Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

Head and neck cancer incidence is rising but the sociodemographic profile is unchanging: a population epidemiological study (2001-2020).

Background: Increasing incidence of head and neck cancers (HNCs), driven by rising rates of oropharynx cancer (OPC), has been recorded around the world. This study examined trends in HNC and subsites (oral cavity, oropharynx, and larynx cancers) in Scotland focusing on assessing whether the sociodemographic profile has changed over the past 20 years. Methods: Scottish Cancer Registry data (2001-2020) including European Age Standardised Rates of HNC and subsites were analysed in multivariate Poisson regression by age, sex, area-based socioeconomic status, and year of diagnosis (with interaction tests). Results: Overall HNC and oral cavity cancer (OCC) incidence remained relatively stable. OPC incidence rates increased by 78%, while larynx cancer incidence declined by 27%. Over time, there were marginal shifts to a slightly older age profile for HNC (p = 0.001) and OCC (p = 0.001), but no changes in OPC (p = 0.86) and larynx cancer (p = 0.29). No shift in the sex profile of HNC was observed except for minor increases in female OCC rates (p = 0.001), and the socioeconomic distribution remained unchanged across all HNC subsites. Conclusions: There have been no significant changes in the sociodemographic profile of HNC in Scotland over the last 20 years, despite the changing trends in HNCs with dramatically increasing incidence rates in OPC and reducing larynx cancer. This information can be used to target or stratify HNC prevention and control.

Population-based cancer incidence and mortality rates and ratios among adults with intellectual disabilities in Scotland: a retrospective cohort study with record linkage.

: Objective : To provide contemporary data on cancer mortality rates within the context of incidence in the population with intellectual disabilities. : Methods : Scotland's 2011 Census was used to identify adults with intellectual disabilities and controls with records linked to the Scottish Cancer Registry and death certificate data (March 2011-December 2019). The control cohort without intellectual disabilities and/or autism were used for indirect standardisation and calculation of crude incident rates/crude mortality rates, and age-sex standardised incident rate ratios/standardised mortality ratios (SIR/SMR), with 95% CIs. : Results : Adults with intellectual disabilities were most likely diagnosed cancers of digestive, specifically colorectal (14.2%), lung (9.3%), breast (female 22.9%), body of the uterus (female 9.3%) and male genital organs (male 17.6%). Higher incident cancers included metastatic cancer of unknown primary origin (female SIR=1.70, male SIR=2.08), body of uterus (female SIR=1.63), ovarian (female SIR=1.59), kidney (female SIR=1.85) and testicular (male SIR=2.49). SMRs were higher, regardless of a higher, similar or lower incidence (female SMR=1.34, male SMR=1.07). Excess mortality risk was found for colorectal (total SMR=1.54, male SMR=1.59), kidney (total SMR=2.01 u, female SMR=2.85 u), female genital organs (SMR=2.34 (ovarian SMR=2.86 u, body of uterus SMR=2.11), breast (female SMR=1.58) and metastatic cancer of unknown primary origin (female SMR=2.50 u, male SMR=2.84). : Conclusions : Adults with intellectual disabilities were more likely to die of cancer than the general population. Reasons for this may include later presentation/diagnosis (so poorer outcomes), poorer treatment/compliance or both. Accessible public health approaches are important for people with intellectual disabilities, and healthcare professionals need to be aware of the different cancer experiences faced by this population.

Trends and socioeconomic inequalities in the dental attendance of adult smokers in Scotland from 2009 to 2019, a repeated cross-sectional study.

