bluuebunny/crossref_metadata_2025 huggingface dataset:
Updates in infection risk and management in acute leukemia
Authors: Logan C. , Koura D. , Taplitz R.
Published: December 2020

Patients with hematologic malignancies are at increased risk of infection, with associated morbidity and mortality. Patients with acute myeloid leukemia (AML) have qualitative and quantitative deficits in granulocytes predisposing to bacterial and fungal infections. Acute lymphoblastic leukemia results in qualitative deficits in lymphocytes, resulting in hypogammaglobulinemia and reduced cell-mediated immunity predisposing to certain bacterial and viral as well as fungal infections. Chemotherapeutic regimens often compound these deficits, result in prolonged periods of severe neutropenia, and disrupt mucosal barriers, further elevating infection risk. Despite advances in antimicrobial therapies and prophylaxis, acute leukemia patients with disease- and treatment-related immunosuppression remain at risk for life-threatening infection, including with resistant organisms, antimicrobial-related adverse events, and higher treatment costs. Additionally, our knowledge of infection risk and drug-drug interactions with new immune-targeted cancer therapeutics is evolving. Here, we review 3 areas in which standard practice is evolving as challenges arise and new experience is gained, including antibiotic use in febrile neutropenia, fungal prophylaxis, and use of targeted therapies.
Sequencing multiple myeloma therapies with and after antibody therapies
Authors: van de Donk Niels W. C. J.
Published: December 2020

In multiple myeloma (MM), treatment selection and sequencing become increasingly complex with the increasing number of therapeutic options, including antibodies. Choice of treatment is dependent on various factors including patient- and tumor-related features. In addition, treatment-related factors, such as type and response to prior therapy, are also critical in terms of the selection of a new treatment regimen. Furthermore, approval status and reimbursement policies influence treatment choice. At the time of first relapse, patients who received a bortezomib-based regimen can switch to lenalidomide-based treatment, whereas patients who received lenalidomide until progression can switch to a proteasome inhibitor–based therapy. Alternatively, there is increasing evidence that pomalidomide-based triplets are also effective following the development of lenalidomide-refractory disease both in early and later relapse settings. Patients who become refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies have a poor prognosis. These triple-class refractory patients may benefit from novel, recently approved agents such as XPO1 inhibitors or from participation in a clinical trial. Furthermore, retreatment with agents that were received in previous lines of therapy can also be considered in heavily pretreated patients, for example, in combination with classic cytotoxic drugs. Importantly, with the increasing use of CD38 antibodies in newly diagnosed and early relapsed/refractory MM, more information is needed on the potential value of retreatment with CD38 antibodies. With the introduction of new immunotherapies with novel modes of action, we also need a better understanding of sequencing of immunotherapeutic agents by taking into account the effect of prior therapy on immune function.
Monoclonal gammopathies of clinical significance
Authors: Dispenzieri Angela
Published: December 2020

“Monoclonal gammopathy of clinical significance” (MGCS) is the term used to describe nonmalignant monoclonal gammopathies causing important disease. MGCS is the differential diagnosis for any patient presenting with what appears to be a monoclonal gammopathy of undetermined significance but is also experiencing other unexplained symptoms. Broadly, these conditions can be separated into symptoms and signs referable to the nerves, the kidneys, and the skin. The first step in making these diagnoses is to consider them. With a particular condition in mind, the next step is to order those tests that can help confirm or dismiss a particular diagnosis. Nearly all of the renal and dermatologic conditions are diagnosed by renal and skin biopsies, respectively. The importance of a highly competent renal pathologist and dermatopathologist cannot be underestimated. Biopsy is less specific for the neuropathic conditions. Because several of the MGCSs are syndromes, recognizing other manifestations is also key. Treatment recommendations for many of these conditions are anecdotal because of their rarity, but for several of the conditions, IV immunoglobulin, rituximab, and plasma cell–directed therapy are the best options.
Existing agents, novel agents, or transplantation for high-risk MDS
Authors: Scott Bart L.
Published: December 2020

