bluuebunny/crossref_metadata_2025 huggingface dataset:
Weight variability and cardiovascular outcomes: a systematic review and meta-analysis
Authors: Massey Robert J. , Siddiqui Moneeza K. , Pearson Ewan R. , Dawed Adem Y.
Published: January 2023

The association between body weight variability and the risk of cardiovascular disease (CVD) has been investigated previously with mixed findings. However, there has been no extensive study which systematically evaluates the current evidence. Furthermore, the impact of ethnicity and type 2 diabetes on this phenomena has not yet been investigated. Therefore, the aim of this study was to comprehensively evaluate the effect of weight variability on risk of CVD (any cardiovascular (CV) event, composite CV outcome, CV death, Stroke, Myocardial Infarction) and the influence of ethnicity and type 2 diabetes status on the observed association. A systematic review and meta-analysis was performed according to the meta-analyses of observational studies in epidemiology (MOOSE) guidelines. The electronic databases PubMed, Web of Science, and the Cochrane Library were searched for studies that investigated the relationship between body weight or BMI variability and CV diseases using Medical Subject Headings (MeSH) terms and keywords. The relative risks (RRs) for the outcomes were collected from studies, pooled, and analysed using a random-effects model to estimate the overall relative risk. Of 5645 articles screened, 23 studies with a total population of 15,382,537 fulfilled the prespecified criteria and were included. Individuals in the highest strata of body weight variability were found to have significantly increased risk of any CV event (RR = 1.27; 95% Confidence Interval (CI) 1.17–1.38; P < 0.0001; I2 = 97.28%), cardiovascular death (RR = 1.29; 95% CI 1.03–1.60; P < 0.0001; I2 = 55.16%), myocardial infarction (RR = 1.32; 95% CI 1.09–1.59; P = 0.0037; I2 = 97.14%), stroke (RR = 1.21; 95% CI 1.19–1.24; P < 0.0001; I2 = 0.06%), and compound CVD outcomes (RR = 1.36; 95% CI 1.08–1.73; P = 0.01; I2 = 92.41%). Similar RRs were observed regarding BMI variability and per unit standard deviation (SD) increase in body weight variability. Comparable effects were seen in people with and without diabetes, in White Europeans and Asians. In conclusion, body weight variability is associated with increased risk of CV diseases regardless of ethnicity or diabetes status. Future research is needed to prove a causative link between weight variability and CVD risk, as appropriate interventions to maintain stable weight could positively influence CVD.
Hospital-based surveillance of severe paediatric malaria in two malaria transmission ecological zones of Burkina Faso
Authors: Tiono Alfred B. , Konaté Amadou T. , Kargougou Désiré , Diarra Amidou , Ouedraogo Issa Nébié , Ouedraogo Amidou , Pagnoni Franco , Modiano David , Sirima Sodiomon B.
Published: January 2023

Background

In the current context of tailoring interventions to maximize impact, it is important that current data of clinical epidemiology guide public health programmes and health workers in the management of severe disease. This study aimed at describing the burden of severe malaria at hospital level in two areas with distinct malaria transmission intensity.

Methods

A hospital-based surveillance was established in two regional hospitals located in two areas exposed to different malaria transmission. Data on paediatric severe malaria admissions were recorded using standardized methods from August 2017 to August 2018 with an interruption during the dry season from April to June 2018.

Results

In total, 921 children with severe malaria cases were enrolled in the study. The mean age was 33.9 (± 1.3) and 36.8 (± 1.6) months in lower malaria transmission (LMT) and higher malaria transmission (HMT) areas (p = 0.15), respectively. The geometric mean of asexual P. falciparum density was significantly higher in the LMT area compared to the HMT area: 22,861 trophozoites/µL (95% CI 17,009.2–30,726.8) vs 11,291.9 trophozoites/µL (95% CI 8577.9–14,864.5). Among enrolled cases, coma was present in 70 (9.2%) participants. 196 patients (21.8%) presented with two or more convulsions episodes prior to admission. Severe anaemia was present in 448 children (49.2%). Other clinical features recorded included 184 (19.9%) cases of lethargy, 99 (10.7%) children with incoercible vomiting, 80 (8.9%) patients with haemoglobinuria, 43 (4.8%) children with severe hypoglycaemia, 37 (4.0%) cases where child was unable to drink/suck, 11 (1.2%) cases of patients with circulatory collapse/shock, and 8 cases (0.9%) of abnormal bleeding (epistaxis). The adjusted odds of presenting with coma, respiratory distress, haemoglobinuria, circulatory collapse/shock and hypoglycaemia were significantly higher (respectively 6.5 (95%CI 3.4–12.1); 1.8 (95%CI 1.0–3.2); 2.7 (95%CI 1.6–4.3); 5.9 (95%CI 1.3–27.9); 1.9 (95%CI 1.0–3.6)) in children living in the HMT area compared to those residing in the LMT area. Overall, forty-four children died during hospitalization (case fatality rate 5.0%) with the highest fatalities in children admitted with respiratory distress (26.0%) and those with hypoglycaemia (25.0%).

