor necrosis factor inhibitor and immunosuppressant failure, there were no statistically significant differences in remission and clinical response rates for Corticosteroid-Yes versus Corticosteroid-No. Among tofacitinib-treated patients, HZ and OIs occurred more frequently in Corticosteroid-Yes versus Corticosteroid-No, regardless of dose (< 20 mg vs. ≥ 20 mg). Infection incidence rates (regardless of severity/seriousness) during tofacitinib induction were generally similar regardless of baseline corticosteroid use. The proportion of tofacitinib-treated patients with HZ was 0.2% for Corticosteroid-No versus 1.1% for Corticosteroid-Yes < 20 mg and 1.0% for Corticosteroid-Yes ≥ 20 mg. Two out of three patients had HZ OIs. CONCLUSIONS: Tofacitinib induction efficacy (clinical response and remission) was similar in baseline corticosteroid subgroups. Infections of interest were rare; HZ and OIs occurred more frequently among those receiving tofacitinib and corticosteroids versus those receiving tofacitinib without corticosteroids. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov (NCT01465763[21/10/2011]; NCT01458951[21/10/2011]).

Low-solute hyponatremia in a kidney transplant recipient.

BACKGROUND AND AIMS: Electrolyte and acid-base disturbances are common in kidney transplant recipients, but there are few reports of low-solute hyponatremia or beer potomania in this population. We report herein a case of low-solute hyponatremia in a kidney transplant recipient with impaired graft function, highlighting key issues in diagnosis and management of low-solute hyponatremia, as well as exploring the pathophysiology of hyponatremia after kidney transplantation. CASE PRESENTATION: A 51-year-old man who had received a cadaveric renal transplant 18 years before presented with symptomatic hyponatremia and seizure. Workup for an underlying intracranial pathology was negative, and subsequent biochemical workup suggested low-solute hyponatremia with potomania, arising from dietary modifications taken by the patient while self-isolating during the COVID-19 pandemic. Correction of hyponatremia was successful with conservative management with close monitoring. CONCLUSION: This case illustrates key points in the diagnosis and management of low-solute hyponatremia and highlights the pathophysiology of hyponatremia after kidney transplantation.

Tobacco purchasing in Australia during regular tax increases: findings from the International Tobacco Control Policy Evaluation Project.

OBJECTIVE: We examined Australian tobacco purchasing trends, the average self-reported price paid within each purchase type and the association between type of tobacco product purchased and participant characteristics, including quit intentions, between 2007 and 2020. METHODS: We analysed data collected from adults who smoked factory-made and/or roll-your-own (RYO) cigarettes in nine waves (2007-2020) of the International Tobacco Control Policy Evaluation Project Australia Survey (nsample=5452, nobservations=11 534). The main outcome measures were type of tobacco products purchased: RYO, carton, pack or pouch size and brand segment. Logistic regression, fit using generalised estimating equations, was estimated the association between the outcome and participant characteristics. RESULTS: The reported price-minimising purchasing patterns increased from 2007 to 2020: any RYO (23.8-43.9%), large-sized pack (2007: 24.0% to 2016: 34.3%); shifting from large-sized to small-sized packs (2020: 37.7%), and economy brand (2007: 37.2% to 2020: 59.3%); shifting from large (2007: 55.8%) to small economy packs (2014: 15.3% to 2020: 48.1%). Individuals with a lower income, a higher nicotine dependence level and no quit intention were more likely to purchase RYO and large-sized packs. CONCLUSION: RYO, large-sized packs and products with a low upfront cost (eg, small RYO pouches and small-sized economy brand packs) may appeal to people on low incomes. Australia's diverse tobacco pack and pouch sizes allow the tobacco industry to influence tobacco purchases. Standardising pack and pouch sizes may reduce some price-related marketing and especially benefit people who have a low income, are highly addicted and have no quit intention.

Vaping on TikTok: a systematic thematic analysis.