The decision algorithm for treatment of advanced myelodysplastic syndrome (MDS) (intermediate- to very high-risk by the revised International Prognostic Scoring System [IPSS-R]) is complex. Often, the appropriate choice is unknown and not currently addressed by available clinical evidence. Although allogeneic hematopoietic cell transplantation (alloHCT) is curative for some patients with MDS, there is a concurrent high risk of mortality and morbidity. Alternatively, although hypomethylating agents (HMAs) have low toxicity, they are not thought to be curative, with a median increase in overall survival of only 9 months. Initial attempts to improve outcomes with HMAs through addition of novel agents failed, but there is hope that newer combination strategies will improve outcomes. Challenging clinical questions include who should be considered for alloHCT, appropriate timing and preparation for alloHCT, and appropriate therapeutic choices for patients who are not candidates for alloHCT. Given the interplay between alloHCT and non-alloHCT approaches, a unified coordinated approach is optimal for patients with advanced MDS. When possible, patients with advanced MDS should be encouraged to enroll into clinical trials that include alloHCT and non-alloHCT approaches.
Genomics of MPN progression
Authors: Patel Anand A. , Odenike Olatoyosi
Published: December 2020

The Philadelphia chromosome–negative (Ph−) myeloproliferative neoplasms (MPNs) are a heterogenous group of hematopoietic stem cell diseases characterized by activated JAK/STAT signaling and a variable propensity toward myelofibrotic and leukemic transformation. Acquisition of somatic mutations in addition to the canonical JAK2, MPL, and CALR mutations found in MPNs is an important catalyst in the clonal evolution and progression of these disorders. In recent years, our increasing understanding of the molecular landscape of Ph− MPNs has generated important prognostic information that informs our approach to risk stratification and therapeutic decision-making. This review will focus on the critical impact of genomics on our approach to management of advanced Ph− MPNs.
Global look at nutritional and functional iron deficiency in infancy
Authors: Zimmermann Michael B.
Published: December 2020

Iron-deficiency anemia (IDA) affects many infants in low- and middle-income countries (LMICs) and may impair cognitive development and adaptive immunity. Effective interventions to improve iron intakes for infants in LMICs are urgently needed. However, absorption of oral iron fortificants and supplements is low, usually <10%, and most of the iron passes into the colon unabsorbed. In randomized controlled trials, provision of iron to infants in LMICs adversely affects their gut microbiome and increases pathogenic Escherichia coli, gut inflammation, and diarrhea. To minimize these detrimental effects of iron, it is important to provide the lowest effective dosage and maximize fractional iron absorption. Prebiotic galacto-oligosaccharides and apo-lactoferrin may prove useful in iron formulations in LMICs because they increase absorption of fortificant iron and at the same time may mitigate the adverse effects of unabsorbed iron on the infant gut. Providing well-absorbed iron early in infancy may improve immune function. Recent data from a Kenyan birth cohort suggest IDA at the time of infant vaccination impairs the response to diphtheria, pertussis, and pneumococcus vaccines. A randomized trial follow-up study reported that providing iron to Kenyan infants at the time of measles vaccination increased antimeasles immunoglobulin G (IgG), seroconversion, and IgG avidity. Because IDA is so common among infants in LMICs and because the vaccine-preventable disease burden is so high, even if IDA only modestly reduces immunogenicity of vaccines, its prevention could have major benefits.
Treatment of immune-mediated cytopenias in patients with primary immunodeficiencies and immune regulatory disorders (PIRDs)
Authors: Seidel Markus G.
Published: December 2020

Severe immune cytopenias (SICs) are rare acquired conditions characterized by immune-mediated blood cell destruction. They may necessitate emergency medical management and long-term immunosuppressive therapy, strongly compromising the quality of life. The initial diagnostic workup involves excluding malignancies, congenital cytopenias, bone marrow failure syndromes, infections, and rheumatologic diseases such as systemic lupus erythematosus. Causal factors for SIC such as primary immunodeficiencies or immune regulatory disorders, which are referred to as inborn errors of immunity (IEIs), should be diagnosed as early as possible to allow the initiation of a targeted therapy and avoid multiple lines of ineffective treatment. Ideally, this therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway; it can also act indirectly, enhancing a countermechanism against the disease-causing defect. Ultimately, the diagnosis of an underling IEI in patients with refractory SIC may lead to evaluation for hematopoietic stem cell transplantation or gene therapy as a definitive treatment. Interdisciplinary care is highly recommended in this complex patient cohort. This case-based educational review supports decision making for patients with immune-mediated cytopenias and suspected inborn errors of immunity.
How do I sequence therapy for follicular lymphoma?
Authors: Salles Gilles
Published: December 2020