Conclusion

The study showed that children in the HMT area have a higher risk of presenting with coma, shock/dehydration, haemoglobinuria, hypoglycaemia, and respiratory distress. Case-fatality rate is higher among patients with respiratory distress or hypoglycaemia. Hospital surveillance provides a reliable and sustainable means to monitor the clinical presentation of severe malaria and tailor the training needs and resources allocation for case management.
What, if anything at all, do African societies themselves owe to their own citizens in terms of health?
Authors: Ngosso Thierry
Published: January 2023

The debate about global justice and health has focused so far on what developed countries owe to developing countries to advance global public health. Less attention has however been paid to the health obligations of developing countries, especially in Sub-Saharan Africa, towards their own people and how this may affect considerations about justice and health in a globalized world. This paper challenges the implicit presumption in global justice theories that African societies, because they are poor, have weaker health obligations toward their own peoples. It makes two main claims. First, despite their economic shortcomings, African governments should have the primary responsibility to protect the domestic side of the human right to health of their own citizens and dumping their own health obligations on rich countries is a disservice to the overall goal of global justice in health. Second, the health obligations of African societies towards their own people should be assessed and grounded also on theirpotentialabilities, and not exclusively on theircurrentabilities. Global justice in health cannot be reduced to what rich countries should do. It must include also what developing countries from Sub-Saharan Africa should do beyond accepting or managing any health assistance.
An exosome-based liquid biopsy signature for pre-operative identification of lymph node metastasis in patients with pathological high-risk T1 colorectal cancer
Authors: Miyazaki Katsuki , Wada Yuma , Okuno Keisuke , Murano Tatsuro , Morine Yuji , Ikemoto Tetsuya , Saito Yu , Ikematsu Hiroaki , Kinugasa Yusuke , Shimada Mitsuo , Goel Ajay
Published: January 2023

Background

According to current guidelines, more than 70% of patients with invasive submucosal colorectal cancer (T1 CRC) undergo a radical operation with lymph node dissection, even though only ~ 10% have lymph node metastasis (LNM). Hence, there is imperative to develop biomarkers that can help robustly identify LNM-positive patients to prevent such overtreatments. Given the emerging interest in exosomal cargo as a source for biomarker development in cancer, we examined the potential of exosomal miRNAs as LNM prediction biomarkers in T1 CRC.

Methods

We analyzed 200 patients with high-risk T1 CRC from two independent cohorts, including a training (n = 58) and a validation cohort (n = 142). Cell-free and exosomal RNAs from pre-operative serum were extracted, followed by quantitative reverse-transcription polymerase chain reactions for a panel of miRNAs.

Results

A panel of four miRNAs (miR-181b, miR-193b, miR-195, and miR-411) exhibited robust ability for detecting LNM in the exosomal vs. cell-free component. We subsequently established a cell-free and exosomal combination signature, successfully validated in two independent clinical cohorts (AUC, 0.84; 95% CI 0.70–0.98). Finally, we developed a risk-stratification model by including key pathological features, which reduced the false positive rates for LNM by 76% without missing any true LNM-positive patients.

Conclusions

Our novel exosomal miRNA-based liquid biopsy signature robustly identifies T1 CRC patients at risk of LNM in a preoperative setting. This could be clinically transformative in reducing the significant overtreatment burden of this malignancy.
Consumption of fruits and vegetables among adolescents in Arab Countries: a systematic review
Authors: Zeidan Widad , Taweel Haneen , Shalash Aisha , Husseini Abdullatif
Published: January 2023

Background

Adolescents’ consumption of fruits and vegetables is inadequate in most Arab countries, leading to a higher risk of poor health outcomes. This systematic review evaluates fruits and vegetables intake among adolescents in Arab countries, the proportion of adolescents meeting the dietary guidelines in these countries, and the dietary assessment tools used to assess fruits and vegetables intake.

