Rice is an important staple food grain consumed by most of the population around the world. With climate and environmental changes, rice has undergone a tremendous stress state which has impacted crop production and productivity. Plant growth hormones are essential component that controls the overall outcome of the growth and development of the plant. Cytokinin is a hormone that plays an important role in plant immunity and defense systems. Trans-zeatin is an active form of cytokinin that can affect plant growth which is mediated by a multi-step two-component phosphorelay system that has different roles in various developmental stages. Systems biology is an approach for pathway analysis to trans-zeatin treated rice that could provide a deep understanding of different molecules associated with them. In this study, we have used a weighted gene co-expression network analysis method to identify the functional modules and hub genes involved in the cytokinin pathway. We have identified nine functional modules comprising of different hub genes which contribute to the cytokinin signaling route. The biological significance of these identified hub genes has been tested by applying well-proven statistical techniques to establish the association with the experimentally validated QTLs and annotated by the DAVID server. The establishment of key genes in different pathways has been confirmed. These results will be useful to design new stress-resistant cultivars which can provide sustainable yield in stress-specific conditions.

Keywords: QTLs; WGCNA; co-expression; cytokinin; hub genes; systems biology.

Potato is one of the most important food crops in the world. Late blight, viruses, soil and tuber-borne diseases, insect-pests mainly aphids, whiteflies, and potato tuber moths are the major biotic stresses affecting potato production. Potato is an irrigated and highly fertilizer-responsive crop, and therefore, heat, drought, and nutrient stresses are the key abiotic stresses. The genus Solanum is a reservoir of genetic diversity, however, a little fraction of total diversity has been utilized in potato breeding. The conventional breeding has contributed significantly to the development of potato varieties. In recent years, a tremendous progress has been achieved in the sequencing technologies from short-reads to long-reads sequence data, genomes of Solanum species (i.e., pan-genomics), bioinformatics and multi-omics platforms such as genomics, transcriptomics, proteomics, metabolomics, ionomics, and phenomics. As such, genome editing has been extensively explored as a next-generation breeding tool. With the available high-throughput genotyping facilities and tetraploid allele calling softwares, genomic selection would be a reality in potato in the near future. This mini-review covers an update on germplasm, breeding, and genomics in potato improvement for biotic and abiotic stress tolerance.

Keywords: abiotic; biotic; breeding; genomics; omics approaches; potato.

Background: Due to high heterogeneity and mortality of low-grade gliomas (LGGs), it is of great significance to find biomarkers for prognosis and immunotherapy. Pyroptosis is emerging as an attractive target in cancer research for its effect on tumor immune microenvironment (TIME). However, the investigation of pyroptosis in LGGs is insufficient. Methods: LGG samples from TCGA and CGGA database were classified into two pyroptosis patterns based on the expression profiles of 52 PRGs using consensus clustering. A prognostic model was constructed by using the LASSO-COX method. ESTIMATE algorithm and single sample gene set enrichment analysis (ssGSEA) were used to characterize the TIME. Based on the differentially expressed genes between two pyroptosis patterns, favorable and unfavorable pyroptosis gene signatures were determined. Pyroptosis score scheme was constructed to quantify the pyroptosis patterns through gene set variation analysis (GSVA) method. Two external datasets and immunotherapy cohort from CGGA and GEO database were used to validate the predictive value of the pyroptosis score. The Human Protein Atlas website and Western blotting were utilized to confirm the expression of the selected genes in the prognostic model in LGGs. Results: Distinct overall survival and immune checkpoint blockage therapeutic responses were identified between two pyroptosis patterns. A low pyroptosis score in LGG patients implies higher overall survival, poor immune cell infiltration, and better response to immunotherapy of immune checkpoint blockage. Conclusion: Our findings provided a foundation for future research targeting pyroptosis and opened a new sight to explore the prognosis and immunotherapy from the angle of pyroptosis in LGGs.

Keywords: immunotherapy response; low-grade glioma; prognosis; pyroptosis; tumor microenvironment.

