bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal approach to T-cell ALL
Authors: O'Dwyer Kristen M.
Published: December 2022

T-lineage acute lymphoblastic leukemia (T-ALL) is curable for most children and adolescent and young adult patients with contemporary frontline chemotherapy regimens. During the past decade, improved survival rates have resulted from the optimization of frontline chemotherapy regimens, the use of minimal residual disease (MRD) assessment for evaluating a patient's risk for relapse, and the intensification of treatment based on the persistence of MRD. Optimization of initial therapy is critical because relapsed T-ALL after initial intensive chemotherapy is incurable for most adult patients. Current T-ALL salvage chemotherapy regimens are minimally effective, and unlike in B-cell ALL, there are no approved antibody therapies or chimeric antigen receptor T-cell therapies for relapsed disease. Immunotherapy and small-molecule inhibitors are beginning to be tested in relapsed T-ALL and have the potential to advance the treatment. Until effective salvage strategies are discovered, however, intensive frontline therapy is required for cure. In this article I review the current frontline chemotherapy regimens for adult patients with T-ALL, summarize the novel targeted and immune therapeutics currently in early-phase clinical trials, and outline how these therapies are helping to define an optimal approach for T-ALL.
The burden of myeloma: novel approaches to disease assessment
Authors: Ho Matthew , Kourelis Taxiarchis
Published: December 2022

Novel therapies in multiple myeloma (MM) have increased the rates of conventional complete remission (CR) in patients. However, patients in CR can have highly heterogeneous outcomes. Novel and more sensitive methods of assessing residual disease burden after therapy will help prognosticate this group better and, ideally, allow individualized therapy adjustments based on response depth in the future. Here, we review novel bone marrow, peripheral blood, and imaging methods for assessing myeloma burden and discuss the opportunities and limitations of incorporating these in everyday clinical practice.
New investigational combinations for higher-risk MDS
Authors: Koenig Kristin L. , Borate Uma
Published: December 2022

Myelodysplastic syndromes (MDS) are typically a hematologic malignancy of older adults characterized by dysplastic hematopoiesis, cytopenia(s), and risk of acute myeloid leukemia transformation. The treatment approach to MDS depends largely on risk stratification of an individual's disease, most commonly using the Revised International Prognostic Scoring System, which takes into account peripheral blood cytopenias and bone marrow blast percentage and cytogenetics. The current standard of care for patients with higher-risk MDS (HR-MDS) includes hypomethylating agents (HMAs), decitabine and azacitidine, and allogenic stem cell transplant for patients able to undergo this therapy. However, leukemic transformation remains a significant challenge, and outcomes with these current therapies are still dismal. There are several novel therapies in development aiming to improve upon the outcomes of single-agent HMA therapy using combination strategies with HMAs. Here we discuss the current standard of care for HR-MDS treatment and explore some of the most promising combination therapies coming out of the pipeline for HR-MDS.
Incorporating novel agents into frontline treatment of Hodgkin lymphoma
Authors: Kambhampati Swetha , Herrera Alex F.
Published: December 2022

Classical Hodgkin lymphoma (cHL) is associated with excellent outcomes with standard frontline chemotherapy or combined modality therapy. However, up to 25% of patients will have relapsed or primary refractory (RR) cHL. Improving the cure rate with frontline treatment, treatment-related complications and late effects, and poor therapy tolerance with high relapse rates in older patients are unmet needs in the initial management of cHL. The introduction of novel therapies, including the CD30-directed antibody drug conjugate brentuximab vedotin and PD-1 blockade (ie, pembrolizumab or nivolumab), has transformed the treatment of RR cHL and has the potential to address these unmet needs in the frontline setting. Incorporation of these potent, targeted immunotherapies into frontline therapy may improve outcomes, may allow for de-escalation of therapy without sacrificing efficacy to reduce treatment complications, and may allow for well-tolerated and targeted escalation of therapy for patients demonstrating an insufficient response. In this article, we provide a case-based approach to the use of novel agents in the frontline treatment of cHL.
Do all patients with primary refractory/first relapse of HL need autologous stem cell transplant?
Authors: Moskowitz Alison J.
Published: December 2022

The standard approach to treatment of primary refractory/first relapse of classical Hodgkin lymphoma (cHL) is administration of second-line therapy (SLT) followed by consolidation with high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). Historically, this approach cured about 50% of patients. Due to improvements in supportive care, positron emission tomography–adaptive strategies, and incorporation of novel agents into SLT, contemporary studies show that about 75% of patients with primary refractory or first relapse of cHL can be cured. Recent studies evaluating incorporation of PD-1 blockade in SLT appear to show even further improvement in remission rates and bring into question whether an aggressive approach that includes HDT/AHCT is needed for everyone. To address this question, several ongoing studies are beginning to explore the possibility of avoiding or delaying HDT/AHCT for patients with primary refractory or first relapse of cHL.
Evidence-based obstetric management of women with sickle cell disease in low-income countries
Authors: Afolabi Bosede B. , Babah Ochuwa A. , Adeyemo Titilope A.
Published: December 2022