Methods

Four databases were searched, MEDLINE, PUBMED, EMBASE, and Web of Science. Studies were eligible if they reported fruit or vegetable consumption among adolescents aged 10 to 19 in 22 Arab countries. The risk of bias in the included studies was assessed by two reviewers independently using the risk of bias tool developed by Hoy et al. Data were extracted and synthesized into three categories; frequency of fruits and vegetables consumption, mean fruits and vegetables consumption, and percentage of adolescents meeting fruits and vegetables consumption recommendations.

Results

The review included 44 articles utilizing 41 cross-sectional studies. Most studies were school-based, and data was collected from both males and females using self-administered questionnaires. Of those, validated questionnaires were used in 28 studies. According to the World Health Organization recommendation, most studies defined five fruits and vegetables servings as the adequacy cutoff point; other definitions were used in some studies. The reported mean consumption ranged between 6.1 times per week and 4.5 servings of fruits and vegetables per day. The proportion of those who met the recommendations of eating five servings per day ranged between 10 and 29%. Fruits were shown to have a lower daily intake than vegetables (4.2 to 53.7% for fruits and 7.8 to 66.3% for vegetables).

Discussion

This review indicated inadequate fruits and vegetables consumption among adolescents in Arab countries and highlighted an increased risk of non-communicable diseases and malnutrition prevalence. A limitation was the incomparability of available data between countries. Further in-depth research on the core reasons behind adolescents’ inadequacy in fruits and vegetables consumption is recommended.
Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies
Authors: Chen Dong , Su Xi , Zhu Lizhang , Jia Hao , Han Bin , Chen Haibo , Liang Qingzhuang , Hu Chenchen , Yang Hao , Liu Lisa , Li Peng , Wei Wei , Zhao Yongsheng
Published: January 2023

Backgrounds

Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed.

Methods

Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively.

Results

We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone.

Conclusions

These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.
Effect of interleukin-1 antagonist on growth of children with colchicine resistant or intolerant FMF
Authors: Pinchevski-Kadir Shiran , Gerstein Maya , Pleniceanu Oren , Yacobi Yonatan , Vivante Asaf , Granat Ortal Erez , Spielman Shiri , Oz Rotem Semo , Tirosh Irit
Published: January 2023

Introduction

Familial Mediterranean Fever (FMF) is the most common monogentic autoinflammatory disease. FMF results from mutations in MEFV, which lead to a pro-inflammatory state and increased production of Interleukin 1 beta subunit (IL-1b) by myeloid cells. Despite the overall positive results obtained with anti-IL-1 agents in FMF patients, little is known about the long-term growth impact of these drugs in the pediatric population.

Objectives

To assess the long-term body weight and height trajectories in children with FMF treated with anti-IL-1 agents.

Methods

We conducted a retrospective analysis of 646 pediatric FMF patients followed in our center, of whom 22 were treated with either anakinra (36.3%) and/or canakinumab (90.9%). Patients were assessed for demographic, clinical and genetic characteristics and were followed for a mean of 3.05 ± 1.75 years. Data of height and weight percentiles were recorded before and after treatment.

Results

The most common indication for IL-1 blockers treatment was colchicine resistance (66.6%). Ninety percent of those patients had a moderate or severe disease according to the Pras score and had higher proportion of M694V homozygosity compared with patients who did not require anti IL-1 agents (95.2% vs. 30.5%, p < 0.001). Overall, anakinra and canakinumab resulted in a complete response in 80% of patients and exhibited low rates of adverse effects. We found a significant increase in height and body weight percentiles following treatment (19.6 ± 16% vs. 30.8 ± 23%, p = 0.007, and 29.5 ± 30% vs. 39.1 ± 36%, p = 0.043, respectively).

Conclusion

Treatment with anti-IL-1 agents in children with FMF is effective and safe and may potentiate long-term growth.
Enterovirus B types cause severe infection in infants aged 0–3 months
Authors: Yang Xiaohan , Duan Lei , Zhan Wenli , Tang Yuan , Liang Lihua , Xie Jia , Luo Mingyong
Published: January 2023

Background

Enterovirus (EV) infections are being increasingly seen in younger infants, often being more severe than in older children. The risk factors of EV infection in infants have been inadequately investigated till date.

Methods

We conducted a retrospective study on hospitalized children with laboratory-confirmed EV infection (50 infants aged 0–3 months and 65 older than 3 months) at a tertiary care center in China. Prevalence, clinical characteristics, and genetic features of the virus were analyzed, and independent predictors for severe infection were assessed.

