Malaria protection due to sickle haemoglobin depends on parasite genotype.

Host genetic factors can confer resistance against malaria1, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member2-4 PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

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.

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.

Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria.

Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C') inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C' inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.

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.

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.

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.

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

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.

Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium.

OBJECTIVE: We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. SUBJECTS AND METHODS: The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. RESULTS: The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites. CONCLUSION: These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.

The COVID-19 pandemic has not changed stage at presentation nor treatment patterns of head and neck cancer: A retrospective cohort study.

OBJECTIVES: To evaluate the impact of the COVID-19 lockdown measures on HNC, by comparing the stage at presentation and treatment of HNC before and after the most severe COVID-19 restrictions. DESIGN: A retrospective cohort study. SETTING: A regional cancer network serving a patient population of 2.4 million. PARTICIPANTS: Newly diagnosed patients with HNC between June and October 2019 (pre-pandemic) and June and October 2021 (post-pandemic). MAIN OUTCOME MEASURES: Symptom duration before diagnosis, stage at diagnosis, patient performance status (PS) and intent of treatment delivered (palliative vs. curative). RESULTS: Five hundred forty-five patients were evaluated-250 in the 2019 and 295 in the 2021 cohort. There were no significant differences in symptom duration between the cohorts (p = .359) or patient PS (p = .821). There were no increased odds of presenting with a late (Stage III or IV) AJCC cancer stage in 2021 compared with 2019 (odds ratio [OR] = 0.90; 95% confidence interval [CI]: 0.76-1.08); nor increased odds of receiving palliative rather than curative treatment in 2021 compared with 2019 (OR = 0.68; 95% CI: 0.45-1.03). CONCLUSION: The predicted stage shift to more advanced disease at the time of diagnosis of HNC due to the COVID-19 pandemic has not been realised in the longer term. In keeping with this, there was no difference in symptom duration, patient PS, or treatment patterns between the 2019 and 2021 cohorts.

A Cohort Study on the Duration of Plasmodium falciparum Infections During the Dry Season in The Gambia.

BACKGROUND: In areas where Plasmodium falciparum malaria is seasonal, a dry season reservoir of blood-stage infection is essential for initiating transmission during the following wet season. METHODS: In The Gambia, a cohort of 42 individuals with quantitative polymerase chain reaction-positive P falciparum infections at the end of the transmission season (December) were followed monthly until the end of the dry season (May) to evaluate infection persistence. The influence of human host and parasitological factors was investigated. RESULTS: A large proportion of individuals infected at the end of the wet season had detectable infections until the end of the dry season (40.0%; 16 of 40). At the start of the dry season, the majority of these persistent infections (82%) had parasite densities >10 p/µL compared to only 5.9% of short-lived infections. Persistent infections (59%) were also more likely to be multiclonal than short-lived infections (5.9%) and were associated with individuals having higher levels of P falciparum-specific antibodies (P = .02). CONCLUSIONS: Asymptomatic persistent infections were multiclonal with higher parasite densities at the beginning of the dry season. Screening and treating asymptomatic infections during the dry season may reduce the human reservoir of malaria responsible for initiating transmission in the wet season.

Systematic overview of systematic reviews and clinical guidelines: assessment and prevention of behavioural risk factors associated with oral cancer to inform dental professionals in primary care dental practices.