Pregnancy in women with sickle cell disease (SCD) is fraught with complications, some of which are life-threatening. Managing pregnancy in these women can be challenging, especially with poor resources, which is often the case in low-income countries. In Nigeria, for instance, up to 90% of patients pay out of pocket for medical care due to the poorly developed health insurance system, and this worsens the morbidity and mortality associated with this condition. We describe a pragmatic approach to routinely managing pregnant women with SCD in the antenatal period, showing the feasibility of effective management of these high-risk pregnancies in limited-resource settings. We also present the case of a pregnant Nigerian woman with SCD who has intrauterine growth restriction (IUGR) and acute chest syndrome (ACS), conditions that are life-threatening for the fetus and the mother, respectively, and require prompt intervention. We highlight how we successfully managed this woman in a cost-effective manner by employing relatively inexpensive tests for diagnosis and treating her effectively with oxygen, appropriate antibiotics and manual exchange blood transfusion for the ACS, and finger pulse oximeters to monitor oxygen saturation. We explore pathophysiological concepts to IUGR in women with SCD and briefly discuss the appropriate mode of delivery, including the options for pain relief in labor.
Incorporating gonadal health counseling into pediatric care of sickle cell patients
Authors: Meacham Lillian R. , Pecker Lydia H. , Gee Beatrice , Mishkin Adrienne
Published: December 2022

Discussions regarding gonadal function and possible disease or treatment-related ovarian or testicular dysfunction, sexual dysfunction, and possible future infertility can be challenging in the sickle cell disease (SCD) pediatric care setting. A construct that stratifies topics into those that are time sensitive and those that require reproductive care expertise vs address gonadal health as a part of normal SCD care may be helpful. Pediatric health care discussions of gonadal function/dysfunction for patients with SCD can include (1) time-sensitive fertility consults preceding the start of gonadotoxic therapy and (2) targeted discussions at key time points during normally scheduled hematology clinic visits. The former conversations are best led by individuals with expertise in the risk for treatment-related infertility and fertility preservation. The latter discussions can be incorporated into targeted regularly scheduled visits with hematologists. These topics can be addressed as a part of planned education in pediatric care for adolescents and incorporated into transition plans as young adults transfer care to adult providers. Although the topics of puberty and gonadal health can be uncomfortable and many complex interdisciplinary and ethical issues arise in this process, these discussions can be aided by the collaterals and teaching handouts presented in this article.
The 5 most frequently asked questions about factor Xa inhibitors
Authors: Wang Tzu-Fei , Carrier Marc
Published: December 2022

Direct oral anticoagulants (DOACs) are commonly used oral factor Xa inhibitors in recent years. However, in some special clinical situations, the appropriate use of these anticoagulants may be of concern. In this article, we address the 5 commonly asked questions regarding their use for the treatment of venous thromboembolism, including in the setting of obesity, renal impairment, gastrointestinal (GI) malignancy, catheter-related thrombosis, and drug-drug interactions. Data on the use of DOACs in the presence of significant obesity or renal failure are mainly observational. Some DOACs are shown to have an increased risk of bleeding in patients with unresected luminal GI malignancy but not others, so selection of appropriate patients is the key. Furthermore, literature on the use of DOACs for catheter-related thrombosis or when drug-drug interactions are of concern is limited, and more research is welcome.
Warm autoimmune hemolytic anemia and the best treatment strategies
Authors: Kuter David J.
Published: December 2022

Warm autoimmune hemolytic anemia (wAIHA) is characterized by evidence of red blood cell (RBC) hemolysis and a direct antiglobulin test positive for IgG and sometimes complement. While varying with the extent of the compensatory increase in RBC production, symptoms of anemia predominate, as does jaundice, the latter often exacerbated by concurrent Gilbert's syndrome. Initial treatment with corticosteroids is highly effective, with over 85% of patients responding but with less than one-third maintaining that response upon weaning. Subsequent rituximab administration in those failing corticosteroids provides complete remission in over 75% of patients and may be long-lasting. Over 50% of patients failing rituximab respond to erythropoiesis-stimulating agents or immunosuppressive agents. Splenectomy is best deferred if possible but does offer long-term remission in over two-thirds of patients. A number of new treatments for wAIHA (fostamatinib, rilzabrutinib, and FcRn inhibitors) show promise. A treatment algorithm for wAIHA is proposed to avoid the excessive use of corticosteroids.
Modulation of ZnO Nanostructure for Efficient Photocatalytic Performance
Authors: Long Peng , Peng Hao , Sun Bolin , Lan Jinshen , Wan Jing , Fei Yuchen , Ye Xiaofang , Qu Shanzhi , Ye Gengnan , He Yilin , Huang Shengli , Li Shuping , Kang Junyong
Published: December 2022

Structure has been considered to play an important role in photocatalytic performance of the semiconductors, but the intrinsic factors were rarely revealed. Herein, ZnO nanomaterials in the structures of thin film, nanowire array and nanosheet array were synthesized, and their structural characteristics, optical properties, photocurrent response and photocatalytic efficiency were compared with each other for illustrating the issue. The photoluminescence intensity decreased in the order of nanosheets, thin film and nanowires for improved lifetime of the photoexcited charges. The absorption of the nanosheets and nanowires improved obviously in the visible range with a redshift of the absorption edge than that of the thin film. The nanowires possessed the highest response current of 82.65 μA at a response time of 2.0 ms in a sensitivity of 87.93 at the light frequency of 1 Hz, and gained the largest catalytic efficiency of 2.45 μg/cm2 h for the methylene blue degradation in UV light. Nevertheless, the improvement of catalytic efficiency of the nanosheets (up to 42.4%) was much larger than that of nanowires (5.7%) and thin film (2.6%) for the Au coating. The analysis revealed that the photocatalytic efficiency of the ZnO nanomaterials was modulated by the structure as it contained different surface area, roughness, defect and doping states, vacancies, polar and non-polar crystalline faces, which would provide structural design of semiconductor nanomaterials for the photoelectric and photocatalytic applications.
Residual choledocholithiasis after choledocholithotomy T-tube drainage: what is the best intervention strategy?
Authors: Zhang Li , Li Lu , Yao Junfang , Chu Feifei , Zhang Yong , Wu Huili
Published: December 2022