Results

Clinical findings showed that severe infection was more common in infants aged 0–3 months than in older children (78.0% vs. 35.4%, p < 0.001), with higher morbidity of pneumonia, meningitis, and sepsis (p < 0.01). EV-B types were detected more frequently in infants aged 0–3 months than in older children (88.0% vs. 7.7%, p < 0.001). Echovirus 11 was the most identified EV-B, and it recombined with E6 in P2 and P3 regions. Risk factors for severe EV infection included EV-B types infection, age less than 3 months, elevated alanine aminotransferase level, abnormal platelet count, and abnormal cerebrospinal fluid characteristics.

Conclusions

Our data indicated that EV-B types mainly cause severe infection in infants aged 0–3 months. Therefore, knowledge about EV-B types could have implications in designing effective intervention and prevention strategies for young infants with severe EV infection.
Investigating the effect of zinc supplementation on probability of relapse and mental health in patients with opioid use disorder undergoing methadone maintenance treatment
Authors: Amini Zahra , HeidariFarsani Ebrahim
Published: January 2023

Background

Considering different factors, such as high withdrawal rates in methadone maintenance treatment (MMT) programs alongside mental health (MH) problems appearing in patients with opioid use disorder and the lack of prior research on the effect of zinc supplementation in this respect, the present study aimed to investigate the effect of zinc supplementation on the probability of relapse (PoR) and MH problems in patients with opioid use disorder undergoing MMT.

Methods

For this purpose, a randomized controlled trial with a clinical basis was fulfilled on a total of 68 patients with opioid use disorder receiving MMT, allocated to two groups, viz. intervention, and control (each one consisting of 34 individuals). Then, the participants in the intervention group were given zinc supplements combined with methadone for three months, and the controls only took methadone, according to the treatment plan. The data were collected using the Relapse Prediction Scale (RPS) and the Depression, Anxiety, and Stress Scale 21 (DASS-21) before, one month after, and at the end of the intervention program.

Findings

Compared to the control group, the likelihood of drug use (p = 0.01), drug craving (p = 0.002), and the RPS total score (p = 0.002) in the intervention group was significantly lower. Moreover, the results revealed a significant decreasing trend in depression (p = 0.01), anxiety (p < 0.001), stress (p = 0.001), and the DASS-21 total score (p = 0.001) in the intervention. Compared to the control group, the DASS-21 total score (p < 0.001) in the intervention group was significantly lower.

Conclusion

Accordingly, it was concluded that zinc supplementation could reduce the PoR and improve MH problems in patients with opioid use disorder experiencing MMT. However, further research is recommended to fill the gaps.

Trial registration

The research protocol has also been listed on the Iranian Registry of Clinical Trials (IRCT) with code no. IRCT2020050904736N1.
CT ventilation image-guided helical Tomotherapy at sparing functional lungs for locally advanced lung cancer: analysis of dose-function metrics and the impact on pulmonary toxicity
Authors: Li Shuangshuang , Liu Juan , Gao Shanbao , Yin Yicai , Zhang Ling , Han Yongchao , Zhang Xishun , Li Yuanyuan , Yan Jing , Hou Zhen
Published: January 2023

Purpose

CT ventilation image (CTVI)-guided radiotherapy that selectively avoids irradiating highly-functional lung regions has potential to reduce pulmonary toxicity. Considering Helical TomoTherapy (HT) has higher modulation capabilities, we investigated the capability and characteristic of HT at sparing functional lungs for locally advanced lung cancer.

Methods and materials

Pretreatment 4DCT scans were carried out for 17 patients. Local lung volume expansion (or contraction) during inspiration is related to the volume change at a given lung voxel and is used as a surrogate for ventilation. The ventilation maps were generated from two sets of CT images (peak-exhale and peak-inhale) by deformable registration and a Jacobian-based algorithm. Each ventilation map was normalized to percentile images. Six plans were designed for each patient: one anatomical plan without ventilation map and five functional plans incorporating ventilation map which designed to spare varying degrees of high-functional lungs that were defined as the top 10%, 20%, 30%, 40%, and 50% of the percentile ventilation ranges, respectively. The dosimetric and evaluation factors were recorded regarding planning target volume (PTV) and other organs at risk (OARs), with particular attention to the dose delivered to total lung and functional lungs. An established dose-function-based normal tissue complication probability (NTCP) model was used to estimate risk of radiation pneumonitis (RP) for each scenario.

Results

Patients were divided into a benefit group (8 patients) and a non-benefit group (9 patients) based on whether the RP-risk of functional plan was lower than that of anatomical plan. The distance between high-ventilated region and PTV, as well as tumor volume had significant differences between the two groups (P < 0.05). For patients in the benefit group, the mean value of fV5, fV10, fV20, and fMLD (functional V5, V10, V20, and mean lung dose, respectively) were significantly lower starting from top 30% functional plan than in anatomical plan (P < 0.05). With expand of avoidance region in functional plans, the dose coverage of PTV is not sacrificed (P > 0.05) but at the cost of increased dose received by OARs.