In the past decade, many new agents have been introduced for the management of follicular lymphoma, and therapeutic strategies have evolved over time. The clinical benefits of the different treatments vary and, at the time of progression, are influenced by patient and disease characteristics, the duration of the interval from last treatment, and the nature of the treatments previously administered. Altogether, this results in a marked heterogeneity of clinical situations encountered during the treatment of these patients. Despite numerous trials performed in the field, there is no single standard of care for patients undergoing second-line treatment or beyond. Furthermore, patients recruited in these studies have characteristics that rarely represent the full spectrum of possible clinical presentations. Therefore, to optimally individualize treatment, all of the risks (short- and long-term) and benefits of the available options should be well known. Discussing the goals of therapy with the patient at each intervention is also critical in providing an optimal sequence of therapy.
Inherited microcytic anemias
Authors: Cappellini Maria Domenica , Russo Roberta , Andolfo Immacolata , Iolascon Achille
Published: December 2020

Inherited microcytic anemias can be broadly classified into 3 subgroups: (1) defects in globin chains (hemoglobinopathies or thalassemias), (2) defects in heme synthesis, and (3) defects in iron availability or iron acquisition by the erythroid precursors. These conditions are characterized by a decreased availability of hemoglobin (Hb) components (globins, iron, and heme) that in turn causes a reduced Hb content in red cell precursors with subsequent delayed erythroid differentiation. Iron metabolism alterations remain central to the diagnosis of microcytic anemia, and, in general, the iron status has to be evaluated in cases of microcytosis. Besides the very common microcytic anemia due to acquired iron deficiency, a range of hereditary abnormalities that result in actual or functional iron deficiency are now being recognized. Atransferrinemia, DMT1 deficiency, ferroportin disease, and iron-refractory iron deficiency anemia are hereditary disorders due to iron metabolism abnormalities, some of which are associated with iron overload. Because causes of microcytosis other than iron deficiency should be considered, it is important to evaluate several other red blood cell and iron parameters in patients with a reduced mean corpuscular volume (MCV), including mean corpuscular hemoglobin, red blood cell distribution width, reticulocyte hemoglobin content, serum iron and serum ferritin levels, total iron-binding capacity, transferrin saturation, hemoglobin electrophoresis, and sometimes reticulocyte count. From the epidemiological perspective, hemoglobinopathies/thalassemias are the most common forms of hereditary microcytic anemia, ranging from inconsequential changes in MCV to severe anemia syndromes.
Approaches for relapsed CLL after chemotherapy-free frontline regimens
Authors: Roeker Lindsey E. , Mato Anthony R.
Published: December 2020

Novel agents, including Bruton’s tyrosine kinase inhibitors (BTKi; ibrutinib, acalabrutinib), venetoclax, and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idelalisib, duvelisib), have fundamentally changed the chronic lymphocytic leukemia (CLL) treatment landscape, allowing for a chemotherapy-free paradigm for many. Randomized trials that demonstrated efficacy of these agents in the relapsed/refractory setting rarely included patients with prior novel agent exposure. Herein, we review available data, including single-arm prospective studies and retrospective cohorts, on outcomes for novel agent approaches after novel agent exposure. We examine data for subsequent treatment options in 3 specific scenarios: (1) progression of disease while receiving BTKi, (2) progression of disease after discontinuation of BTKi for intolerance, and (3) after treatment with venetoclax. Data are most robust for venetoclax-based regimens after progression on BTKi. For patients who experience progression of disease after discontinuation of BTKi for intolerance, venetoclax-based regimens and retreatment with BTKi (depending on severity of initial intolerance) are 2 data-driven options. After frontline venetoclax/obinutuzumab, subsequent treatment approaches depend on whether patients experience progression of disease during or after discontinuation of their fixed duration frontline regimen and whether venetoclax/obinutuzumab was discontinued for intolerance. After progression of disease while on venetoclax, we recommend BTKi as second-line therapy. For patients who experience progression after completion or premature discontinuation (because of intolerance) of fixed duration venetoclax/obinutuzumab, either BTKi or retreatment with venetoclax (with aggressive supportive care if prior intolerance) are reasonable considerations. Subsequent lines of therapy in these scenarios include PI3Ki and consideration of cellular therapies. Finally, clinical trial enrollment for interested patients in any line of therapy is recommended.
Extrahematopoietic manifestations of the short telomere syndromes
Authors: Schratz Kristen E.
Published: December 2020

The short telomere syndromes encompass a spectrum of clinical manifestations that present from infancy to late adulthood. They are caused by mutations in telomerase and other telomere maintenance genes and have a predominantly degenerative phenotype characterized by organ failure across multiple systems. They are collectively one of the most common inherited bone marrow failure syndromes; however, their most prevalent presentations are extrahematopoietic. This review focuses on these common nonhematologic complications, including pulmonary fibrosis, liver pathology, and immunodeficiency. The short telomere syndrome diagnosis informs clinical care, especially in guiding diagnostic evaluations as well as in the solid organ transplant setting. Early recognition allows an individualized approach to screening and management. This review illustrates a myriad of extrahematopoietic presentations of short telomere syndromes and how they impact clinical decisions.
CAR T cells vs allogeneic HSCT for poor-risk ALL
Authors: Diorio Caroline , Maude Shannon L.
Published: December 2020