Background

The best intervention approach for residual choledocholithiasis after choledocholithotomy T-tube drainage remains controversial, especially during the period of indwelling T tube and the formation of a sinus. The purpose of the study was to estimate the effects of two therapeutic modalities, namely endoscopic retrograde cholangiopancreatography (ERCP) and choledochfiberscope via the T-tube sinus tract (CDS) on residual choledocholithiasis after choledocholithotomy T-tube drainage.

Methods

A total of 112 patients with residual choledocholithiasis after choledochotomy were included in the study, 50 of which underwent ERCP and 62 patients experienced choledochoscopy via the T-tube sinus tract. The primary outcome measures included the success rate of remove biliary stones, T-tube drainage time, and the average length of hospital stay. The secondary objective was to consider incidence of adverse events including cholangitis, bile leakage, T-tube migration, pancreatitis, bleeding and perforation. After hospital discharge, patients were followed up for two years and the recurrence of choledocholithiasis was recorded.

Results

There was no significant difference in the success rate of stone removal between the two groups. Compared to CDS group, T-tube drainage time and the average length of hospital stay was significantly shorter in the ERCP group. The incidence of complications (cholangitis and bile leakage) in the ERCP group was lower than that in the CDS group, but there was no statistically significant difference. When the T-tube sinus tract is not maturation, ERCP was the more appropriate endoscopic intervention to remove residual choledocholithiasis, particularly complicated with cholangitis at this time period.

Conclusions

ERCP is a safe and effective endoscopic intervention to remove residual choledocholithiasis after choledocholithotomy T-tube Drainage without the condition of T-tube sinus tract restriction.
Study of thyroid function among COVID-19-affected and non-affected people during pre and post-vaccination
Authors: Razu Mamudul Hasan , Hossain Md. Iqbal , Ahmed Zabed Bin , Bhowmik Mousumi , Hasan Md. Kazy Ebnul , Kibria Md. Kaderi , Moni Dil Afroj , Khan Mala
Published: December 2022

The novel coronavirus COVID-19 has caused a global pandemic with many long-ranging effects on the physiological balance of the human body. The impact of COVID-19 on the thyroid axis remains uncertain. Our aim was to assess the long-term consequences of COVID-19 infection and its vaccination with thyroid hormones. Thirty laboratory-confirmed COVID-19-positive patients with no vaccination record, thirty COVID-19-negative patients with vaccination records, and ten healthy subjects were retrospectively, and cross-sectionally enrolled in this study. An ELISA assay was performed to evaluate thyroid function tests, including the total triiodothyronine (TT3), total thyroxine (TT4), and thyroid stimulating hormone (TSH). We found decreased levels of TT3, average or low plasma T4 levels, and standard or slightly decreased TSH levels in unvaccinated COVID-19-positive patients than in the healthy group, while the vaccinated COVID-19-negative group had normal thyroid hormone levels compared to controls. The correlation between TT3 and TSH levels gradually shifted from no association to a negative pattern in the unvaccinated COVID-19-positive group. Again, a highly significant negative correlation between TSH and TT3 was observed on days above 150, although a slight fluctuation was noted on day 90. This pilot study from Bangladesh shows that abnormalities in thyroid function can be observed during COVID-19 infection and after vaccination, which gradually recovers over time.
Research, education, ethics consultation: evaluating a Bioethics Unit in an Oncological Research Hospital
Authors: De Panfilis Ludovica , Magelssen Morten , Costantini Massimo , Ghirotto Luca , Artioli Giovanna , Turola Elena , Perin Marta
Published: December 2022

Background

This study aims to quantitatively and qualitatively evaluate the activities of a Bioethics Unit (BU) 5 years since its implementation (2016–2020). The BU is a research unit providing empirical research on ethical issues related to clinical practice, clinical ethics consultation, and ethical education for health care professionals (HPS).

Methods

We performed an explanatory, sequential, mixed-method, observational study, using the subsequent qualitative data to explain the initial quantitative findings. Quantitative data were collected from an internal database and analyzed by descriptive analysis. Qualitative evaluation was performed by semi-structured interviews with 18 HPs who were differently involved in the BU’s activities and analyzed by framework analysis.

Results

Quantitative results showed an extensive increment of the number of BU research projects over the years and the number of work collaborations with other units and wards. Qualitative findings revealed four main themes, concerning: 1. the reasons for contacting the BU and the type of collaboration; 2. the role of the bioethicist; 3. the impact of BU activities on HPs, in terms of developing deeper and more mature thinking; 4. the need to extend ethics support to other settings. Overall, our results showed that performing both empirical bioethics research and more traditional clinical ethics activities at the same unit would produce an impetus to increase collaboration and spread an 'ethical culture' among local HPs.