Artemisinin is a natural bioactive sesquiterpene lactone containing an unusual endoperoxide 1, 2, 4-trioxane ring. It is derived from the herbal medicinal plant Artemisia annua and is best known for its use in treatment of malaria. However, recent studies also indicate the potential for artemisinin and related compounds, commonly referred to as artemisinins, in combating viral infections, inflammation and certain cancers. Moreover, the different potential modes of action of artemisinins make these compounds also potentially relevant to the challenges the world faces in the COVID-19 pandemic. Initial studies indicate positive effects of artemisinin or Artemisia spp. extracts to combat SARS-CoV-2 infection or COVID-19 related symptoms and WHO-supervised clinical studies on the potential of artemisinins to combat COVID-19 are now in progress. However, implementing multiple potential new uses of artemisinins will require effective solutions to boost production, either by enhancing synthesis in A. annua itself or through biotechnological engineering in alternative biosynthesis platforms. Because of this renewed interest in artemisinin and its derivatives, here we review its modes of action, its potential application in different diseases including COVID-19, its biosynthesis and future options to boost production.

Keywords: Artemisia annua; COVID-19; SARS-CoV-2; artemisinin; malaria; sesquiterpene lactone.

Dental implant surgery involves the insertion of a dental implant into the alveolar bone; the success of the surgery depends on the initial stability of the implant. The objective of this study was to examine the effects of dental implant insertion approaches in clinical surgery and in accordance with the standards of American Society for Testing and Materials on initial implant stability. Three insertion approaches were used for dental implant placement (Branemark Systems NobelSpeedy Groovy, Nobel Biocare AB, Gothenburg, Sweden) in two types of artificial bone-good bone (GB) and poor bone (PB). The three insertion approaches were as follows: (1) continuous rotation insertion (CRI): using a torque testing machine to continuously screw in an implant to completion and (2 and 3) intermittent rotation insertion (IRI)_90 and IRI_80: using CRI to bury an implant to 90% and 80% of its full length followed by IRI to complete the implantation, respectively. The maximum insertion torque value (ITV), periotest value (PTV), and implant stability quotient (ISQ) were measured and compared. The results indicated that bone quality and insertion approach both affected implant stability. Insertion approaches affected all three implant stability indicators differently in the GB and PB groups (p = 0.008). In GB groups, the insertion approach primarily affected ITV, whereas in PB groups, it primarily affected PTV. The effect of the insertion approach was less apparent for ISQ. Overall, in both the GB and PB groups, the implant stability for IRI_80 was greater than that for IRI_90, and the implant stability for IRI_90 was greater than that for CRI. Future in vitro studies should adopt an insertion approach that complies with the clinical practice for dental implant surgery. Dentists should adjust the timing for IRI in dental implant surgery to achieve greater initial dental implant stability.

Introduction: Numerous studies have shown that hypnotherapy (HT) is effective in irritable bowel syndrome (IBS) using traditional symptom severity end points. However, there is now interest in capturing the patient's perception of their illness and treatment because what patients expect from their treatment may differ from that of their healthcare provider.

Objective: To record patient perceptions and expectations of hypnotherapy as well as their symptom response.

Methods: 150 consecutive IBS patients (116 females, 34 males, aged 16-81 years) receiving hypnotherapy completed questionnaires recording IBS symptom severity, quality of life, noncolonic symptoms, anxiety and depression levels before and after treatment. Their expectations and perceptions of HT were also recorded, including a free text reflection.

Results: 121 patients (81%) responded to treatment consistent with our previous experience. Symptom severity scores, noncolonic symptoms, quality of life, anxiety and depression significantly all improved after HT (p < 0.001). Expectancy of an improvement with hypnotherapy was greater in those who did not respond to treatment (63%) than those who did (57%, p < 0.001). Scepticism and apprehension were common before treatment and replaced with enthusiasm afterwards. Free text responses after treatment were overwhelmingly positive. Patients also reported a variety of other benefits and even 20 of 29 symptom nonresponders (70%) still considered treatment worthwhile.

Conclusion: Although initially perceived negatively, hypnotherapy improved symptoms and resulted in a wide range of additional benefits. Expectation did not necessarily influence outcome. Recording IBS symptoms alone does not fully capture the patient's experience of treatment and needs to be considered in future research.