BACKGROUND: Smoking continues to be the single largest cause of preventable disease and death and a major contributor to health inequalities. Dental professionals are well placed to offer behavioural support in combination with pharmacotherapy to increase smoking cessation rates across the population. We aimed to assess the trends and socioeconomic inequalities in the dental attendance of adult smokers in Scotland from 2009 to 2019 and examine the potential population reach of dental settings for smoking cessation interventions. METHODS: A secondary analysis was conducted of combined Scottish Health Surveys (SHeS) from 2009/11, 2013/15 and 2017/19. 'Recent' dental attendance (within the past two years) was the focus and descriptive analysis examined attendance of self-reported smokers compared to non-smokers and stratified by the area-based Scottish Index of Multiple Deprivation (SIMD) and individual socioeconomic measures (income, education, and occupation). Generalised linear models were used to model recent attendance in non-smokers relative to smokers adjusted by the socioeconomic measures, for each of the survey cohorts separately. Absolute differences and risk ratios were calculated with 95% Confidence Intervals (CI). RESULTS: Recent dental attendance was generally high and increased in both smokers (70-76%) and non-smokers (84-87%) from 2009/11 to 2017/19 and increased across all SIMD groups. After adjustment for sociodemographic variables, the adjusted Risk Difference (aRD) for recent attendance between non-smokers and smokers was 8.9% (95% CI 4.6%, 13.2%) by 2017/19. Within smokers, recent attendance was 7-9% lower in those living in the most deprived areas compared to those living in the least deprived areas over the three surveys. CONCLUSIONS: SHeS data from 2009 to 2019 demonstrated that a high and increasing proportion of smokers in the population attend the dentist, albeit slightly less frequently than non-smokers. There were large inequalities in the dental attendance of smokers, to a lesser extent in non-smokers, and these persisted over time. Dental settings provide a good potential opportunity to deliver population-level smoking cessation interventions, but smokers in the most deprived groups and older age groups may be harder to reach. Consideration should be given to ensure that these groups are given appropriate proportionate support to take up preventive interventions.

Revealing the profound influence of diapause on gene expression: Insights from the annual transcriptome of the copepod Calanus finmarchicus.

Annual rhythms are observed in living organisms with numerous ecological implications. In the zooplanktonic copepod Calanus finmarchicus, such rhythms are crucial regarding its phenology, body lipid accumulation, and global carbon storage. Climate change drives annual biological rhythms out of phase with the prevailing environmental conditions with yet unknown but potentially catastrophic consequences. However, the molecular dynamics underlying phenology are still poorly described. In a rhythmic analysis of C. finmarchicus annual gene expression, results reveal that more than 90% of the transcriptome shows significant annual rhythms, with abrupt and dramatic upheaval between the active and diapause life cycle states. This work explores the implication of the circadian clock in the annual timing, which may control epigenetic mechanisms to profoundly modulate gene expression in response to calendar time. Results also suggest an increased light sensitivity during diapause that would ensure the photoperiodic entrainment of the endogenous annual clock.

Development and external validation of a head and neck cancer risk prediction model.

BACKGROUND: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. METHODS: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. RESULTS: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64). CONCLUSION: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction.

Obesity and dental caries in childhood: trends in prevalence and socioeconomic inequalities-a multicohort population-wide data linkage study.

OBJECTIVES: To quantify levels of coexisting obesity and caries experience in children in Scotland, and any associated socioeconomic inequalities over the years 2011/2012-2017/2018. DESIGN: A multicohort population-wide data linkage study. SETTING: Local authority primary schools in Scotland. PATIENTS: 335 361 primary 1 (approximately 5 years old) schoolchildren in Scotland between 2011/2012 and 2017/2018. MAIN OUTCOME MEASURES: Prevalence and inequalities in coexisting caries and obesity. RESULTS: The prevalence of coexisting obesity and caries experience was 3.4% (n=11 494 of 335 361) and did not change over the 7 years. Children living in the 20% most deprived areas had more than sixfold greater odds of coexisting obesity and caries experience than children from the 20% least deprived areas (adjusted OR=6.63 (95% CI=6.16 to 7.14; p<0.001)). There was a large persistent socioeconomic gradient across the Scottish Index of Multiple Deprivation groups, with the Slope and Relative Indices of Inequality remaining unchanged over the 7 cohort years. CONCLUSIONS: Despite improvements in oral health in children in Scotland, the prevalence of coexisting obesity and caries experience has remained static, with large persistent inequalities. These conditions are likely to signal increased risk of chronic conditions including multimorbidity in adulthood and therefore early identification of children most at risk and timely intervention tackling common risk factors should be developed and evaluated.