Conclusions

Our findings contribute to a growing body of literature on the models of clinical ethics support services and the role of empirical research in bioethics internationally. They also prepare the ground for the implementation of a multidisciplinary Clinical Ethics Committee (CEC) that aims to support the BU’s ethics consultation service within the local context.
Bronchial eosinophils, neutrophils, and CD8 + T cells influence asthma control and lung function in schoolchildren and adolescents with severe treatment-resistant asthma
Authors: Eller Miriam Cardoso Neves , Pierantozzi Vergani Karina , Saraiva-Romanholo Beatriz Mangueira , de Souza Xavier Costa Natália , de Brito Jôse Mára , Antonangelo Leila , Faria Caroline Silvério , Rodrigues Joaquim Carlos , Mauad Thais
Published: December 2022

Background

Studies in adult severe treatment-resistant asthma (STRA) have demonstrated heterogeneous pathophysiology. Studies in the pediatric age group are still scarce, and few include bronchial tissue analysis.

Objective

We investigated 6–18-year-old patients diagnosed with STRA in Sao Paulo, Brazil, by characterizing the different lung compartments and their correlations with asthma control and lung function.

Methods

Inflammatory profiles of 13 patients with a confirmed diagnosis of STRA were analyzed using blood, induced sputum, bronchoalveolar lavage, viral and bacterial screens and endobronchial biopsy. Inflammatory cells, cytokines, and basement membrane thickening were tested for correlations with the asthma control test (ACT) and spirometry and plethysmography parameters.

Results

Endobronchial biopsy specimens from 11 patients were viable for analysis. All biopsies showed eosinophilic infiltration. Submucosal (SM) eosinophils and neutrophils were correlated with worse lung function (pre-BD FEV1), and SM neutrophils were correlated with fixed obstruction (post-BD FEV1). Intraepithelial (IE) neutrophils were positively correlated with lung function (pre-BD sGaw). CD8 + T cells had the highest density in the IE and SM layers and were positively correlated with ACT and negatively correlated with the cytokines IL1β, IL2, IL5, IL7, IL10, IL12, IL17, GCSF, MCP-1, INF-δ, and TNFα in sputum supernatant. The ASM chymase + mast cell density correlated positively with quality-of-life score (pAQLQ) and ACT.

Conclusion

Eosinophils and SM neutrophils correlated with worse lung function, while IE neutrophils correlated with better lung function. Most importantly, CD8 + T cells were abundant in bronchial biopsies of STRA patients and showed protective associations, as did chymase + mast cells.
Blood Krebs von den Lungen-6 levels predict treatment response to antifibrotic therapy in patients with idiopathic pulmonary fibrosis
Authors: Choi Myeong Geun , Choi Sun Mi , Lee Jae Ha , Kim Joong-Yub , Song Jin Woo
Published: December 2022

Background

Antifibrotic therapy can slow disease progression (DP) in patients with idiopathic pulmonary fibrosis (IPF). However, the prognostic biomarkers for DP in patients with IPF receiving antifibrotic therapy have not been identified. Therefore, we aimed to evaluate the prognostic efficacy of serum Krebs von den Lungen-6 (KL-6) for DP in patients with IPF receiving antifibrotic therapy.

Methods

The clinical data of 188 patients with IPF who initiated antifibrotic therapy at three tertiary hospitals was retrospectively analyzed. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, diffusing capacity for carbon monoxide ≥ 15%, acute exacerbation, or deaths during 6 months after antifibrotic therapy.

Results

The mean age of patients was 68.9 years, 77.7% were male, and DP occurred in 43 patients (22.9%) during follow-up (median, 7.6 months; interquartile range, 6.2–9.8 months). There was no difference in baseline KL-6 levels between the DP and no-DP groups; however, among patients with high baseline KL-6 levels (≥ 500 U/mL), changes in KL-6 levels over 1 month were higher in the DP group than those in the non-DP group, and higher relative changes in KL-6 over 1 month were independently associated with DP (odds ratio, 1.043; 95% confidence interval 1.005–1.084) in the multivariable logistic analysis adjusted for age and FVC. In the receiver operating characteristic curve analysis, the 1-month change in KL-6 was also useful for predicting DP (area under the curve = 0.707; P < 0.012).

Conclusions

Our data suggest that the relative change in KL-6 over 1 month might be useful for predicting DP in patients with IPF receiving antifibrotic therapy when baseline KL6 is high.
Associations between migraine and major cardiovascular events in type 2 diabetes mellitus
Authors: Cheon Dae Young , Han Kyungdo , Yang Ye Seul , Kim Yerim , Lee Sang-Hwa , Kim Chulho , Sohn Jong-Hee , Oh Mi Sun , Lee Byung-Chul , Lee Minwoo , Yu Kyung-Ho
Published: December 2022

Background

Migraine is one of the most common primary headache disorders and a well-known risk factor for cardiovascular disorders. We aimed to investigate the association between migraine and major cardiovascular outcomes, including myocardial infarction (MI), ischemic stroke (IS), and cardiovascular death (CVD) in people with type 2 diabetes.

Research design and methods

A total of 2,229,598 people from the nationwide Korean National Health Insurance Service database with type 2 diabetes but without a previous history of MI and IS were included in this study. We identified patients over 20 years of age with migraine using the claim data of International Statistical Classification of Diseases Related Health Problems, Tenth Revision (ICD-10) code G43. The patients with migraine were divided according to their migraine aura status.