Keywords: expectations; hypnotherapy; irritable bowel syndrome; perceptions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus responsible for the pandemic coronavirus disease 19 (COVID-19). It has significant impact on human health and public safety along with negative social and economic consequences. Vaccination against SARS-CoV-2 is likely the most effective approach to sustainably control the global COVID-19 pandemic. Vaccination is highly effective in reducing the risk of severe COVID-19 disease. Mass-scale vaccination will help us in attaining herd immunity and will lessen the negative impact of the disease on public health, social and economic conditions. The present pandemic stimulated the development of several effective vaccines based on different platforms. Although the vaccine is safe and efficacious, rare cases of thrombosis and thrombocytopenia following the use of vaccination with the ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India) or the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) have been reported globally. This review focussed on the definition, epidemiology, pathogenesis, clinical features, diagnosis, and management of vaccine associated thrombosis.

Keywords: COVID-19 vaccine; heparin-induced thrombocytopenia; platelet factor-4; thrombosis; vaccine-induced immune thrombotic thrombocytopenia.

Online shopping has led to the rapid development of e-commerce, and at the same time, the pressure of offline distribution has increased abruptly. Therefore, a current development trend is to share end-to-end distribution against the background of the Internet. The main research content of this paper is the benefit distribution mechanism of shared end distribution. Based on an analysis of the current situation of interest distribution, this paper proposes factors that affect interest distribution from the perspectives of individuals and groups. The suitable income distribution mode of enterprise alliances is chosen from two dimensions-cooperation mode and coordination mechanism. Based on extant theory, this paper proposes a benefit distribution scheme-selection mechanism based on the modified Shapley value method and takes the terminal distribution in the Haidian District of Beijing as an example. The revised income distribution results better reflect the income-generating abilities of different enterprises within a cooperative organization and assign different benefit proportions to this cooperative organization based on different income-generating capacities to provide development incentives and, at the same time, better achieve income distribution.

Objective: This study describes the radiographic diagnosis and nonoperative chiropractic management for a case of a chronic calcaneonavicular coalition in an adult patient.

Background: Calcaneonavicular coalition is a congenital/acquired condition of the tarsal bones often diagnosed in individuals 8-12 years old. Considering its rare presentation (less than 1% of the population), there remains little literature on the conservative management of this condition.

Case presentation: Chronic calcaneonavicular coalition in a 35-year-old recreational athlete is presented.

Management/outcome: Following radiographic diagnosis, the patient was placed in a walking boot for four-weeks. After removal of the boot, the patient was managed nonoperatively. They reported a full resolution of symptoms with noted return to all pre-injury activities.

Summary: Presentation of calcaneonavicular coalition may be dependent on many factors, including age, medical history, and chronicity of the condition. Previous medical background may include recurrent inversion ankle sprains, aggravated with activity, and alleviated with rest. Nonoperative management of calcaneonavicular coalition may be considered as a viable intervention.

Objectif: Cette étude présente le diagnostic à l’aide de radiographies et la prise en charge non chirurgicale par la chiropratique d’un cas de coalition calcanéonaviculaire chronique chez un patient adulte.

Contexte: La coalition calcanéo-naviculaire est une affection congénitale ou acquise des tarses souvent diagnostiquée chez des individus âgés de 8 à 12 ans. Comme il s’agit d’une affection rare (moins de 1% de la population), il existe peu de littérature sur le traitement conservateur de cette affection.

Présentation du cas: Présentation d’une coalition calcanéo-naviculaire chronique chez un athlète amateur de 35 ans.

Prise en charge/résultat: Après le diagnostic établi à l’aide de radiographies, le patient a été placé dans une botte de marche orthopédique pendant quatre semaines. Après le retrait de la botte, le patient a été pris en charge de manière non chirurgicale. Tous ses symptômes sont disparus et il a pu reprendre toutes les activités qu’il avait avant sa blessure.

Résumé: La survenue d’une coalition calcanéonaviculaire peut dépendre de nombreux facteurs, dont l’âge, les antécédents médicaux et la chronicité de l’affection. Les antécédents médicaux peuvent inclure des entorses récurrentes de la cheville en inversion, aggravées par l’activité et soulagées par le repos. La prise en charge non chirurgicale de la coalition calcanéo-naviculaire peut être considérée comme une intervention viable.

Keywords: calcaneonavicular coalition; chiropractic; chiropratique; coalition calcanéo-naviculaire; coalition tarsienne; conservateur; conservative; non-operative management; tarsal coalition; traitement non chirurgical.