Latin American Consensus on the Treatment of Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is well known as a serious health problem worldwide, especially in low-income countries or those with limited resources, such as most countries in Latin America. International guidelines cannot always be applied to a population from a large region with specific conditions. This study established a Latin American guideline for care of patients with head and neck cancer and presented evidence of HNSCC management considering availability and oncologic benefit. A panel composed of 41 head and neck cancer experts systematically worked according to a modified Delphi process on (1) document compilation of evidence-based answers to different questions contextualized by resource availability and oncologic benefit regarding Latin America (region of limited resources and/or without access to all necessary health care system infrastructure), (2) revision of the answers and the classification of levels of evidence and degrees of recommendations of all recommendations, (3) validation of the consensus through two rounds of online surveys, and (4) manuscript composition. The consensus consists of 12 sections: Head and neck cancer staging, Histopathologic evaluation of head and neck cancer, Head and neck surgery-oral cavity, Clinical oncology-oral cavity, Head and neck surgery-oropharynx, Clinical oncology-oropharynx, Head and neck surgery-larynx, Head and neck surgery-larynx/hypopharynx, Clinical oncology-larynx/hypopharynx, Clinical oncology-recurrent and metastatic head and neck cancer, Head and neck surgery-reconstruction and rehabilitation, and Radiation therapy. The present consensus established 48 recommendations on HNSCC patient care considering the availability of resources and focusing on oncologic benefit. These recommendations could also be used to formulate strategies in other regions like Latin America countries.

Expression of the MSPDBL2 antigen in a discrete subset of Plasmodium falciparum schizonts is regulated by GDV1 but may not be linked to sexual commitment.

The Plasmodium falciparum merozoite surface protein MSPDBL2 is a polymorphic antigen targeted by acquired immune responses, and normally expressed in only a minority of mature schizonts. The potential relationship of MSPDBL2 to sexual commitment is examined, as variable mspdbl2 transcript levels and proportions of MSPDBL2-positive mature schizonts in clinical isolates have previously correlated with levels of many sexual stage parasite gene transcripts, although not with the master regulator ap2-g. It is demonstrated that conditional overexpression of the gametocyte development protein GDV1, which promotes sexual commitment, also substantially increases the proportion of MSPDBL2-positive schizonts in culture. Conversely, truncation of the gdv1 gene is shown to prevent any expression of MSPDBL2. However, across diverse P. falciparum cultured lines, the variable proportions of MSPDBL2 positivity in schizonts do not correlate significantly with variable gametocyte conversion rates, indicating it is not involved in sexual commitment. Confirming this, examining a line with endogenous hemagglutinin-tagged AP2-G showed that the individual schizonts expressing MSPDBL2 are mostly different from those expressing AP2-G. Using a selection-linked integration system, modified P. falciparum lines were engineered to express an intact or disrupted version of MSPDBL2, showing the protein is not required for sexual commitment or early gametocyte development. Asexual parasite multiplication rates were also not affected by expression of either intact or disrupted MSPDBL2 in a majority of schizonts. Occurring alongside sexual commitment, the role of the discrete MSPDBL2-positive schizont subpopulation requires further investigation in natural infections where it is under immune selection. IMPORTANCE: Malaria parasites in the blood are remarkably variable, able to switch antigenic targets so they may survive within humans who have already developed specific immune responses. This is one of the challenges in developing vaccines against malaria. MSPDBL2 is a target of naturally acquired immunity expressed in minority proportions of schizonts, the end stages of each 2-day replication cycle in red blood cells which contain merozoites prepared to invade new red blood cells. Results show that the proportion of schizonts expressing MSPDBL2 is positively controlled by the expression of the regulatory gametocyte development protein GDV1. It was previously known that expression of GDV1 leads to increased expression of AP2-G which causes parasites to switch to sexual development, so a surprising finding here is that MSPDBL2-positive parasites are mostly distinct from those that express AP2-G. This discrete antigenic subpopulation of mostly asexual parasites is regulated alongside sexually committed parasites, potentially enabling survival under stress conditions.

Impact of the COVID-19 pandemic on stage and incidence of head and neck cancer: A rapid review and meta-analysis.

