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Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects
Get PDFThe risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response.
Methods
Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D).
Results
Six hundred twenty-nine genes were associated with 25-OHD level (P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E−07; downregulated gene-set P < 2.6E−05) and corresponding GO terms (P = 2.90E−02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66–1.00]) and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI 0.77–0.89]; PPP1CC AUC=0.91 [95%CI 0.86–0.95])
Use of systemic glucocorticoids and risk of breast cancer in a prospective cohort of postmenopausal women
Get PDFGlucocorticoids could theoretically decrease breast cancer risk through their anti-inflammatory effects or increase risk through immunosuppression. However, epidemiological evidence is limited regarding the associations between glucocorticoid use and breast cancer risk.
Methods
We investigated the association between systemic glucocorticoid use and breast cancer incidence in the E3N cohort, which includes 98,995 women with information on various characteristics collected from repeated questionnaires complemented with drug reimbursement data available from 2004. Women with at least two reimbursements of systemic glucocorticoids in any previous 3-month period since January 1, 2004, were defined as exposed. We considered exposure as a time-varying parameter, and we used multivariable Cox regression models to estimate hazard ratios (HRs) of breast cancer. We performed a competing risk analysis using a cause-specific hazard approach to study the heterogeneity by tumour subtype/stage/grade.
Results
Among 62,512 postmenopausal women (median age at inclusion of 63 years old), 2864 developed breast cancer during a median follow-up of 9 years (between years 2004 and 2014). Compared with non-exposure, glucocorticoid exposure was not associated with overall breast cancer risk [HR = 0.94 (0.85–1.05)]; however, it was associated with a higher risk of in situ breast cancer and a lower risk of invasive breast cancer [HRinsitu = 1.34 (1.01–1.78); HRinvasive = 0.86 (0.76–0.97); Phomogeneity = 0.01]. Regarding the risk of invasive breast cancer, glucocorticoid exposure was inversely associated with oestrogen receptor (ER)-positive breast cancer [HRER+ = 0.82 (0.72–0.94); HRER− = 1.21 (0.88–1.66); Phomogeneity = 0.03]; it was also inversely associated with the risk of stage 1 or stage 2 tumours but positively associated with the risk of stage 3/4 breast cancers [HRstage1 = 0.87 (0.75–1.01); HRstage2 = 0.67 (0.52–0.86); HRstage3/4 = 1.49 (1.02–2.20); Phomogeneity = 0.01].
Conclusion
This study suggests that the association between systemic glucocorticoid use and breast cancer risk may differ by tumour subtype and stage
Understanding the role of the paramedic in primary care: a realist review
Get PDFSince 2002, paramedics have been working in primary care within the United Kingdom (UK), a transition also mirrored within Australia, Canada and the USA. Recent recommendations to improve UK NHS workforce capacities have led to a major push to increase the numbers of paramedics recruited into primary care. However, gaps exist in the evidence base regarding how and why these changes would work, for whom, in what context and to what extent. To understand the ways in which paramedics impact (or not) the primary care workforce, we conducted a realist review.
Methods
A realist approach aims to provide causal explanations through the generation and articulation of contexts, mechanisms and outcomes. Our search of electronic databases was supplemented with Google and citation checking to locate grey literature including news items and workforce reports. Included documents were from the UK, Australia, Canada and the Americas—countries within which the paramedic role within primary care is well established.
Results
Our searches resulted in 205 included documents, from which data were extracted to produce context-mechanism-outcome configurations (CMOCs) within a final programme theory. Our results outline that paramedics are more likely to be effective in contributing to primary care workforces when they are supported to expand their existing role through formal education and clinical supervision. We also found that unless paramedics were fully integrated into primary care services, they did not experience the socialisation needed to build trusting relationships with patients or physicians. Indeed, for patients to accept paramedics in primary care, their role and its implications for their care should be outlined by a trusted source.