Objectives: 1) To determine which characteristics of adolescent athletes with SRC are associated with 'early' versus 'late' presentation for multimodal treatment; 2) to build a propensity score to investigate the effects of treatment timing during the management of SRCs.

Methods: Associations between early (0-7 days) versus late (8-28 days) presentation for treatment and pre-specified sociodemographic, pre-injury and injury characteristics were investigated in a historical cohort study of 2949 multi-sport athletes across Canada aged 12-18 years diagnosed with a SRC in community-based healthcare clinics.

Results: Early presentation was associated with being male, completing a pre-injury baseline assessment, and responding 'yes' or 'no' to having a diagnosed learning disability. Older athletes who reported previous SRCs were less likely to present early. The propensity score demonstrated an area under the curve of 0.71 (95% CI, 0.69 to 0.73).

Conclusions: Male athletes with a completed baseline assessment were more likely to seek early treatment following a SRC, and older athletes who reported a greater number of previous SRCs were less likely to present early. External validation of the propensity score is needed before examining the impact of treatment timing on adolescent athlete recovery outcomes.

Objectifs: 1) Trouver les caractéristiques des athlètes adolescents ayant subi une CCLS qui sont associées à la consultation précoce et à une consultation tardive; 2) établir un score de propension pour étudier les effets du moment du traitement pendant la prise en charge de la CCLS.

Méthodologie: Les liens entre la consultation précoce (de 0 à 7 jours) et la consultation tardive (de 8 à 28 jours) et les caractéristiques sociodémographiques, les caractéristiques avant la blessure et les caractéristiques après des blessure prédéterminées ont été examinés au cours d’une étude de cohorte historique menée auprès de 2 949 adolescents multisports répartis dans toutes les régions du Canada, âgés de 12 à 18 ans, chez lesquels une CCLS avait été diagnostiquée dans des cliniques de santé communautaires.

Résultats: La consultation précoce a été associée au sexe masculin, à une évaluation de départ avant la blessure et à la présence ou à l’absence d’un trouble de l’apprentissage. Les athlètes plus âgés ayant signalé des CCLS antérieures étaient moins susceptibles de consulter précocement. Le score de propension a démontré une aire sous la courbe de 0,71 (IC à 95 %: 0,69 à 0,73).

Conclusions: Les athlètes masculins ayant subi une évaluation de départ étaient plus susceptibles de consulter précocement après une CCRS alors que les athlètes âgés ayant déclaré un plus grand nombre de CCRS antérieures étaient moins susceptibles de consulter précocement. Une validation externe du score de propension serait nécessaire avant d’examiner l’effet du moment de la consultation sur les résultats de récupération chez les athlètes adolescents.

Keywords: chiropractic; chiropratique; commotion; commotion liée au sport; concussion; lésion cérébrale traumatique légère; mild traumatic brain injury; multi-modal treatment; rehabilitation; réadaptation; sport related concussion; traitement multimodal.

Objective: We present a case of an elite cyclist that hesitated to follow the medical advice from her practitioners, as she was determined to train and compete resulting in delayed diagnosis and management of a rare hip pathology.

Case presentation: A 51-year old elite female cyclist had a history of years of hip pain with insidious onset. The chiropractor in this case observed a lack of response to treatment, and advised the patient to get an MRI with suspicion of a labral tear. She eventually agreed to further investigations and was diagnosed with Non-Hodgkin's follicular lymphoma and a labral tear.

Summary: Elite athletes are not immune to serious pathology. Chiropractors should be vigilant and ensure to investigate any patients with a lack of response to conservative management. Chiropractors should be aware of the risk of athletic patients that continue to train and compete when advised not to.

Objectif: Nous présentons le cas d’une cycliste d’élite qui a hésité à suivre les conseils médicaux de ses praticiens, car elle était déterminée à s’entraîner et à participer à des compétitions, ce qui a retardé le diagnostic et la prise en charge d’une pathologie rare de la hanche.

Présentation du cas: Une cycliste d’élite de 51 ans avait des antécédents de douleurs à la hanche depuis des années; le début de ses douleurs avait été insidieux. Le chiropraticien a observé une absence de réponse au traitement et a conseillé à la patiente de subir un examen par IRM en soupçonnant une déchirure du labrum. La patiente a fini par accepter de subir des examens complémentaires. Un lymphome folliculaire non hodgkinien et une déchirure labrum ont été diagnostiqués.