OBJECTIVES: This rapid review aims to evaluate the impact of the COVID-19 pandemic on incidence of head and neck cancer (HNC) and stage distribution at diagnosis. DESIGN: Rapid review and meta-analysis. PARTICIPANTS: Comparative data for new HNC patients between a pre-pandemic cohort (before March 2020) and a pandemic cohort (after March 2020 during the lockdown period). MAIN OUTCOMES MEASURED: Data on tumour stage, incidence, referral pathway (number of new patient referrals), or workload levels (number of HNC treatments). Data on stage were summarised as odds ratios (OR) with 95% confidence intervals (CI), and data related to changes in numbers of diagnoses, referrals, and workload levels were summarised as a narrative synthesis. RESULTS: A total of 31 reports were included in this review. Individually 16 out of 23 studies did not show a significant impact on stage relative to the pre-pandemic period. However, the meta-analysis revealed that patients diagnosed with HNC during the pandemic were 16% more likely to have nodal involvement (OR = 1.16; 95% CI 1.00-1.35), 17% more likely to have a late overall stage (OR = 1.17; 95% CI 1.01-1.36), and 32% more likely to present with advanced tumour extent (T3 and T4 stage) (OR = 1.32; 95% CI 1.08-1.62). Data on incidence was extremely limited and not currently sufficient to assess trends in burden of disease. CONCLUSIONS: This review indicates that during the COVID-19 pandemic, there was upstaging of HNC at diagnosis, suggesting the provision of care to HNC patients was significantly affected.

Asymptomatic Plasmodium falciparum carriage at the end of the dry season is associated with subsequent infection and clinical malaria in Eastern Gambia.

BACKGROUND: Chronic carriage of asymptomatic low-density Plasmodium falciparum parasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear. METHODS: In a 2-years study (December 2014 to December 2016) in eastern Gambia, nine cross-sectional surveys using molecular parasite detection were performed in the dry and wet season. During the 2016 malaria transmission season, passive case detection identified episodes of clinical malaria. RESULTS: Among the 5256 samples collected, 444 (8.4%) were positive for P. falciparum. A multivariate model identified village of residence, male sex, age ≥ 5 years old, anaemia, and fever as independent factors associated with P. falciparum parasite carriage. Infections did not cluster over time within the same households or recurred among neighbouring households. Asymptomatic parasite carriage at the end of dry season was associated with a higher risk of infection (Hazard Ratio, HR = 3.0, p < 0.0001) and clinical malaria (HR = 1.561, p = 0.057) during the following transmission season. Age and village of residence were additional predictors of infection and clinical malaria during the transmission season. CONCLUSION: Chronic parasite carriage during the dry season is associated with an increased risk of malaria infection and clinical malaria. It is unclear whether this is due to environmental exposure or to other factors.

What factors influence refugees' attendance to dental care services?

DATA SOURCES: Four electronic databases: MEDLINE (via Ovid), Embase (via Ovid), Web of Science, and American Psychology Association PsycINFO. STUDY SELECTION: Quantitative observational or interventional studies, published until the end of February 2022 with no restrictions to date, language, or region of publication. DATA EXTRACTION AND SYNTHESIS: Screening performed by one author and a second author independently reviewed a random sample of 10% of the articles. Disagreements were resolved in consultation with a third author. RESULTS: The results were presented as a narrative review due to large heterogeneity of data. Nine studies met the eligibility criteria and most of them were rated as fair quality. The main factors influencing refugees access to dental care services were demographic and socioeconomic characteristics and English language proficiency. CONCLUSIONS: The review suggests that individual-level factors may have a predisposing effect on refugees' access, but had limited evidence on other enabling and contextual factors.

Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

Squamous Cell Carcinoma of the Oral Cavity, Oropharynx, and Larynx: A Scoping Review of Treatment Guidelines Worldwide.

Head and neck cancer (HNC) treatments have been based on single or multimodal therapies with surgery, radiotherapy (RT), chemotherapy, and immunotherapy. However, treatment recommendations among countries may differ due to technological/human resources and usual local practices. This scoping review aims to identify, compare, and map the clinical practice guidelines (CPGs) for treating squamous cell carcinoma (SCC) of the oral cavity, oropharynx, and larynx worldwide. A search strategy on global CPGs for HNC was performed by using five electronic databases and grey literature. CPGs were selected for inclusion using EndNote-20 and Rayyan online software. No language or publication date restrictions were applied. The results were analyzed descriptively considering the most updated CPG version. In total, 25 CPGs covering the head and neck region (10), the larynx (7), the oral cavity (5), and the oropharynx (3), were found in 13 geographical regions, and 19 were developed by medical societies from 1996 to 2023. Surgery and RT remain the main modalities for early-stage HNC, with surgery preferred in low-resource countries, and RT in selected cases, especially in the larynx/oropharynx aiming to achieve a cure with organ preservation. Human papillomavirus infection for oropharyngeal SCC is not tested in some Asian countries and there is still no consensus to treat p16-positive cases differently from p16-negative. Recommendations for larynx preservation vary according to facilities in each country, however, individualized choice is emphasized. Inequality across countries/continents is evident, with a similar pattern of recommendations among developed as well as developing ones. No CPGs were found in Latin America as well as Oceania countries, where the incidence of HNC is high and limitations of access to treatment may be encountered.