Conclusion

Ventilation image-guided HT plans can reduce the dose received by highly-functional lung regions with a range up to top 50% ventilated area. The spatial distribution of ventilation and tumor size were critical factors to better select patients who could benefit from the functional plan.
Who should operate patients presenting with emergent colon cancer? A comparison of short- and long-term outcome depending on surgical sub-specialization
Authors: Arnarson Örvar , Syk Ingvar , Butt Salma Tunå
Published: January 2023

Background

Colorectal cancer presents as emergencies in 20% of the cases. Emergency resection is associated with high postoperative morbidity and mortality. The specialization of the operating team in the emergency settings differs from the elective setting, which may have an impact on outcome. The aim of this study was to evaluate short- and long-term outcomes following emergent colon cancer surgery depending on sub-specialization of the operating team.

Methods

This is a retrospective population study based on data from the Swedish Colorectal Cancer Registry (SCRCR). In total, 656 patients undergoing emergent surgery for colon cancer between 2011 and 2016 were included. The cohort was divided in groups according to specialization of the operating team: (1) colorectal team (CRT); (2) emergency surgical team (EST); (3) general surgical team (GST). The impact of specialization on short- and long-term outcomes was analyzed.

Results

No statistically significant difference in 5-year overall survival (CRT 48.3%; EST 45.7%; GST 42.5%;p = 0.60) or 3-year recurrence-free survival (CRT 80.7%; EST 84.1%; GST 77.7%21.1%;p = 0.44) was noted between the groups. Neither was any significant difference in 30-day mortality (4.4%; 8.1%; 5.5%,p = 0.20), 90-day mortality (8.8; 11.9; 7.9%,p = 0.37) or postoperative complication rate (35.5%, 35.9 30.7,p = 0.52) noted between the groups. Multivariate analysis adjusted for case-mix showed no difference in hazard ratios for long-term survival or postoperative complications. The rate of permanent stoma after 3 years was higher in the EST group compared to the CRT and GST groups (34.5% vs. 24.3% and 23.9%, respectively;p < 0.0.5).

Conclusion

Surgical sub-specialization did not significantly affect postoperative complication rate, nor short- or long-term survival after emergent operation for colon cancer. Patients operated by emergency surgical teams were more likely to have a permanent stoma after 3 years.
Posterior cruciate ligament reconstruction using PCL inlay technique with the patient supine in bicruciate ligament injury reconstruction
Authors: Piedade Sergio Rocha , Laurito Gerson Muraro , Migliorini Filippo , Maffulli Nicola
Published: January 2023

Background

Surgical reconstruction of the posterior cruciate ligament (PCL) can be technically challenging given the proximity of the popliteal artery to the PCL tibial insertion. This "no-safe zone" makes some knee surgeons less confident and willing to perform this surgical procedure.

Surgical technique

We present a PCL tibial inlay reconstruction technique using a set of instruments involving three tools (a slot cut, a bone plug positioner, and an impactor).

Conclusion

This set of instruments allows a more reproducible posteromedial approach and to produce a PCL tibial slot in a posterior cruciate ligament inlay reconstruction with the patient supine in bicruciate ligament injury reconstruction.
On Top of Everything: a study protocol for a cluster-randomised controlled trial testing a teacher training programme to teach mindfulness among students in Danish upper secondary schools and schools of health and social care
Authors: Beck Michelle Sand , Juul Lise , Frydenberg Morten , Fjorback Lone Overby
Published: January 2023

Background

Mental health is decreasing among young people in Denmark. Our primary aim is to evaluate the effectiveness of a teacher training programme to teach mindfulness as part of regular classroom teaching in Danish upper secondary schools and schools of health and social care on students’ self-reported mental well-being 6 months from baseline. Secondary aims are (1) to evaluate the effectiveness in a vulnerable subgroup as well as in the total population of students 3 and 6 months from baseline using other outcome measures on mental health and (2) to investigate the facilitators and barriers among teachers to implement mindfulness in schools.

Methods

This pragmatic cluster-randomised two-arm superiority trial includes 30 upper secondary schools, 13 schools of health and social care, 76 teachers, and approximately 1100 students aged 16 to 24 years. Our intervention is multi-level and consists of (a) a teacher training programme and (b) a mindfulness programme delivered to students. Students in control schools receive education as usual. Our primary study population is the total population of students. The primary outcome is changes in the short version of the Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS). We also evaluate the effectiveness in a vulnerable subgroup (the 15% with the lowest SWEMWBS score), as well as in the total population of students 3 and 6 months from baseline using other outcome measures on mental health. Data will be analysed using repeated measurement models taking clusters into account. Facilitators and barriers among teachers to implement mindfulness in schools will be investigated through qualitative focus group interviews.