Aims/objectives Tobacco and alcohol are recognised as the major modifiable risk factors for oral cancer, the incidence of which is rising globally and predicted to increase. This paper aimed to: 1) appraise and synthesise best practice evidence for assessing the major behavioural risk factors for oral cancer and delivering behaviour change interventions (for example, advice, counselling, signposting/referral to preventive services); and 2) assess appropriateness for implementation by dental professionals in primary care.Methods A systematic overview was undertaken of systematic reviews and international clinical guidelines. This involved: systematically searching and collating the international literature on assessing oral cancer risk and delivering preventive interventions within primary care; quality appraising and assessing the risk of bias using validated tools; synthesising the evidence for best practice; and assessing application of key findings to the dental setting.Results and conclusions There is clear evidence for the effectiveness of a 'brief', in-person, motivational intervention for sustained tobacco abstinence or reduced alcohol consumption, following risk factor assessment. Evidence for combined behavioural interventions is lacking. There is no firm conclusion with regards to optimal duration of brief interventions (range 5-20 minutes). For tobacco users, longer (10-20 minutes) and intensive (more than 20 minutes, with follow-up visits) interventions are more effective in increasing quit rates compared to no intervention; very brief (less than five minutes) interventions in a single session show comparable effectiveness to the longer/more intensive interventions. For alcohol users, 10-15-minute multi-contact interventions were most effective, compared to no intervention or very brief (less than five minutes) intervention or intensive intervention; brief interventions of five-minute duration were equally effective. There is limited direct evidence from the dental practice setting (one high-quality systematic review relating to tobacco prevention and none relating to alcohol). Thus, very brief, or brief advice of up to five minutes, should be trialled for tobacco and alcohol respectively in a dental practice setting, after risk assessment tailored to patient motivational status. Exploring delivery by the dental team is supported, as effectiveness was generally independent of primary care provider.

Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy.

BACKGROUND: Oral cavity and oropharyngeal cancers are the most common cancers arising in the head and neck. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients. This review updates one last published in 2011. OBJECTIVES: To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal squamous cell carcinoma results in improved overall survival, improved disease-free survival and/or improved locoregional control, when incorporated as either induction therapy given prior to locoregional treatment (i.e. radiotherapy or surgery), concurrent with radiotherapy or in the adjuvant (i.e. after locoregional treatment with radiotherapy or surgery) setting. SEARCH METHODS: An information specialist searched 4 bibliographic databases up to 15 September 2021 and used additional search methods to identify published, unpublished and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and that evaluated the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration. DATA COLLECTION AND ANALYSIS: For this update, we assessed the new included trials for their risk of bias and at least two authors extracted data from them. Our primary outcome was overall survival (time to death from any cause). Secondary outcomes were disease-free survival (time to disease recurrence or death from any cause) and locoregional control (response to primary treatment). We contacted trial authors for additional information or clarification when necessary. MAIN RESULTS: We included 100 studies with 18,813 participants. None of the included trials were at low risk of bias.  For induction chemotherapy, we reported the results for contemporary regimens that will be of interest to clinicians and people being treated for oral cavity and oropharyngeal cancers. Overall, there is insufficient evidence to clearly demonstrate a survival benefit from induction chemotherapy with platinum plus 5-fluorouracil prior to radiotherapy (hazard ratio (HR) for death 0.85, 95% confidence interval (CI) 0.70 to 1.04, P = 0.11; 7427 participants, 5 studies; moderate-certainty evidence), prior to surgery (HR for death 1.06, 95% CI 0.71 to 1.60, P = 0.77; 198 participants, 1 study; low-certainty evidence) or prior to concurrent chemoradiation (CRT) with cisplatin (HR for death 0.71, 95% CI 0.37 to 1.35, P = 0.30; 389 participants, 2 studies; low-certainty evidence). There is insufficient evidence to support the use of an induction chemotherapy regimen with cisplatin plus 5-fluorouracil plus docetaxel prior to CRT with cisplatin (HR for death 1.08, 95% CI 0.80 to 1.44, P = 0.63; 760 participants, 3 studies; low-certainty evidence).  There is insufficient evidence to support the use of adjuvant chemotherapy over observation only following surgery (HR for death 0.95, 95% CI 0.73 to 1.22, P = 0.67; 353 participants, 5 studies; moderate-certainty evidence). Among studies that compared post-surgical adjuvant CRT, as compared to post-surgical RT, adjuvant CRT showed a survival benefit (HR 0.84, 95% CI 0.72 to 0.98, P = 0.03; 1097 participants, 4 studies; moderate-certainty evidence). Primary treatment with CRT, as compared to radiotherapy alone,  was associated with a reduction in the risk of death (HR for death 0.74, 95% CI 0.67 to 0.83, P < 0.00001; 2852 participants, 24 studies; moderate-certainty evidence).  AUTHORS' CONCLUSIONS: The results of this review demonstrate that chemotherapy in the curative-intent treatment of oral cavity and oropharyngeal cancers only seems to be of benefit when used in specific circumstances together with locoregional treatment. The  evidence does not show a clear survival benefit from the use of induction chemotherapy prior to radiotherapy, surgery or CRT. Adjuvant CRT reduces the risk of death by 16%, as compared to radiotherapy alone. Concurrent chemoradiation as compared to radiation alone is associated with a greater than 20% improvement in overall survival; however, additional research is required to inform how the specific chemotherapy regimen may influence this benefit.