Interventions for the treatment of oral cavity and oropharyngeal cancers: surgical treatment.

BACKGROUND: Surgery is a common treatment option in oral cavity cancer (and less frequently in oropharyngeal cancer) to remove the primary tumour and sometimes neck lymph nodes. People with early-stage disease may undergo surgery alone or surgery plus radiotherapy, chemotherapy, immunotherapy/biotherapy, or a combination of these. Timing and extent of surgery varies. This is the third update of a review originally published in 2007. OBJECTIVES: To evaluate the relative benefits and harms of different surgical treatment modalities for oral cavity and oropharyngeal cancers. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 9 February 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared two or more surgical treatment modalities, or surgery versus other treatment modalities, for primary tumours of the oral cavity or oropharynx. DATA COLLECTION AND ANALYSIS: Our primary outcomes were overall survival, disease-free survival, locoregional recurrence, and recurrence; and our secondary outcomes were adverse effects of treatment, quality of life, direct and indirect costs to patients and health services, and participant satisfaction. We used standard Cochrane methods. We reported survival data as hazard ratios (HRs). For overall survival, we reported the HR of mortality, and for disease-free survival, we reported the combined HR of new disease, progression, and mortality; therefore, HRs below 1 indicated improvement in these outcomes. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified four new trials, bringing the total number of included trials to 15 (2820 participants randomised, 2583 participants analysed). For objective outcomes, we assessed four trials at high risk of bias, three at low risk, and eight at unclear risk. The trials evaluated nine comparisons; none compared different surgical approaches for excision of the primary tumour. Five trials evaluated elective neck dissection (ND) versus therapeutic (delayed) ND in people with oral cavity cancer and clinically negative neck nodes. Elective ND compared with therapeutic ND probably improves overall survival (HR 0.64, 95% confidence interval (CI) 0.50 to 0.83; I2 = 0%; 4 trials, 883 participants; moderate certainty) and disease-free survival (HR 0.56, 95% CI 0.45 to 0.70; I2 = 12%; 5 trials, 954 participants; moderate certainty), and probably reduces locoregional recurrence (HR 0.58, 95% CI 0.43 to 0.78; I2 = 0%; 4 trials, 458 participants; moderate certainty) and recurrence (RR 0.58, 95% CI 0.48 to 0.70; I2 = 0%; 3 trials, 633 participants; moderate certainty). Elective ND is probably associated with more adverse events (risk ratio (RR) 1.31, 95% CI 1.11 to 1.54; I2 = 0%; 2 trials, 746 participants; moderate certainty). Two trials evaluated elective radical ND versus elective selective ND in people with oral cavity cancer, but we were unable to pool the data as the trials used different surgical procedures. Neither study found evidence of a difference in overall survival (pooled measure not estimable; very low certainty). We are unsure if there is a difference in effect on disease-free survival (HR 0.57, 95% CI 0.29 to 1.11; 1 trial, 104 participants; very low certainty) or recurrence (RR 1.21, 95% CI 0.63 to 2.33; 1 trial, 143 participants; very low certainty). There may be no difference between the interventions in terms of adverse events (1 trial, 148 participants; low certainty). Two trials evaluated superselective ND versus selective ND, but we were unable to use the data. One trial evaluated supraomohyoid ND versus modified radical ND in 332 participants. We were unable to use any of the primary outcome data. The evidence on adverse events was very uncertain, with more complications, pain, and poorer shoulder function in the modified radical ND group. One trial evaluated sentinel node biopsy versus elective ND in 279 participants. There may be little or no difference between the interventions in overall survival (HR 1.00, 95% CI 0.90 to 1.11; low certainty), disease-free survival (HR 0.98, 95% CI 0.90 to 1.07; low certainty), or locoregional recurrence (HR 1.04, 95% CI 0.91 to 1.19; low certainty). The trial provided no usable data for recurrence, and reported no adverse events (very low certainty). One trial evaluated positron emission tomography-computed tomography (PET-CT) following chemoradiotherapy (with ND only if no or incomplete response) versus planned ND (before or after chemoradiotherapy) in 564 participants. There is probably no difference between the interventions in overall survival (HR 0.92, 95% CI 0.65 to 1.31; moderate certainty) or locoregional recurrence (HR 1.00, 95% CI 0.94 to 1.06; moderate certainty). One trial evaluated surgery plus radiotherapy versus radiotherapy alone and provided very low-certainty evidence of better overall survival in the surgery plus radiotherapy group (HR 0.24, 95% CI 0.10 to 0.59; 35 participants). The data were unreliable because the trial stopped early and had multiple protocol violations. In terms of adverse events, subcutaneous fibrosis was more frequent in the surgery plus radiotherapy group, but there were no differences in other adverse events (very low certainty). One trial evaluated surgery versus radiotherapy alone for oropharyngeal cancer in 68 participants. There may be little or no difference between the interventions for overall survival (HR 0.83, 95% CI 0.09 to 7.46; low certainty) or disease-free survival (HR 1.07, 95% CI 0.27 to 4.22; low certainty). For adverse events, there were too many outcomes to draw reliable conclusions. One trial evaluated surgery plus adjuvant radiotherapy versus chemotherapy. We were unable to use the data for any of the outcomes reported (very low certainty). AUTHORS' CONCLUSIONS: We found moderate-certainty evidence based on five trials that elective neck dissection of clinically negative neck nodes at the time of removal of the primary oral cavity tumour is superior to therapeutic neck dissection, with increased survival and disease-free survival, and reduced locoregional recurrence. There was moderate-certainty evidence from one trial of no difference between positron emission tomography (PET-CT) following chemoradiotherapy versus planned neck dissection in terms of overall survival or locoregional recurrence. The evidence for each of the other seven comparisons came from only one or two studies and was assessed as low or very low-certainty.

Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1.

Malaria parasites break down host haemoglobin into peptides and amino acids in the digestive vacuole for export to the parasite cytoplasm for growth: interrupting this process is central to the mode of action of several antimalarial drugs. Mutations in the chloroquine (CQ) resistance transporter, pfcrt, located in the digestive vacuole membrane, confer CQ resistance in Plasmodium falciparum, and typically also affect parasite fitness. However, the role of other parasite loci in the evolution of CQ resistance is unclear. Here we use a combination of population genomics, genetic crosses and gene editing to demonstrate that a second vacuolar transporter plays a key role in both resistance and compensatory evolution. Longitudinal genomic analyses of the Gambian parasites revealed temporal signatures of selection on a putative amino acid transporter (pfaat1) variant S258L, which increased from 0% to 97% in frequency between 1984 and 2014 in parallel with the pfcrt1 K76T variant. Parasite genetic crosses then identified a chromosome 6 quantitative trait locus containing pfaat1 that is selected by CQ treatment. Gene editing demonstrated that pfaat1 S258L potentiates CQ resistance but at a cost of reduced fitness, while pfaat1 F313S, a common southeast Asian polymorphism, reduces CQ resistance while restoring fitness. Our analyses reveal hidden complexity in CQ resistance evolution, suggesting that pfaat1 may underlie regional differences in the dynamics of resistance evolution, and modulate parasite resistance or fitness by manipulating the balance between both amino acid and drug transport.

Inequalities in access to NHS primary care dental services in Scotland during the COVID-19 pandemic.

Introduction This study aimed to quantify the impact of the COVID-19 pandemic on access and inequalities in primary care dental services among children and adults in Scotland.Methods Access was measured as any NHS Scotland primary care dental contacts derived from administrative data from January 2019 to May 2022, linked to the area-based Scottish Index of Multiple Deprivation for children and adults, and related to population denominator estimates from National Record Scotland. Inequalities for pre-pandemic (January 2019-January 2020) and recent (December 2021-February 2022, and March 2022-May 2022) periods for both children and adults were calculated and compared using the slope index of inequality and relative index of inequality.Results Following the first lockdown (March 2020) there was a dramatic fall to near zero dental contacts, followed by a slow recovery to 64.8% of pre-pandemic levels by May 2022. There was initial widening of relative inequalities in dental contacts in early 2022, which, more recently, had begun to return to pre-pandemic levels.Conclusion COVID-19 had a major impact on access to NHS primary dental care, and while inequalities in access are apparent as services recover from lockdown, these inequalities are not a new phenomenon.