Discussion

The trial will estimate the effectiveness of a population-based strategy on mental health in Danish young people enrolled in education.

Trial registration

ClinicalTrials.govNCT04610333. Registered on October 10 2020.
A comparison of covariate adjustment approaches under model misspecification in individually randomized trials
Authors: Tackney Mia S. , Morris Tim , White Ian , Leyrat Clemence , Diaz-Ordaz Karla , Williamson Elizabeth
Published: January 2023

Adjustment for baseline covariates in randomized trials has been shown to lead to gains in power and can protect against chance imbalances in covariates. For continuous covariates, there is a risk that the the form of the relationship between the covariate and outcome is misspecified when taking an adjusted approach. Using a simulation study focusing on individually randomized trials with small sample sizes, we explore whether a range of adjustment methods are robust to misspecification, either in the covariate–outcome relationship or through an omitted covariate–treatment interaction. Specifically, we aim to identify potential settings where G-computation, inverse probability of treatment weighting (IPTW), augmented inverse probability of treatment weighting (AIPTW) and targeted maximum likelihood estimation (TMLE) offer improvement over the commonly used analysis of covariance (ANCOVA). Our simulations show that all adjustment methods are generally robust to model misspecification if adjusting for a few covariates, sample size is 100 or larger, and there are no covariate–treatment interactions. When there is a non-linear interaction of treatment with a skewed covariate and sample size is small, all adjustment methods can suffer from bias; however, methods that allow for interactions (such as G-computation with interaction and IPTW) show improved results compared to ANCOVA. When there are a high number of covariates to adjust for, ANCOVA retains good properties while other methods suffer from under- or over-coverage. An outstanding issue for G-computation, IPTW and AIPTW in small samples is that standard errors are underestimated; they should be used with caution without the availability of small-sample corrections, development of which is needed. These findings are relevant for covariate adjustment in interim analyses of larger trials.
Pragmatic cluster randomized trial to evaluate effectiveness and implementation of EHR-facilitated collaborative symptom control in cancer (E2C2): addendum
Authors: Herrin Jeph , Finney Rutten Lila J. , Ruddy Kathryn J. , Kroenke Kurt , Cheville Andrea L.
Published: January 2023

We previously described the hypotheses, outcomes, design, and analysis for E2C2, a pragmatic stepped-wedge trial to assess an intervention to improve symptom control in patients with cancer. Subsequent consideration of the design and cohort led to the addition of a second primary hypothesis. This article describes and presents the rationale for this second hypothesis. This addendum also details a revised analytic approach, necessitated by inconsistencies in the original analytic plan. The design, outcomes, and other aspects of the protocol remain unchanged.
Phenotypic variability in traits related to flight dispersal in the wing dimorphic species Triatoma guasayana
Authors: Gigena Gisel V. , Rodríguez Claudia S. , Fiad Federico G. , Hernández María Laura , Carbajal-de-la-Fuente Ana Laura , Piccinali Romina V. , Sánchez Casaccia Paz , Rojas de Arias Antonieta , Lobbia Patricia , Abrahan Luciana , Bustamante Gomez Marinely , Espinoza Jorge , Cano Florencia , Nattero Julieta
Published: January 2023

Background

Triatoma guasayana is considered an emerging vector of Chagas disease in the Southern Cone of South America. The presence of a triatomine population with brachypterous individuals, in which both wings are reduced, has recently been reported for this species. The aim of the present study was to determine if flight-related traits varied across populations, if these traits could explain differences in flight capacity across populations and if flight-related traits are associated with geographic and/or climatic variation.

Methods

The study involved 66 male T. guasayana specimens from 10 triatomine populations. Digital images of wing, head and pronotum were used to estimate linear and geometric morphometric variables. Variations in size and shape were analysed using one-way analysis of variance and canonical variate analysis (CVA), respectively. Mantel tests were applied to analyse the relationship between morphometric and geographic distances, and the association between size measurements was analysed using Pearson’s correlation. We explored covariation between size and shape variables using partial least square analyses (PLS). The association of geographic and climatic variables with size measurements was tested using linear regression analyses. We performed PLS analyses for shape measurements.