Lessons learned from the INHANCE consortium: An overview of recent results on head and neck cancer.

OBJECTIVE: To summarize the latest evidence on head and neck cancer epidemiology from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. SUBJECTS AND METHODS: INHANCE was established in 2004 to elucidate the etiology of head and neck cancer through pooled analyses of individual-level data on a large scale. We summarize results from recent INHANCE-based publications updating our 2015 overview. RESULTS: Seventeen papers were published between 2015 and May 2020. These studies further define the nature of risks associated with tobacco and alcohol, and occupational exposures on head and neck cancer. The beneficial effects on incidence of head and neck cancer were identified for good oral health, endogenous and exogenous hormonal factors, and selected aspects of diet related to fruit and vegetables. INHANCE has begun to develop risk prediction models and to pool follow-up data on their studies, finding that ~30% of cases had cancer recurrence and 9% second primary cancers, with overall- and disease-specific 5-year-survival of 51% and 57%, respectively. CONCLUSIONS: The number and importance of INHANCE scientific findings provides further evidence of the advantages of large-scale internationally collaborative projects and will support the development of prevention strategies.

A systematic review of interventions to link families with preschool children from healthcare services to community-based support.

BACKGROUND: Supporting patients to access community-based support may be a key intervention to address the wider determinants of health. There is a lack of evidence synthesis around the most effective methods for linking individuals from health services to organizations within communities, especially those aimed at supporting families with young children. METHODS: Papers were identified from seven databases covering peer-reviewed and grey literature. The Effective Public Health Practice Project and the Critical Appraisal Skills Programme Qualitative quality appraisal tools were used to assess methodological quality. Thematic narrative data synthesis based on study quality was performed. RESULTS: Twenty-four unique publications were included in the review with a range of study designs and variable methodological quality. A broad typology of intervention processes for undertaking linking was developed defining three distinct approaches: signposting, referral and facilitation. Active processes, such as facilitation, appeared more successful at linking families to community support. CONCLUSIONS: This was the first systematic review to focus on interventions that link families with young children to community-based support organizations. It identified a typology for linking interventions, and whilst there were limitations in the quality of evidence available, it showed a tendency for more active interventions to be more effective in linking families to community support.

A malaria parasite subtilisin propeptide-like protein is a potent inhibitor of the egress protease SUB1.

Subtilisin-like serine peptidases (subtilases) play important roles in the life cycle of many organisms, including the protozoan parasites that are the causative agent of malaria, Plasmodium spp. As with other peptidases, subtilase proteolytic activity has to be tightly regulated in order to prevent potentially deleterious uncontrolled protein degradation. Maturation of most subtilases requires the presence of an N-terminal propeptide that facilitates folding of the catalytic domain. Following its proteolytic cleavage, the propeptide acts as a transient, tightly bound inhibitor until its eventual complete removal to generate active protease. Here we report the identification of a stand-alone malaria parasite propeptide-like protein, called SUB1-ProM, encoded by a conserved gene that lies in a highly syntenic locus adjacent to three of the four subtilisin-like genes in the Plasmodium genome. Template-based modelling and ab initio structure prediction showed that the SUB1-ProM core structure is most similar to the X-ray crystal structure of the propeptide of SUB1, an essential parasite subtilase that is discharged into the parasitophorous vacuole (PV) to trigger parasite release (egress) from infected host cells. Recombinant Plasmodium falciparum SUB1-ProM was found to be a fast-binding, potent inhibitor of P. falciparum SUB1, but not of the only other essential blood-stage parasite subtilase, SUB2, or of other proteases examined. Mass-spectrometry and immunofluorescence showed that SUB1-ProM is expressed in the PV of blood stage P. falciparum, where it may act as an endogenous inhibitor to regulate SUB1 activity in the parasite.