Results

Migraine was present in 6.3% of the study population. Cases observed for MI, IS, CVD, and all-cause death were 2.6%, 3.6%, 5.9%, and 7.9%, respectively. The diagnosis of migraine was significantly associated with an increased risk of MI, IS, and CVD. The results remained significant after adjusting for covariates, including age, sex, body mass index, alcohol intake, smoking habits, physical activity, economic status, hypertension history, dyslipidemia, and duration of type 2 diabetes (MI, adjusted hazard ratio [aHR]: 1.182, 95% confidence interval [CI]: 1.146–1.219; IS, aHR: 1.111, 95% CI 1.082–1.14; CVD, aHR: 1.143, 95% CI 1.12–1.167). In particular, the presence of aura was associated with a higher risk of MI development compared to the non-aura group. The difference became more prominent with progressing age.

Conclusions

In this nationwide population-based study, people with type 2 diabetes and migraines were found to be at a significantly higher risk for major cardiovascular events, including MI, IS, and CVD. The risk of MI and CVD significantly increased with the presence of aura symptoms among patients with migraine.
Association of biomarkers and risk scores with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus
Authors: Halabi Amera , Potter Elizabeth , Yang Hilda , Wright Leah , Sacre Julian W. , Shaw Jonathan E. , Marwick Thomas H.
Published: December 2022

Background

Subclinical LV dysfunction (LVD) identifies heart failure (HF) risk in type 2 diabetes mellitus (T2DM). We sought the extent to which clinical scores (ARIC-HF, WATCH-DM), natriuretic peptides (NTpBNP) and troponin (hs-TnT) were associated with subclinical LV dysfunction (LVD). These associations could inform the ability of these tests to identify which patients should undergo echocardiography.

Methods

Participants with T2DM were prospectively recruited from three community-based populations. ARIC-HF risk at 4 years and WATCH-DM scores were calculated from clinical data. NTpBNP and hs-TnT were measured using an electro-chemiluminescence assay. All underwent a comprehensive echocardiogram. We calculated the sensitivity and specificity of clinical scores and biomarkers to identify abnormal global longitudinal strain (GLS ≥ −16%)), diastolic function (E/e’ ≥ 14 or e’ < 8 cm/s), left atrial volume index (LAV > 34 ml/m2) and LV hypertrophy (LV mass index > 88 g/m2 (F) > 102 g/m2(M)).

Results

Of 804 participants (median age 69 years [inter-quartile range (IQR) 65–73], 36% female), clinical scores suggested significant HF risk (median ARIC-HF 8% [IQR 4–12]; WATCH-DM 10 points [IQR 8–12]), and the median NTpBNP was 50 pg/mL [IQR 25–101] and hs-TnT 9.6 pg/mL [IQR 6.8–13.6]. Abnormal GLS was present in 126 (17%), elevated E/e’ in 114 (15%), impaired e’ in 629 (78%), increased LAV in 351 (44%) and LV hypertrophy in 113 (14%). After adjustments for age, body-mass index, and renal function, each standard deviation increase in NTpBNP was associated with a GLS increase of 0.32 (p < 0.001) and hs-TnT increase by 0.26 (p < 0.001). Similar trends were observed with ARIC-HF (standardised β = 0.22, p < 0.001) and WATCH-DM (standardised β = 0.22, p < 0.001) in univariable analyses. However, none of the risk assessment tools provided satisfactory discrimination for abnormal GLS (AUC 63%), diastolic indices (e’ AUC 54–61%) or LV mass (AUC 59–67%). At a sensitivity of 90%, there was an unacceptably low (< 50%) specificity.

Conclusion

Although risk assessment based on clinical scores or biomarkers would be desirable to stratify HF risk in people with T2DM, they show a weak relationship with subclinical LVD.
Disease patterns of coronary heart disease and type 2 diabetes harbored distinct and shared genetic architecture
Authors: Xiao Han , Ma Yujia , Zhou Zechen , Li Xiaoyi , Ding Kexin , Wu Yiqun , Wu Tao , Chen Dafang
Published: December 2022

Background

Coronary heart disease (CHD) and type 2 diabetes (T2D) are two complex diseases with complex interrelationships. However, the genetic architecture of the two diseases is often studied independently by the individual single-nucleotide polymorphism (SNP) approach. Here, we presented a genotypic-phenotypic framework for deciphering the genetic architecture underlying the disease patterns of CHD and T2D.

Method

A data-driven SNP-set approach was performed in a genome-wide association study consisting of subpopulations with different disease patterns of CHD and T2D (comorbidity, CHD without T2D, T2D without CHD and all none). We applied nonsmooth nonnegative matrix factorization (nsNMF) clustering to generate SNP sets interacting the information of SNP and subject. Relationships between SNP sets and phenotype sets harboring different disease patterns were then assessed, and we further co-clustered the SNP sets into a genetic network to topologically elucidate the genetic architecture composed of SNP sets.

Results

We identified 23 non-identical SNP sets with significant association with CHD or T2D (SNP-set based association test, P < 3.70 × $${10}^{-4}$$

10

-
4

). Among them, disease patterns involving CHD and T2D were related to distinct SNP sets (Hypergeometric test, P < 2.17 × $${10}^{-3}$$

10

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3

). Accordingly, numerous genes (e.g., KLKs, GRM8, SHANK2) and pathways (e.g., fatty acid metabolism) were diversely implicated in different subtypes and related pathophysiological processes. Finally, we showed that the genetic architecture for disease patterns of CHD and T2D was composed of disjoint genetic networks (heterogeneity), with common genes contributing to it (pleiotropy).