INTRODUCTION: The rising popularity of TikTok among adolescents may influence their awareness and perceptions of e-cigarette use via user-generated content. This study aimed to examine how e-cigarette/vaping-related videos are portrayed on TikTok. METHODS: The nine most viewed hashtag based keywords were used to identify popular e-cigarette/vaping-related videos on TikTok (n=1000) from its inception (earliest upload date: January 2019) to November 2020. Five researchers independently coded the number of views, likes, user category and theme. RESULTS: A final sample of 808 e-cigarette/vaping-related videos that met study criteria were included. Collectively, these videos were viewed over 1.5 billion times, with a median view count of 1 000 000 (range 112 900-78 600 000) and a median 'likes' count of 143 000 (range 10 000-1 000 000). A majority of the videos portrayed e-cigarette use positively (63%; collectively viewed over 1.1 billion times). Neutral depictions of e-cigarette use were viewed a total of 290 million times (24%) and negative depictions of e-cigarettes were viewed a total of 193 million times (13%). The video themes included (not mutually exclusively): 'comedy and joke' (52%; total of 618 million views), 'lifestyle and acceptability' (35%; 459 million), 'marketing' (29%; 392 million), 'vaping tricks' (20%; 487 million), 'nicotine and addiction' (20%; 194 million), 'creativity' (16%; 322 million) and 'warning' (11%; 131 million). CONCLUSION: Our findings illustrated that positively framed e-cigarette and vaping-related postings available without age restrictions on TikTok-a rising video-sharing platform that is popular among adolescents-have been viewed many times. Effective age restrictions are needed to reduce adolescents' potential exposure to videos that portray vaping positively.

Efficacy of smokeless tobacco for smoking cessation: a systematic review and meta-analysis.

OBJECTIVE: Smoking remains prevalent in many countries despite rigorous tobacco control strategies. The use of Swedish snus, a type of low-nitrosamine smokeless tobacco, has been promoted as a tobacco harm reduction strategy. DATA SOURCES AND STUDY SELECTION: Three databases were searched for studies that assessed the effectiveness of snus in promoting smoking abstinence. A total of 28 studies were reviewed (5 randomised controlled trials (RCTs), 7 longitudinal and 16 cross-sectional studies). DATA EXTRACTION: Separate meta-analyses were conducted by study type, pooling effect estimates where outcome measures and design were sufficiently comparable. Study details and quality assessment (Risk of Bias 2 for RCTs, Newcastle-Ottawa Scale for observational studies) are provided for each study. DATA SYNTHESIS: While the meta-analysis of RCTs did not show a significant association between snus use and smoking cessation (risk ratio (RR)=1.33, 95% CI 0.71 to 2.47 and RR=0.62, 95% CI 0.27 to 1.41), the results of the meta-analysis of longitudinal cohort studies (RR=1.38, 95% CI 1.05 to 1.82, p=0.022) and cross-sectional studies (OR=1.87, 95% CI 1.29 to 2.72, p=0.001) indicated that use of snus was associated with an increased likelihood of quitting or having quit smoking. There was significant heterogeneity in the cross-sectional studies, and leave-one-out analysis indicated that the longitudinal cohort results were driven by one study. Most studies examined were subject to an elevated risk of bias. CONCLUSION: There is weak evidence for the use of snus for smoking cessation. Better RCTs and longitudinal studies are needed; meanwhile, existing cessation aids may be better placed than snus to promote abstinence.

Predicting the long-term effects of electronic cigarette use on population health: a systematic review of modelling studies.

OBJECTIVE: To systematically review and synthesise the findings of modelling studies on the population impacts of e-cigarette use and to identify potential gaps requiring future investigation. DATA SOURCE AND STUDY SELECTION: Four databases were searched for modelling studies of e-cigarette use on population health published between 2010 and 2023. A total of 32 studies were included. DATA EXTRACTION: Data on study characteristics, model attributes and estimates of population impacts including health outcomes and smoking prevalence were extracted from each article. The findings were synthesised narratively. DATA SYNTHESIS: The introduction of e-cigarettes was predicted to lead to decreased smoking-related mortality, increased quality-adjusted life-years and reduced health system costs in 29 studies. Seventeen studies predicted a lower prevalence of cigarette smoking. Models that predicted negative population impacts assumed very high e-cigarette initiation rates among non-smokers and that e-cigarette use would discourage smoking cessation by a large margin. The majority of the studies were based on US population data and few studies included factors other than smoking status, such as jurisdictional tobacco control policies or social influence. CONCLUSIONS: A population increase in e-cigarette use may result in lower smoking prevalence and reduced burden of disease in the long run, especially if their use can be restricted to assisting smoking cessation. Given the assumption-dependent nature of modelling outcomes, future modelling studies should consider incorporating different policy options in their projection exercises, using shorter time horizons and expanding their modelling to low-income and middle-income countries where smoking rates remain relatively high.

A detailed look at the European Medicines Agency's recommendations for use of Janus kinase inhibitors in patients with atopic dermatitis.