Results

Wing size differed significantly across triatomine populations. The CVA showed that wing shape of the brachypterous population is well discriminated from that of the other populations. The Mantel test showed a positive and significant association between wing shape and geographic distances. The heads of the brachypterous population were significantly larger than those of the other populations. Similar to wing shape, the head shape of the brachypterous population was well discriminated from those of the other populations. Pronotum width did not show significant differences across populations. Geographic and climatic factors were associated with size and shape of both the wing and head, but not with pronotum width.

Conclusions

Most of the traits related to flight dispersal varied across populations. Wing shape and head shape were found to be better markers for differentiated morphological variation across populations. Head measurements also varied in accordance with this condition. Geographic and climatic variables were associated with most of the flight-related traits.

Graphical Abstract
Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort
Authors: Saleh Rasha N. M. , Hornberger Michael , Ritchie Craig W. , Minihane Anne Marie
Published: January 2023

Background

The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.

Methods

The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.

Results

APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.

Conclusion

HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.
Transient central hypoxemia due to intermittent high-degree atrioventricular block in a heart-transplanted patient diagnosed during routine electroencephalography: a case report
Authors: Raboud Matthieu , Humm Andrea M. , Vivekanantham Hari , Suter Philipp
Published: January 2023

Background

Bradycardia frequently occurs in heart-transplanted patients, mainly as a temporally restricted manifestation early after transplantation and often without symptoms. A high-degree atrioventricular block is mostly symptomatic through cerebral hypoxia induced through cerebral hypoperfusion. Only a few published cases show this specific electroencephalography result in this context. The purpose of this case is to bring attention to atypical manifestations of typical cardiac complications after heart transplantation and the importance of perseverance in the diagnostic.

Case presentation

A Central European man in his 50s with history of heart transplantation 31 years previously was admitted to the internal medicine ward for short-lived recurrent episodes of generalized weakness with multiple falls but without loss of consciousness. During routine electroencephalography, the patient perceived this recurrent sensation. This episode coincided with a transient third-degree atrioventricular block followed 8–10 seconds later by a generalized slowing of the electroencephalography, reflecting cerebral hypoxia due to cerebral hypoperfusion. Holter monitoring confirmed the diagnosis. A pacemaker was implanted, consequently resolving the episodes.

Conclusion

This case report illustrates the pathophysiological central hypoxemic origin of episodes of generalized weakness caused by a high-degree atrioventricular block in a patient surviving 29 years after heart transplant. It highlights the benefit of electroencephalography as a diagnostic tool in well-selected patients.
The role of etoposide in the treatment of adult patients with hemophagocytic lymphohistiocytosis
Authors: Zondag Timo C. E. , Lika Aglina , van Laar Jan A. M.
Published: January 2023

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92–1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.
A review of Janus kinase inhibitors for the treatment of Covid-19 pneumonia
Authors: Tanaka Yoshiya
Published: January 2023

Background

In inflamed tissue, immune cells are accumulated, and various intercellular signals are involved in the pathogenesis. Janus kinases (JAKs) are typical tyrosine kinases involved in mediating the signaling of multiple cytokines and growth factors and induce the transcription of molecules related to inflammation or immunity via the transcription factor signal transducers and activators of transcription (STAT). Hence, they have garnered significant interest as a therapeutic target. JAK inhibitors have been evaluated as a major drug for remission induction in the treatment of autoimmune diseases such as rheumatoid arthritis.

Body

Covid-19 infection due to SARS-CoV-2 has caused a pandemic, with approximately 660 million infections and 6.7 million deaths worldwide (January, 2023). The prognosis is poor and the major causes of death are respiratory failure attributed to rapid pneumonia, thromboembolism due to a cytokine storm, and multi-organ failure. As a treatment modality, molecular targeted therapy, such as cytokine-targeting therapy, is attracting attention, in addition to antiviral drugs. Baricitinib, a JAK inhibitor, is used for the treatment of severe pneumonia, in addition to antiviral drugs and glucocorticoids. The mechanism of action of baricitinib includes inhibition of viral receptor-mediated endocytosis, which involves the NF-κB activating kinase (NAK) family, and mediating the anti-cytokine effects via JAK 1/2 inhibition. It improves severe pneumonia and reduces mortality.