Conclusions
Our realist review highlights the complexity surrounding the introduction of paramedics into primary care roles. As well as offering an insight into understanding the paramedic professional identity, we also discuss the range of expectations this professional group will face in the transition to primary care. These expectations come from patients, general practitioners (family physicians) and paramedics themselves. This review is the first to offer insight into understanding the impact paramedics may have on the international primary care workforce and shaping how they might be optimally deployed
Surgical Approach for Spinal Tumors: Our Experience in Combined Military Hospital Dhaka
Get PDF1) Background: spinal tumors not only causes structural problem but also it affects body functionality, too. Surgery has a key role in management of patients with spinal tumor. The aim of this study is that to observe their clinical profile, functional outcomes and prognostic factors. (2) Methods: 20 retrospectively consecutive patients with spinal tumors operated over a period of 2 years were analyzed. (3) Results: nine (45%) were intradural and 11(55%) were extradural. Mean age at surgery was 45.05 years (range 20–80 years). The common clinical features were pain, limb weakness and autonomic involvement. Schwannoma was common in intradural extramedullary group whereas astrocytoma and ependymoma was common in intramedullary group. In this case, 16 (80%) patients had improvement following surgery and 4 (20%) remained the same, none had deterioration. Common complications were persistent pain (1 case) and autonomic involvement (1 case). (4) Conclusion: spinal tumors need early exploration and excision and usually patients recover well without any residual effe
Determinants of Success and Early Complications in Common Femoral Artery Endarterectomy: A Retrospective Study
Get PDFIntroduction: Common femoral artery endarterectomy (CFE) is considered a relatively simple, successful and safe procedure in the literature, but major complications can occur. This retrospective study was performed in order to define characteristics contributing to success or failure after common femoral artery endarterectomy, either performed as a single or hybrid procedure. Methods: A total of 298 patients who underwent CFE in our hospital between 1 January 2011 and 1 January 2017 were included. After exclusion, 227 patients were analyzed. Patient characteristics and outcomes were derived from the patient records. Follow-up was 30 days postoperatively. Outcomes were analyzed by the chi-square test and regression analysis. Clinical success was defined as a combination of technical success, improvement in the ankle-brachial index, increased walking distance and “no complications.” Results: The procedure was clinically successful in 74.4% of the patients, and in 25.6%, a complication occurred. The Rutherford class improved in 65.1% of the patients with 1.6 (SD 1.3) class points. The ankle-brachial index improved in 44.8% of the cases, with an average of 116.6%. The most contributing factors for complications such as death, unplanned amputation, surgical site infection, thrombosis and longer hospital admission were emergency operation and a higher ASA classification. Significantly more complications also occurred in patients with renal failure, congestive heart disease, a high Rutherford classification and previous groin incision. A higher Rutherford class was the only factor correlating with an increase in the ankle-brachial index. When single CFE (48.9% of cases) and hybrid procedures (51.1%) were compared, no significant difference in success or failure was found. Conclusion: Limb ischemia requiring emergency operation and preoperative comorbidity were identified as the most important factors predictive for complications following femoral artery endarterectomy. Combining femoral endarterectomy with an endovascular intervention does not seem to increase the risk of a postoperative complication
Intralobar Pulmonary Sequestration with Anomalous Artery Arising from the Celiac Trunk
Get PDFPulmonary saequestration is a rare congenital malformation characterized by a dysplastic portion of lung parenchyma supplied by an anomalous artery originating from the aorta or its branches. The worldwide incidence of pulmonary sequestration among all congenital lung malformations in children ranges from 1.5% to 6.4%. There are two main types of pulmonary sequestration according to the localization of the malformation, i.e., intrapulmonary sequestration (dysplastic tissue located inside a lobe of the normal lung) and extrapulmonary sequestration. Our case presentation aims to make physicians aware of this rare anomaly which may be difficult to diagnose because of its oligosymptomatic course prior to first presentation. We present the case of a 10-year-old girl who suffered from a second episode of prolonged pneumonia of the left lower lobe. Contrast-enhanced-computed-tomography (CT) scan of the thoraco-abdominal segment of the aorta and its branches revealed intrapulmonary sequestration localized at the left lower lobe of the lung. The intrapulmonary sequester was perfused by a large artery arising from the celiac trunk. The girl underwent open surgery with ligation of the anomalous feeding artery and atypical pulmonary resection of the affected area of the left lower lobe. Postoperatively, the child recovered without any complications
Adverse childhood experiences and child mental health: an electronic birth cohort study
Get PDFAdverse childhood experiences (ACEs) are negatively associated with a range of child health outcomes. In this study, we explored associations between five individual ACEs and child mental health diagnoses or symptoms. ACEs included living with someone who had an alcohol-related problem, common mental health disorder or serious mental illness, or experienced victimisation or death of a household member.
Methods
We analysed data from a population-level electronic cohort of children in Wales, UK, (N = 191,035) between the years of 1998 and 2012. We used Cox regression with discrete time-varying exposure variables to model time to child mental health diagnosis during the first 15 years of life. Child mental health diagnoses include five categories: (i) externalising symptoms (anti-social behaviour), (ii) internalising symptoms (stress, anxiety, depression), (iii) developmental delay (e.g. learning disability), (iv) other (e.g. eating disorder, personality disorders), and (v) any mental health diagnosis, which was created by combining externalising symptoms, internalising symptoms and other. Our analyses were adjusted for social deprivation and perinatal risk factors.
Results
There were strong univariable associations between the five individual ACEs, sociodemographic and perinatal factors (e.g. gestational weight at birth) and an increased risk of child mental health diagnoses. After adjusting for sociodemographic and perinatal aspects, there was a remaining conditional increased risk of any child mental health diagnosis, associated with victimisation (conditional hazard ratio (cHR) 1.90, CI 95% 1.34–2.69), and living with an adult with a common mental health diagnosis (cHR 1.63, CI 95% 1.52–1.75). Coefficients of product terms between ACEs and deprivation were not statistically significant.