Résumé: Les athlètes d’élite ne sont pas à l’abri d’une pathologie grave. Les chiropraticiens doivent être vigilants et s’assurer d’examiner tous les patients réfractaires à un traitement conservateur. Les chiropraticiens doivent être conscients du risque que représentent les patients sportifs qui continuent à s’entraîner et à participer à des compétitions alors qu’on leur a conseillé de ne pas le faire.

Keywords: chiropractic; chiropratique; cyclist; cycliste; diagnosis; diagnostic; douleur; elite; hanche; hip; labrum; lymphoma; lymphome; pain; élite.

Aim: To assess the oxygen saturation in DHCWs using N95 and 3 ply surgical masks and determine the presence of any other subjective discomfort in them.

Settings and design: A repeated measure observational study conducted at the Tertiary Care Dental Institute situated in Goa, a western coastal region of India recording humid conditions year around.

Methods and material: Participants constituted 60 frontline DHCWs wearing N95 masks and 60 DHCWs working in non-clinical setting wearing surgical masks. After completion of a self-administered questionnaire their oxygen saturation and pulse rate were monitored at baseline, 60mins and 120mins using pulse oximetry. Statistical Analysis: Mann Whitney u test compared oxygen saturation between the two groups. Friedmann and Wilcoxon signed rank test with Bonferroni correction computed differences within group at various time intervals. Binary logistic and linear regression was used to compare the study variables with outcome measure. p value was set at < 0.05.

Results and conclusion: Oxygen saturation reported a significant drop post one hour of wearing N95 masks which increased in the second hour. Prolonged use of N95 mask in humid environment adds to the body's physiological burden or perceptions of discomfort and exertion. Efforts need to be taken to address this for better compliance to the use of these protective gears.

Keywords: COVID-19; Dental Health Care Workers; discomfort; humid; personal protective equipment.

Objective: Silicosis as an incurable occupational disease is common in industries and processes that contain silica dust. Since engineering controls can reduce the risk of silicosis, the goal of this study was to design, implement and evaluate industrial ventilation systems and filtration for silica dust, which is emitted from hydrocone crusher and screener units in a mineral processing company.

Methods: In this project, local exhaust ventilation (LEV) system was designed and installed using the standard and valid guidelines. The dust concentration was measured in two stages before and after installation of the ventilation system in the workplace, silica emission sources and also in the workers' inhalation area. Finally, the efficiency of the system was determined.

Results: The efficiency of LEV system in reducing workplace dust concentration and dust emission sources was 79.8% and 84.92% respectively. Furthermore, the efficiency of system in reducing the Respirable Crystalline Silica (RCS) at the worker's inhalation area was 92.13%. The collection efficiency of filtration system for total particles was 99.67 %.

Conclusion: The results indicate that with designation and installation of the local exhaust ventilation (LEV) system and also installation of bag filter to collect dust, the concentration of dust in the workplace and in the inhalation area of workers has decreased significantly. As a result, this system can be used to control dust in similar industries.

Keywords: Filtration; mining; silica; ventilation.

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects^1-4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action^4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation⁶. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase⁷, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase⁸, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.

Background Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in chronic kidney disease (CKD) is unknown. Methods We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.73m² We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. Results At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP had a lower eGFR and were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE) compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or endstage kidney disease (ESKD) over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. Conclusion In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.

Objective: We investigated whether interankle blood pressure difference (IAND) can predict major adverse cardiovascular events (MACEs) in patients with cryptogenic stroke (CS) without peripheral artery disease (PAD).

Design: A retrospective cohort study.

Setting: Retrospective medical record data of patients with first-ever acute cerebral infarction who were admitted between 1 January 2007 and 31 July 2013.

Participants: CS patients admitted within 7 days of symptom onset were included.

Outcome measures: MACEs were defined as stroke recurrence, myocardial infarction occurrence, or death. Survival analyses were conducted using the Kaplan-Meier method and Cox regression analysis.

Methods: Consecutive CS patients without PAD who underwent ankle-brachial index (ABI) measurements were enrolled. PAD was defined if a patient had an ABI of <0.90 or a history of angiographically confirmed PAD. Systolic and diastolic IANDs were calculated as follows: right ankle blood pressure-left ankle blood pressure.