Selective Caries Removal in Permanent Teeth (SCRiPT) for the treatment of deep carious lesions: a randomised controlled clinical trial in primary care.

BACKGROUND: Dental caries is one of the most prevalent non-communicable disease globally and can have serious health sequelae impacting negatively on quality of life. In the UK most adults experience dental caries during their lifetime and the 2009 Adult Dental Health Survey reported that 85% of adults have at least one dental restoration. Conservative removal of tooth tissue for both primary and secondary caries reduces the risk of failure due to tooth-restoration, complex fracture as well as remaining tooth surfaces being less vulnerable to further caries. However, despite its prevalence there is no consensus on how much caries to remove prior to placing a restoration to achieve optimal outcomes. Evidence for selective compared to complete or near-complete caries removal suggests there may be benefits for selective removal in sustaining tooth vitality, therefore avoiding abscess formation and pain, so eliminating the need for more complex and costly treatment or eventual tooth loss. However, the evidence is of low scientific quality and mainly gleaned from studies in primary teeth. METHOD: This is a pragmatic, multi-centre, two-arm patient randomised controlled clinical trial including an internal pilot set in primary dental care in Scotland and England. Dental health professionals will recruit 623 participants over 12-years of age with deep carious lesions in their permanent posterior teeth. Participants will have a single tooth randomised to either the selective caries removal or complete caries removal treatment arm. Baseline measures and outcome data (during the 3-year follow-up period) will be assessed through clinical examination, patient questionnaires and NHS databases. A mixed-method process evaluation will complement the clinical and economic outcome evaluation and examine implementation, mechanisms of impact and context. The primary outcome at three years is sustained tooth vitality. The primary economic outcome is net benefit modelled over a lifetime horizon. Clinical secondary outcomes include pulp exposure, progession of caries, restoration failure; as well as patient-centred and economic outcomes. DISCUSSION: SCRiPT will provide evidence for the most clinically effective and cost-beneficial approach to managing deep carious lesions in permanent posterior teeth in primary care. This will support general dental practitioners, patients and policy makers in decision making. Trial Registration Trial registry: ISRCTN. TRIAL REGISTRATION NUMBER: ISRCTN76503940. Date of Registration: 30.10.2019. URL of trial registry record: https://www.isrctn.com/ISRCTN76503940?q=ISRCTN76503940%20&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search .

Population Genomic Structure and Recent Evolution of Plasmodium knowlesi, Peninsular Malaysia.

Most malaria in Malaysia is caused by Plasmodium knowlesi parasites through zoonotic infection from macaque reservoir hosts. We obtained genome sequences from 28 clinical infections in Peninsular Malaysia to clarify the emerging parasite population structure and test for evidence of recent adaptation. The parasites all belonged to a major genetic population of P. knowlesi (cluster 3) with high genomewide divergence from populations occurring in Borneo (clusters 1 and 2). We also observed unexpected local genetic subdivision; most parasites belonged to 2 subpopulations sharing a high level of diversity except at particular genomic regions, the largest being a region of chromosome 12, which showed evidence of recent directional selection. Surprisingly, we observed a third subpopulation comprising P. knowlesi infections that were almost identical to each other throughout much of the genome, indicating separately maintained transmission and recent genetic isolation. Each subpopulation could evolve and present a broader health challenge in Asia.