Conclusion

The SNP-set approach deciphered the complexity of both genotype and phenotype as well as their complex relationships. Different disease patterns of CHD and T2D share distinct genetic architectures, for which lipid metabolism related to fibrosis may be an atherogenic pathway that is specifically activated by diabetes. Our findings provide new insights for exploring new biological pathways.
Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis
Authors: Quereda Cristina , Pastor Àngels , Martín-Nieto José
Published: December 2022

Dystroglycan (DG) is a glycoprotein composed of two subunits that remain non-covalently bound at the plasma membrane: α-DG, which is extracellular and heavily O-mannosyl glycosylated, and β-DG, an integral transmembrane polypeptide. α-DG is involved in the maintenance of tissue integrity and function in the adult, providing an O-glycosylation-dependent link for cells to their extracellular matrix. β-DG in turn contacts the cytoskeleton via dystrophin and participates in a variety of pathways transmitting extracellular signals to the nucleus. Increasing evidence exists of a pivotal role of DG in the modulation of normal cellular proliferation. In this context, deficiencies in DG glycosylation levels, in particular those affecting the so-called matriglycan structure, have been found in an ample variety of human tumors and cancer-derived cell lines. This occurs together with an underexpression of the DAG1 mRNA and/or its α-DG (core) polypeptide product or, more frequently, with a downregulation of β-DG protein levels. These changes are in general accompanied in tumor cells by a low expression of genes involved in the last steps of the α-DG O-mannosyl glycosylation pathway, namely POMT1/2, POMGNT2, CRPPA, B4GAT1 and LARGE1/2. On the other hand, a series of other genes acting earlier in this pathway are overexpressed in tumor cells, namely DOLK, DPM1/2/3, POMGNT1, B3GALNT2, POMK and FKTN, hence exerting instead a pro-oncogenic role. Finally, downregulation of β-DG, altered β-DG processing and/or impaired β-DG nuclear levels are increasingly found in human tumors and cell lines. It follows that DG itself, particular genes/proteins involved in its glycosylation and/or their interactors in the cell could be useful as biomarkers of certain types of human cancer, and/or as molecular targets of new therapies addressing these neoplasms.
Association of physical activity, sedentary behaviour, and daylight exposure with sleep in an ageing population: findings from the Whitehall accelerometer sub-study
Authors: Le Cornu Quentin , Chen Mathilde , van Hees Vincent , Léger Damien , Fayosse Aurore , Yerramalla Manasa S. , Sabia Séverine
Published: December 2022

Background

Ageing is accompanied by changes in sleep, while poor sleep is suggested as a risk factor for several health outcomes. Non-pharmacological approaches have been proposed to improve sleep in elderly; their impact remains to be investigated. The aim of this study was to examine the independent day-to-day associations of physical behaviours and daylight exposure with sleep characteristics among older adults.

Methods

Data were drawn from 3942 participants (age range: 60–83 years; 27% women) from the Whitehall II accelerometer sub-study. Day-to-day associations of objectively-assessed daytime physical behaviours (sedentary behaviour, light-intensity physical activity (LIPA), moderate-to-vigorous physical activity (MVPA), mean acceleration, physical activity chronotype) and daylight exposure (proportion of waking window with light exposure > 1000 lx and light chronotype) with sleep characteristics were examined using mixed models.

Results

A 10%-increase in proportion of the waking period spent sedentary was associated with 5.12-minute (4.31, 5.92) later sleep onset and 1.76-minute shorter sleep duration (95%confidence interval: 0.86, 2.66). Similar increases in LIPA and MVPA were associated with 6.69 (5.67, 7.71) and 4.15 (2.49, 5.81) earlier sleep onset respectively and around 2-minute longer sleep duration (2.02 (0.87, 3.17) and 2.23 (0.36, 4.11), respectively), although the association was attenuated for MVPA after adjustment for daylight exposure (1.11 (− 0.84, 3.06)). A 3-hour later physical activity chronotype was associated with a 4.79-minute later sleep onset (4.15, 5.43) and 2.73-minute shorter sleep duration (1.99, 3.47). A 10%-increase in proportion of waking period exposed to light> 1000 lx was associated with 1.36-minute longer sleep (0.69, 2.03), independently from mean acceleration. Associations found for sleep duration were also evident for duration of the sleep windows with slightly larger effect size (for example, 3.60 (2.37, 4.82) minutes for 10%-increase in LIPA), resulting in associations with sleep efficiency in the opposite direction (for example, − 0.29% (− 0.42, − 0.16) for 10%-increase in LIPA). Overall, associations were stronger for women than for men.

Conclusions

In this study, higher levels of physical activity and daylight exposure were associated with slightly longer sleep in older adults. Given the small effect sizes of the associations, increased physical activity and daylight exposure might not be enough to improve sleep.
Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Petter Elisabeth , Scheibenbogen Carmen , Linz Peter , Stehning Christian , Wirth Klaus , Kuehne Titus , Kelm Marcus
Published: December 2022

Background

Muscle fatigue and pain are key symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Although the pathophysiology is not yet fully understood, there is ample evidence for hypoperfusion which may result in electrolyte imbalance and sodium overload in muscles. Therefore, the aim of this study was to assess levels of sodium content in muscles of patients with ME/CFS and to compare these to healthy controls.