Results: A total of 612 patients were enrolled and followed up for a median 2.6 (interquartile range, 1.0-4.3) years. In the Cox regression analysis, systolic and diastolic IANDs ≥15 mm Hg were independently associated with MACEs in CS patients without PAD (hazard ratio (HR) 2.115, 95% confidence interval (CI) 1.230 to 3.635 and HR 2.523, 95% CI 1.086 to 5.863, respectively). In the subgroup analysis, systolic IAND ≥15 mm Hg was independently associated with MACEs in older patients (age ≥65 years) (HR 2.242, 95% CI 1.170 to 4.298) but not in younger patients (age <65 years).

Conclusions: Large IAND is independently associated with the long-term occurrence of MACEs in patients with CS without PAD. In particular, the association between IAND and MACEs is only valid in elderly patients.

Keywords: neurology; stroke; vascular medicine.

Objective: To document socioepidemiological theories used to explain the relationship between socioeconomic disadvantage and multimorbidity.

Design: Scoping review.

Methods: A search strategy was developed and then applied to multiple electronic databases including Medline, Embase, PsychInfo, Web of Science, Scielo, Applied Social Sciences, ERIC, Humanities Index and Sociological Abstracts. After the selection of studies, data were extracted using a data charting plan. The last search was performed on the 28 September 2021. Extracted data included: study design, country, population subgroups, measures of socioeconomic inequality, assessment of multimorbidity and conclusion on the association between socioeconomic variables and multimorbidity. Included studies were further assessed on their use of theory, type of theories used and context of application. Finally, we conducted a meta-narrative synthesis to summarise the results.

Results: A total of 64 studies were included in the review. Of these, 33 papers included theories as explanations for the association between socioeconomic position and multimorbidity. Within this group, 16 explicitly stated those theories and five tested at least one theory. Behavioural theories (health behaviours) were the most frequently used, followed by materialist (access to health resources) and psychosocial (stress pathways) theories. Most studies used theories as post hoc explanations for their findings or for study rationale. Supportive evidence was found for the role of material, behavioural and life course theories in explaining the relationship between social inequalities and multimorbidity.

Conclusion: Given the widely reported social inequalities in multimorbidity and its increasing public health burden, there is a critical gap in evidence on pathways from socioeconomic disadvantage to multimorbidity. Generating evidence of these pathways will guide the development of intervention and public policies to prevent multimorbidity among people living in social disadvantage. Material, behavioural and life course pathways can be targeted to reduce the negative effect of low socioeconomic position on multimorbidity.

Keywords: epidemiology; public health; social medicine.

Objective: To determine if there is a difference in overall survival of patients with epithelial ovarian cancer in rural, urban, and metropolitan settings in the United States.

Methods: We performed a retrospective cohort study using 2004-2016 National Cancer Database (NCDB) data including high and low grade, stage I-IV disease. Bivariate analyses used Student's t-test for continuous variables and χ² test for dichotomous variables. Kaplan-Meier curves estimated survival of patients based on location of residence, and univariate analyses using Cox proportional HR assessed survival based on baseline characteristics. Multivariate analysis was performed to account for significant covariates. Propensity score matching was used to validate the multivariate survival model. For all tests, p<0.05 was considered statistically significant.

Results: A total of 111 627 patients were included with a mean age of 62.5 years for metroolitan (range 18-90), 64.0 years for rural (range 19-90) and 63.2 years for urban areas (range 18-90). Of all patients included, 94 290 were in a metropolitan area (counties >1 million population or 50 000-999 999), 15 386 were in an urban area (population of 10 000-49 999), and 1951 were in a rural area (non-metropolitan/non-core population). Univariate Cox proportional hazards models showed clinically significant differences in survival in patients from metropolitan, urban, and rural areas. Multivariate Cox proportional hazards models showed a clinically significant increase in HRs for patients in rural settings (HR 1.17; 95% CI 1.06 to 1.29). Increasing age and stage, non-insured status, non-white race, and comorbidity were also significant for poorer survival.

Conclusion: Patients with ovarian cancer who live in rural settings with small populations and greater distance to tertiary care centers have poorer survival. These differences hold after controlling for stage, age, and other significant risk factors related to poorer outcomes. To improve clinical outcomes, we need further studies to identify which of these factors are actionable.