Conclusion
The increased risk of child mental health diagnosis associated with victimisation, or exposure to common mental health diagnoses, and alcohol problems in the household supports the need for policy measures and intervention strategies for children and their families
Evaluation of the safety profile of COVID-19 vaccines: a rapid review
Get PDFThe rapid process of research and development and lack of follow-up time post-vaccination aroused great public concern about the safety profile of COVID-19 vaccine candidates. To provide comprehensive overview of the safety profile of COVID-19 vaccines by using meta-analysis technique.
Methods
English-language articles and results posted on PubMed, Embase, Web of Science, PMC, official regulatory websites, and post-authorization safety surveillance data were searched through June 12, 2021. Publications disclosing safety data of COVID-19 candidate vaccines in humans were included. A meta-analysis of proportions was performed to estimate the pooled incidence and the pooled rate ratio (RR) of safety outcomes of COVID-19 vaccines using different platforms.
Results
A total of 87 publications with safety data from clinical trials and post-authorization studies of 19 COVID-19 vaccines on 6 different platforms were included. The pooled rates of local and systemic reactions were significantly lower among inactivated vaccines (23.7%, 21.0%), protein subunit vaccines (33.0%, 22.3%), and DNA vaccines (39.5%, 29.3%), compared to RNA vaccines (89.4%, 83.3%), non-replicating vector vaccines (55.9%, 66.3%), and virus-like particle vaccines (100.0%, 78.9%). Solicited injection-site pain was the most common local reactions, and fatigue and headache were the most common systemic reactions. The frequency of vaccine-related serious adverse events was low (< 0.1%) and balanced between treatment groups. Vaccine platforms and age groups of vaccine recipients accounted for much of the heterogeneity in safety profiles between COVID-19 vaccines. Reporting rates of adverse events from post-authorization observational studies were similar to results from clinical trials. Crude reporting rates of adverse events from post-authorization safety monitoring (passive surveillance) were lower than in clinical trials and varied between countries.
Conclusions
Available evidence indicates that eligible COVID-19 vaccines have an acceptable short-term safety profile. Additional studies and long-term population-level surveillance are strongly encouraged to further define the safety profile of COVID-19 vaccines
The economic value of changing mortality risk in low- and middle-income countries: a systematic breakdown by cause of death
No full textWe develop a framework for quantifying monetary values associated with changes in disease-specific mortality risk in low- and middle-income countries to help quantify trade-offs involved in investing in mortality reduction due to one disease versus another.
Methods
We monetized the changes in mortality risk for communicable and non-communicable diseases (CD and NCD, respectively) between 2017 and 2030 for low-income, lower-middle-income, and upper-middle-income countries (LICs, LMICs, and UMICs, respectively). We modeled three mortality trajectories (“base-case”, “high-performance”, and “low-performance”) using Global Burden of Disease study forecasts and estimated disease-specific mortality risk changes relative to the base-case. We assigned monetary values to changes in mortality risk using value of a statistical life (VSL) methods and conducted multiple sensitivity analyses.
Results
In terms of NCDs, the absolute monetary value associated with changing mortality risk was highest for cardiovascular diseases in older age groups. For example, being on the low-performance trajectory relative to the base-case in 2030 was valued at 6800; 28,300 (32,400), and 27,200; $33,300) for females aged 70–74 years in LICs, LMICs, and UMICs, respectively. Changing the mortality rate from the base-case to the high-performance trajectory was associated with high monetary value for CDs as well, especially among younger age groups. Estimates were sensitive to assumptions made in calculating VSL.
Conclusions
Our framework provides a priority setting paradigm to best allocate investments toward the health sector and enables intersectoral comparisons of returns on investments from health interventions
Persistence and baseline determinants of seropositivity and reinfection rates in health care workers up to 12.5 months after COVID-19
Get PDFWe assessed the duration and baseline determinants of antibody responses to SARS-CoV-2 spike antigens and the occurrence of reinfections in a prospective cohort of 173 Spanish primary health care worker patients followed initially for 9 months and subsequently up to 12.5 months after COVID-19 symptoms onset. Seropositivity to SARS-CoV-2 spike and receptor-binding domain antigens up to 149–270 days was 92.49% (90.17% IgG, 76.3% IgA, 60.69% IgM). In a subset of 64 health care workers who had not yet been vaccinated by April 2021, seropositivity was 96.88% (95.31% IgG, 82.81% IgA) up to 322–379 days post symptoms onset. Four suspected reinfections were detected by passive case detection, two among seronegative individuals (5 and 7 months after the first episode), and one low antibody responder. Antibody levels significantly correlated with fever, hospitalization, anosmia/hypogeusia, allergies, smoking, and occupation. Stable sustainment of IgG responses raises hope for long-lasting COVID-19 vaccine immunity