BACKGROUND: Oral Janus kinase inhibitors (JAKi) have been approved for the treatment of several chronic inflammatory conditions, including rheumatoid arthritis (RA) and atopic dermatitis (AD). Prompted by new evidence, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recently reassessed the benefit-risk balance of oral JAKi. The PRAC recommended that oral JAKi should be used only if no suitable alternatives are available in patients ≥65 years of age, or who have a history of atherosclerotic cardiovascular (CV) disease, other CV risk factors (e.g. history of long-term smoking) or have malignancy risk factors, and used with caution in patients at risk of pulmonary embolism or deep vein thrombosis. The European Commission's final decision was issued in March 2023. OBJECTIVES: Our goal was to highlight the PRAC recommendations, especially in the context of oral JAKi use in AD. METHODS: Authors summarized the PRAC recommendations, the new clinical evidence on oral JAKi safety and key differences between patients with RA and AD. RESULTS: Risk of developing adverse events of special interest (e.g. cardiovascular events, malignancy) is higher in patients with RA than in patients with AD, because of the higher prevalence of the underlying risk factors. CONCLUSIONS: The benefit-risk profile of JAKi approved for AD remains favourable, including use as first-line systemic therapy for patients with AD <65 years of age and without CV or malignancy risk factors.

Abrocitinib efficacy and safety in patients with moderate-to-severe atopic dermatitis: Results from phase 3 studies, including the long-term extension JADE EXTEND study.

BACKGROUND: Abrocitinib improved signs and symptoms of moderate-to-severe atopic dermatitis (AD) at 12 or 16 weeks in phase 3 studies with a manageable safety profile. Further understanding of the abrocitinib long-term efficacy and safety profile is important for its appropriate use in treating chronic AD. OBJECTIVE: To evaluate the abrocitinib efficacy up to 48 weeks and long-term safety in patients with moderate-to-severe AD. METHODS: JADE EXTEND (NCT03422822) is an ongoing, phase 3, long-term extension study that enrolled patients from previous abrocitinib AD trials. This analysis focusses on patients from the phase 3 JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871) and JADE COMPARE (NCT03720470) studies who completed the full treatment period of placebo or abrocitinib (200 mg or 100 mg once daily) and subsequently entered JADE EXTEND. Efficacy endpoints included the proportion of patients achieving skin clearance (Investigator's Global Assessment [IGA] 0/1 [clear/almost clear]; ≥75% improvement in Eczema Area and Severity Index [EASI-75]) and itch response (Peak Pruritus Numerical Rating Scale [PP-NRS] severity ≥4-point improvement). Safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs and TEAEs leading to discontinuation. Data cut-off: April 22, 2020. RESULTS: As of the data cut-off, ~70% and ~45% of patients received abrocitinib for ≥36 and ≥48 weeks, respectively. Nasopharyngitis, atopic dermatitis, nausea and upper respiratory tract infections were the most frequent TEAEs. Serious TEAEs occurred in 7% and 5% and TEAEs leading to study discontinuation occurred in 9% and 7% of patients receiving abrocitinib 200 mg and 100 mg, respectively. Week 48 efficacy responses with abrocitinib 200 mg and 100 mg were as follows: IGA 0/1 52% and 39%; EASI-75 82% and 67%, and PP-NRS severity ≥4-point improvement 68% and 51%. CONCLUSIONS: In patients with moderate-to-severe AD, long-term abrocitinib treatment resulted in clinically meaningful skin and pruritus improvement. The long-term safety profile was manageable and consistent with previous reports.

HCMV-induced signaling through gB-EGFR engagement is required for viral trafficking and nuclear translocation in primary human monocytes.

Previous analysis of postentry events revealed that human cytomegalovirus (HCMV) displays a unique, extended nuclear translocation pattern in monocytes. We determined that c-Src signaling through pentamer engagement of integrins is required upon HCMV entry to avoid sorting of the virus into late endosomes and subsequent degradation. To follow up on this previous study, we designed experiments to investigate how HCMV-induced signaling through the other major axis-the epidermal growth factor receptor (EGFR) kinase-regulates viral postentry events. Here we show that HCMV induces chronic and functional EGFR signaling that is distinct to the virus as compared to the natural EGFR ligand: EGF. This chronic EGFR kinase activity in infected monocytes is required for the proper subcellular localization of the viral particle during trafficking events, as well as for promoting translocation of viral DNA into the host nucleus. Our data indicate that HCMV glycoprotein B (gB) binds to EGFR at the monocyte surface, the virus and EGFR are internalized together, and gB remains bound to EGFR throughout viral postentry events until de-envelopment to promote the chronic EGFR kinase activity required for viral trafficking and nuclear translocation. These data highlight how initial EGFR signaling via viral binding is necessary for entry, but not sufficient to promote each viral trafficking event. HCMV appears to manipulate the EGFR kinase postentry, via gB-EGFR interaction, to be active at the critical points throughout the trafficking process that leads to nuclear translocation and productive infection of peripheral blood monocytes.