Keywords: gynecology; neoplasms; ovarian cancer; quality of life (PRO)/palliative care.

The US Food and Drug Administration (FDA) has recently added a new 'black box warning' on all currently approved Janus kinase (JAK) inhibitors indicated for the treatment of arthritis and other inflammatory conditions based on results from the ORAL Surveillance study of tofacitinib versus tumour necrosis factor alpha inhibitors in rheumatoid arthritis. This is a warning difficult to ignore because the data, being from a randomised controlled trial, are of high fidelity and hard to reproach. It is especially problematic because safety data for all the other JAK inhibitors will be pending for several years. So how might we proceed, without being bound by our stasis? The lack of absolute certainty seems to require a pragmatic approach to the routine care use of JAK inhibitors. The patients who were at greatest risk were older and had other risk factors for the corresponding adverse events, in keeping with effect modification. This highlights the need to focus on risk stratification when tailoring therapy. In this viewpoint, we propose a simple illustration to guide clinical decision-making. First, identify general risk factors for venous thromboembolic event (VTE), major adverse cardiac event (MACE) and cancer (age>65 years and smoking) and whether there is a previous history of VTE, MACE or cancer. Then, evaluate risk based on the number of other risk factors for VTE and the number of other risk factors for MACE. Ultimately, 'treat-to-target' will in the end always be 'treat-to-agreement'. As we have done in the past, and will do in the future, the optimal treatment strategy will have to be tailored based on individual patient risk factors and preferences in a shared-decision process.

Keywords: antirheumatic agents; arthritis, psoriatic; arthritis, rheumatoid; spondylitis, ankylosing; therapeutics.

Objective: To investigate the joint associations of fresh fruit intake and physical activity with glycaemic control in adult patients with diabetes mellitus (DM).

Design: It was an observational study involving adult patients with DM through a face-to-face questionnaire survey, physical measurements and laboratory examinations. Data were analysed by introducing a generalised linear mixed model, and a significant difference was set at p<0.05.

Setting: Nanjing, Jiangsu, China.

Participants: A total of 5663 adult patients with DM from the 2017 Nanjing Chronic Disease and Risk Factor Surveillance were recruited.

Results: Based on the food frequency questionnaire, fresh fruit intake was classified as 'not eat', '1~99 g/day' and '≥100 g/day'. Physical activity level was calculated based on the data of Global Physical Activity Questionnaire and classified into insufficient physical activity (<600 MET-min/week) and sufficient physical activity (≥600 MET-min/week). The likelihood of glycaemic control in adult patients with DM with fresh fruit intake ≥100 g/day was 37.8% (OR: 1.378; 95% CI: 1.209 to 1.571) higher than those with fresh fruit intake <100 g/day, which was 26% (OR: 1.260; 95% CI: 1.124 to 1.412) higher in adult patients with DM with sufficient physical activity than those with insufficient physical activity. Adult patients with DM with fresh fruit intake ≥100 g/day and sufficient physical activity presented the greatest likelihood of glycaemic control (OR: 1.758; 95% CI: 1.471 to 2.102) compared with those with both fresh fruit intake <100 g/day and insufficient physical activity.

Conclusions: Fresh fruit intake ≥100 g/day combined with sufficient physical activity is associated with a significantly higher likelihood of glycaemic control in adult patients with DM.

Keywords: diabetes; fresh fruit intake; glycaemic control; physical activity.

Objectives: We aimed to identify area-based socioeconomic inequalities in diabetes management and to examine whether the distribution of healthcare resources could explain area-based inequalities in diabetes management.

Design: Cross-sectional multilevel analysis from national survey data.

Setting and participants: Data were derived from the 2018 Korean Community Health Survey. Study subjects included 23 760 participants aged 30 years or older with diabetes diagnosed by a doctor.

Main outcome measures: The dependent variables were self-reported good glycaemic control, haemoglobin A1c (HbA1c) testing, recognition of the term HbA1c, and diabetic complications testing. Area Deprivation Index was used as an area-based measure of socioeconomic position. Factors related to regional healthcare resources-the coefficient of variation (CV) value of clinics and the number of physicians per 1000-were considered as potential mediating variables in explaining the association between diabetes management and area deprivation. A multilevel logistic regression analysis was used.