Conclusion

Thus, the development of molecular targeted drugs with elucidated pathological mechanisms may aid in controlling Covid-19 infection.
Causal impact of fire on a globally rare wetland plant: a 40-year Bayesian time series analysis
Authors: Landau Deborah , Cahalan Gabriel Devin , Natesan Batley Prathiba
Published: January 2023

Background

Canby’s dropwort (Oxypolis canbyi (J.M. Coult. & Rose) Fernald) was listed as federally endangered in 1986, yet the species has continued to decline and is no longer found in 11 counties throughout its former range. The seasonal wetlands in which this forb occurs are disappearing from the landscape, often closing in and transitioning to wet forest or are drained and converted to agriculture. We document the effects of reintroducing fire to the only population of O. canbyi in Maryland and examine the resulting population increase using Bayesian interrupted time series analysis with a counterfactual.

Results

After cutting woody vegetation, 3.74 times more stems of dropwort per year were produced over the baseline of no intervention. Subsequently, after fire was reintroduced, 10.80 times more dropwort stems per year were produced in comparison to the time period after cutting woody vegetation. The counterfactual prediction showed that in the absence of intervention with fire, dropwort stem production would likely have declined.

Conclusions

Cutting woody vegetation set the stage for the growth of fine fuels by increasing sun exposure on wetland grasses. It was only after fire was reintroduced that the population of plants expanded significantly in extent and flower production. A process for model selection with a directed acyclic graph followed by Bayesian interrupted time series analysis and a counterfactual was useful for causal inference. Application of fire is an important step in the recovery of the federally endangered dropwort.
Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants inATM,BRCA1,BRCA2,CHEK2, andPALB2
Authors: Yadav Siddhartha , Boddicker Nicholas J. , Na Jie , Polley Eric C. , Hu Chunling , Hart Steven N. , Gnanaolivu Rohan D. , Larson Nicole , Holtegaard Susan , Huang Huaizhi , Dunn Carolyn A. , Teras Lauren R. , Patel Alpa V. , Lacey James V. , Neuhausen Susan L. , Martinez Elena , Haiman Christopher , Chen Fei , Ruddy Kathryn J. , Olson Janet E. , John Esther M. , Kurian Allison W. , Sandler Dale P. , O'Brien Katie M. , Taylor Jack A. , Weinberg Clarice R. , Anton-Culver Hoda , Ziogas Argyrios , Zirpoli Gary , Goldgar David E. , Palmer Julie R. , Domchek Susan M. , Weitzel Jeffrey N. , Nathanson Katherine L. , Kraft Peter , Couch Fergus J.
Published: January 2023

PURPOSE

To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

METHODS

The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status.

RESULTS

Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2.

CONCLUSION

Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.
High-Dose Once-Daily Thoracic Radiotherapy in Limited-Stage Small-Cell Lung Cancer: CALGB 30610 (Alliance)/RTOG 0538
Authors: Bogart Jeffrey , Wang Xiaofei , Masters Gregory , Gao Junheng , Komaki Ritsuko , Gaspar Laurie E. , Heymach John , Bonner James , Kuzma Charles , Waqar Saiama , Petty William , Stinchcombe Thomas E. , Bradley Jeffrey D. , Vokes Everett
Published: January 2023

PURPOSE

Although level 1 evidence supports 45-Gy twice-daily radiotherapy as standard for limited-stage small-cell lung cancer, most patients receive higher-dose once-daily regimens in clinical practice. Whether increasing radiotherapy dose improves outcomes remains to be prospectively demonstrated.

METHODS

This phase III trial, CALGB 30610/RTOG 0538 (ClinicalTrials.gov identifier: NCT00632853 ), was conducted in two stages. In the first stage, patients with limited-stage disease were randomly assigned to receive 45-Gy twice-daily, 70-Gy once-daily, or 61.2-Gy concomitant-boost radiotherapy, starting with either the first or second (of four total) chemotherapy cycles. In the second stage, allocation to the 61.2-Gy arm was discontinued following planned interim toxicity analysis, and the study continued with two remaining arms. The primary end point was overall survival (OS) in the intention-to-treat population.

RESULTS

Trial accrual opened on March 15, 2008, and closed on December 1, 2019. All patients randomly assigned to 45-Gy twice-daily (n = 313) or 70-Gy once-daily radiotherapy (n = 325) are included in this analysis. After a median follow-up of 4.7 years, OS was not improved on the once-daily arm (hazard ratio for death, 0.94; 95% CI, 0.76 to 1.17; P = .594). Median survival is 28.5 months for twice-daily treatment, and 30.1 months for once-daily treatment, with 5-year OS of 29% and 32%, respectively. Treatment was tolerable, and the frequency of severe adverse events, including esophageal and pulmonary toxicity, was similar on both arms.

CONCLUSION

Although 45-Gy twice-daily radiotherapy remains the standard of care, this study provides the most robust information available to help guide the choice of thoracic radiotherapy regimen for patients with limited-stage small-cell lung cancer.