Methods

Six female patients with ME/CFS and six age, BMI and sex matched controls underwent 23Na-MRI of the left lower leg using a clinical 3T MR scanner before and after 3 min of plantar flexion exercise. Sodium reference phantoms with solutions of 10, 20, 30 and 40 mmol/L NaCl were used for quantification. Muscle sodium content over 40 min was measured using a dedicated plugin in the open-source DICOM viewer Horos. Handgrip strength was measured and correlated with sodium content.

Results

Baseline tissue sodium content was higher in all 5 lower leg muscle compartments in ME/CFS compared to controls. Within the anterior extensor muscle compartment, the highest difference in baseline muscle sodium content between ME/CFS and controls was found (mean ± SD; 12.20 ± 1.66 mM in ME/CFS versus 9.38 ± 0.71 mM in controls, p = 0.0034). Directly after exercise, tissue sodium content increased in gastrocnemius and triceps surae muscles with + 30% in ME/CFS (p = 0.0005) and + 24% in controls (p = 0.0007) in the medial gastrocnemius muscle but not in the extensor muscles which were not exercised. Compared to baseline, the increase of sodium content in medial gastrocnemius muscle was stronger in ME/CFS than in controls with + 30% versus + 17% to baseline at 12 min (p = 0.0326) and + 29% versus + 16% to baseline at 15 min (p = 0.0265). Patients had reduced average handgrip strength which was associated with increased average muscle tissue sodium content (p = 0.0319, R2 = 0.3832).

Conclusion

Muscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength. These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.
A comparison of health-related factors between patients diagnosed with ME/CFS and patients with a related symptom picture but no ME/CFS diagnosis: a cross-sectional exploratory study
Authors: Bernhoff Gabriella , Rasmussen-Barr Eva , Bunketorp Käll Lina
Published: December 2022

Background

In chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), the capacity for activity and participation is strongly limited. The disease definition is very broad, and considering the lack of evidence for best treatment, it is important to understand what is ME/CFS-specific in the biopsychosocial perspective in comparison with similar syndromes. The objective was to study the difference between those diagnosed with ME/CFS and those with similar symptoms but no ME/CFS diagnosis for self-perceived level of physical activity, work ability, anxiety/depression, and health-related quality of life.

Methods

This was a clinical cross-sectional study with data collected from mailed questionnaires. The following variables were compared between patients diagnosed with ME/CFS (n = 205) and those with similar symptoms but no diagnosis (n = 57); level of physical activity, Work ability index (WAI), Hospital anxiety and depression scale (HAD-A/HAD-D), and RAND-36 Physical functioning, Role limitations due to physical health problems, Role limitations due to personal or emotional problems, Social functioning, Energy/fatigue, Bodily pain, Emotional well-being, and General health perceptions. The Chi-squared test (nominal data), the Mann-Whitney U test, the Student’s t test and regression analysis were used to analyze the data.

Results

The group diagnosed with ME/CFS had a more impaired physical and mental exertion ability as compared to the group that had similar symptoms but was not diagnosed with ME/CFS, shown by a RAND-36 lower index of physical role functioning, social functioning, energy, worse pain and poorer overall health (p ≤ 0.05). In contrast, no significant group differences emerged for weekly level of physical activity, work ability, anxiety/depression, and RAND-36 Emotional role limitation and well-being.

Conclusion

Our results indicate that those with a diagnosis of ME/CFS are characterized by an impaired ability for physical or mental exertion, worse pain, and poorer overall health as compared to individuals with similar symptoms but for whom ME/CFS-diagnosis was not established. The results may be cautiously interpreted as support when focusing on patients’ self-care in terms of management of energy levels. The results must however be verified in future studies.
Association of leukocyte mitochondrial DNA copy number with longitudinal C-reactive protein levels and survival in older adults: a cohort study
Authors: Wu I-Chien , Liu Chin-San , Cheng Wen-Ling , Lin Ta-Tsung , Chen Hui-Ling , Chen Pei-Fen , Wu Ray-Chin , Huang Chen-Wei , Hsiung Chao A. , Hsu Chih-Cheng
Published: December 2022

Background

Systemic chronic inflammation occurs with age. The association of the leukocyte mitochondrial DNA copy number, a measure of mitochondrial function in aging, with the temporal profile of serum high-sensitivity C-reactive protein and mortality risk remains uncertain. The objectives of this study were to examine the association of the leukocyte mitochondrial DNA copy number with longitudinal high-sensitivity C-reactive protein levels and the association of the longitudinal high-sensitivity C-reactive protein levels with mortality risk.

Methods

This prospective cohort study included 3928 adults aged ≥ 55 years without systemic inflammation in the baseline examination of the Healthy Aging Longitudinal Study in Taiwan, which started in 2009. Each participant received leukocyte mitochondrial DNA copy number measurement using a fluorescence-based quantitative polymerase chain reaction at baseline, serum high-sensitivity C-reactive protein measurements at baseline and the follow-up examination five years later, and the ascertainment of all-cause death (until November 30, 2021). The relationships among the leukocyte mitochondrial DNA copy number, longitudinal serum high-sensitivity C-reactive protein levels, and time to all-cause mortality were examined using the joint longitudinal and survival modeling analysis.