Results: Compared with the least deprived quintile, the likelihoods of not taking HbA1c tests, not recognising the term HbA1c, and not taking diabetic complication tests in the most deprived quintile were approximately 1.5 times (95% CI 1.25 to 1.80), 2.6 times (95% CI 1.97 to 3.45) and two times (95% CI 1.67 to 2.48) higher, respectively. In the most deprived quintile, CV value of clinics was the highest and the number of doctors was the lowest. Regional healthcare resource factors explained inequalities in managing diabetes by 14%-18%, especially in the most deprived quintile.

Conclusions: The results in this study suggest that socioeconomic inequalities in diabetes management may be explained by regional healthcare resource disparities. Policy interventions for a more even distribution of healthcare resources would likely reduce the magnitude of regional socioeconomic inequalities in diabetes management.

Keywords: diabetes & endocrinology; health policy; health services administration & management; public health.

Objectives: To assess the effects of individual educational level in adulthood and parental educational level during childhood, as well as combinations of individual and parental educational levels, on multimorbidity classes.

Design and setting: In this longitudinal study, we used data from a random sample of the Danish population aged 32-56 years without multimorbidity in 2010 (n=102 818). The study population was followed until 2018. Information on individual and parental educational levels and chronic conditions was obtained from national registers. Multinomial logistic regression analyses were adjusted for sex, age and ethnicity.

Outcome measure: Seven multimorbidity classes were identified using latent class analysis based on 47 chronic conditions. Persons deceased during follow-up comprised a separate class.

Results: We found an independent effect of individual educational level on five multimorbidity groups and death, most pronounced for the multimorbidity group 'Many conditions' (OR=1.89, 95% CI 1.58 to 2.26 for medium and OR=3.22, 95% CI 2.68 to 3.87 for short compared with long educational level) and of parental education on four groups and death, most pronounced for the multimorbidity group 'Many conditions' (OR=1.36, 95% CI 1.07 to 1.73 for medium and OR=1.48, 95% CI 1.15 to 1.89 for short compared with long educational level). Odds of belonging to four multimorbidity classes increased with lower combination of individual and parental educational levels, most pronounced for the multimorbidity group 'Many conditions'.

Conclusion: As both individual and parental educational levels contribute to the risk of multimorbidity, it is important to address inequality throughout the life course to mitigate multimorbidity. Future studies could adopt a life course approach to investigate the mediating role of behavioural, clinical, environmental and other social factors.

Keywords: epidemiology; public health; social medicine.

Isoform-specific functions of Numb in the development of cancers, especially in the initiation of epithelial-to-mesenchymal transition (EMT) remains controversial. We study the specific function of Numb-PRRL isoform in activated EMT of pancreatic ductal adenocarcinoma (PC), which is distinguished from our previous studies that only focused on the total Numb protein. Numb-PRRL isoform was specifically overexpressed and silenced in PC cells combining with TGF-β1 and EGF stimulus. We systematically explored the potential effect of Numb-PRRL in the activated EMT of PC in vitro and in vivo. The total Numb protein was overexpressed in the normal pancreatic duct and well-differentiated PC by IHC. However, Numb-PRRS isoform but not Numb-PRRL showed dominant expression in PC tissues. Numb-PRRL overexpression promoted TGF-β1-induced EMT in PANC-1 and Miapaca-2 cells. TGF-β1-induced EMT-like cell morphology, cell invasion, and migration were enhanced in Numb-PRRL overexpressing groups following the increase of N-cadherin, Vimentin, Smad2/3, Snail1, Snail2, and cleaved-Notch1 and the decrease of E-cadherin. Numb-PRRL overexpression activated TGFβ1-Smad2/3-Snail1 signaling was significantly reversed by the Notch1 inhibitor RO4929097. Conversely, Numb-PRRL silencing inhibited EGF-induced EMT in AsPC-1 and BxPC-3 cells following the activation of EGFR-ERK/MAPK signaling via phosphorylating EGFR at tyrosine 1045. In vivo, Numb-PRRL overexpression or silencing promoted or inhibited subcutaneous tumor size and distant liver metastases via regulating EMT and Snail signaling, respectively. Numb-PRRL promotes TGF-β1- and EGF-induced EMT in PC by regulating TGF-β1-Smad2/3-Snail and EGF-induced EGFR-ERK/MAPK signaling.