Results

Of the 3928 participants (mean age: 69 years; 2060 [52%] were women), 837 (21%) died during follow-up. In the adjusted analysis, one standard deviation lower natural log-transformed baseline leukocyte mitochondrial DNA copy number was associated with an increase of 0.05 (95% confidence interval [CI], 0.02 to 0.08) standard deviation in serum high-sensitivity C-reactive protein in subsequent years. An increase of 1 standard deviation in instantaneous high-sensitivity C-reactive protein levels was associated with a hazard ratio (HR) for all-cause mortality of 1.22 (95% CI, 1.14 to 1.30). Similar results were obtained after further adjusting for baseline high-sensitivity C-reactive protein levels (HR [95% CI], 1.27 [1.16 to 1.38]) and after excluding those with serum high-sensitivity C-reactive protein above 10 mg/L (HR [95% CI], 1.21[1.11 to 1.31]) or 3 mg/L (HR [95% CI], 1.19 [1.06 to 1.31]) during follow-up.

Conclusions

A lower leukocyte mitochondrial DNA copy number was associated with persistently higher high-sensitivity C-reactive protein levels. Moreover, these higher time-varying high-sensitivity C-reactive protein levels were instantaneously associated with a higher risk of death.
Why is the prevailing model of joint manipulation (still) incorrect?
Authors: Evans David W.
Published: December 2022

For manipulation, this paper addresses arguably the most fundamental question that can be asked about any therapeutic intervention: what is it? In answering this question, this paper presents the prevailing model of joint manipulation (of Sandoz) and explains why this influential model is fundamentally flawed. The early research on ‘joint cracking’ that led to the development of this model is described in chronological order, alongside how this research was misinterpreted, which gave rise to the model’s flaw. Of concern, the flaw in this model makes worrying predictions that could lead to dangerous clinical decisions. Understandably, these predictions have attracted criticism over the use of manipulation as a therapeutic intervention. A corrected model, first published by Evans and Breen more than 15 years ago, is then presented and explained. Unlike the flawed model, this corrected model makes predictions in line with all available empirical data and additionally provides reassuring answers to critics. Many current definitions of manipulation have inherited the flaw from Sandoz’s model. Hence, a better, empirically derived definition, consistent with the corrected model, is now required.
Diversity of the chiropractic profession in Canada: a cross-sectional survey of Canadian Chiropractic Association members
Authors: Southerst Danielle , Bakaa Nora , Côté Pierre , Macedo Luciana , Carlesso Lisa , MacDermid Joy , Mior Silvano
Published: December 2022

Background

Little is known about the diversity of the chiropractic profession with respect to gender, sexual orientation, race, ethnicity and community of practice. This knowledge is important as profession representation of key equity seeking groups may impact quality of care and access for vulnerable communities. The aim of this cross-sectional survey was to explore the diversity of the chiropractic profession in Canada.

Methods

All registered members of the Canadian Chiropractic Association (N = 7721) were invited to participate in a web-based survey between May and June 2021. Survey questions explored diversity with respect to personal demographics (age, sex, gender, sexual orientation, race, ethnicity, language) and practice characteristics (community setting, practice type). Where possible, survey data was compared to data from the 2016 Census of the Canadian population.

Results

We received a total of 3143 survey responses (response rate—41%). The average age of our sample was 44.7 years (standard deviation 12.7). Forty-five percent were female with the same proportion (45.2%) self-identifying as women. Ninety-one percent of the sample self-identified as heterosexual. With respect to race, 80% of respondents were Caucasian. Seventy percent of chiropractors in our sample identified with Canadian ancestry and 29% with European ancestry. In comparison to the Canadian population, some visible minorities were underrepresented. The greatest discrepancy between the Canadian population and our sample was in the proportion of Black and Indigenous chiropractors. With respect to ethnicity, chiropractors identifying themselves with Canadian ancestry were overrepresented in our sample compared to others, specifically those with North American Indigenous and South, Central and Latin American ancestry. Sixty-one percent of chiropractors practiced in major cities and most work in interdisciplinary clinics (42% Complementary and Alternative Medicine and 33% rehabilitation).

Conclusions

This study provides an initial description of diversity within the chiropractic profession in Canada. Women represent less than 50% of the profession nationally. Overall, there is little racial and ethnic diversity in the chiropractic profession compared to the Canadian population, with Black and Indigenous peoples being underrepresented. Future work should focus strategies to foster the development of a more diverse chiropractic workforce.
Endoscopic-assisted descending aortic replacement through a small intercostal incision: a case report
Authors: Wada Takeshi , Sako Hidenori , Kizu Kenya , Tashima Takahiro , Takayama Tetsushi , Miyamoto Shinji
Published: December 2022

Background

Descending aortic replacement often involves making large incisions; thus, it results in massive invasions. We report the case of a patient with dilated descending aorta treated using endoscopic-assisted descending aortic replacement with essentially minimal invasions.

Case presentation

We performed endoscopic-assisted descending aortic replacement with a single incision involving six wounds by trocar puncturing on a 59-year-old man who was diagnosed with dilated descending aorta by stent graft-induced new entry. Subsequently, the patient was discharged on postoperative day 11 without any complications.

Conclusions

Despite minor incisions, our approach can be indicated to almost the same group of patients in whom the conventional approach can be performed. Our procedure involved a single incision of only 8 cm and six wounds by trocar puncturing. Thus, endoscopic-assisted surgery can be a useful option in descending aortic surgery.