For subgroups of children with B-cell acute lymphoblastic leukemia (B-ALL) at very high risk of relapse, intensive multiagent chemotherapy has failed. Traditionally, the field has turned to allogeneic hematopoietic stem cell transplantation (HSCT) for patients with poor outcomes. While HSCT confers a survival benefit for several B-ALL populations, often HSCT becomes standard-of-care in subsets of de novo ALL with poor risk features despite limited or no data showing a survival benefit in these populations, yet the additive morbidity and mortality can be substantial. With the advent of targeted immunotherapies and the transformative impact of CD19-directed chimeric antigen receptor (CAR)–modified T cells on relapsed or refractory B-ALL, this approach is currently under investigation in frontline therapy for a subset of patients with poor-risk B-ALL: high-risk B-ALL with persistent minimal residual disease at the end of consolidation, which has been designated very high risk. Comparisons of these 2 approaches are fraught with issues, including single-arm trials, differing eligibility criteria, comparisons to historical control populations, and vastly different toxicity profiles. Nevertheless, much can be learned from available data and ongoing trials. We will review data for HSCT for pediatric B-ALL in first remission and the efficacy of CD19 CAR T-cell therapy in relapsed or refractory B-ALL, and we will discuss an ongoing international phase 2 clinical trial of CD19 CAR T cells for very-high-risk B-ALL in first remission.
Fundamentals of immunology for understanding immunotherapy for lymphoma
Authors: Ansell Stephen M.
Published: December 2020

An effective antitumor immune response in patients with lymphoma would eradicate the malignant B cells and cure the patient of the disease. This, however, does not occur, and a suboptimal antitumor response results in persistence and subsequent progression of the patient’s disease. The goals of immunotherapy are therefore to restore an effective antitumor immune response by promoting immune recognition, optimizing immune activation, and supporting persistence of the immune response resulting in subsequent immunological memory. Multiple mechanisms, however, are present within the tumor microenvironment that account for an inadequate immune response. These include loss of major histocompatibility complex expression on tumor cells and subsequent inadequate antigen presentation, increased expression of immunosuppressive ligands on malignant cells, populations of immune cells with suppressive function present in the tumor, and cytokines secreted by the malignant cell or other cells in the microenvironment that promote immune exhaustion or suppress the immune response. Successful immunotherapeutic strategies are specifically addressing these issues by promoting antigen presentation, improving recognition of the malignant cell, directly activating T cells and natural killer cells, and blocking immune checkpoint signaling that would suppress the immune response. Many of these approaches have proven highly successful in patients with various subtypes of lymphoma and are now being incorporated into standard clinical practice.
Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors?
Authors: Rea Delphine
Published: December 2020

The paradigm for managing patients with chronic myeloid leukemia is evolving. In the recent past, restoring a normal life expectancy while patients are receiving never-ending targeted therapy with BCR–ABL1 tyrosine kinase inhibitors through prevention of progression to blast phase and mitigation of iatrogenic risks was considered the best achievable outcome. Now, long-term treatment-free remission with continued response off tyrosine kinase inhibitor therapy is recognized as the most optimal benefit of treatment. Indeed, numerous independent clinical trials provided solid proof that tyrosine kinase inhibitor discontinuation was feasible in patients with deep and sustained molecular responses. This article discusses when tyrosine kinase inhibitors may be safely stopped in clinical practice on the basis of the best and latest available evidence.
Lack of association between multiple polymorphisms in aryl hydrocarbon receptor (AhR) gene and cancer susceptibility
Authors: Li He , Luo Li , Wang Dan , Duan Jun , Zhang Rui
Published: December 2020

Background

The aryl hydrocarbon receptor (AhR) is commonly known as an environmental sensor. Polymorphisms in AhR gene have been implicated in susceptibility to cancer. However, the results were controversial. This study was conducted to quantitatively summarize the association between AhR polymorphisms and cancer risk by meta-analysis.

Methods

Relevant reports were searched in four databases (Embase, PubMed, Wanfang, and China National Knowledge Infrastructure). We used pooled odds ratio (OR) and 95% confidence interval (95% CI) to evaluate the strength of the association in both standard and cumulative meta-analysis. Subgroup and sensitivity analysis was also performed, and between-study heterogeneity and publication bias were checked.

Results

A total of seventeen studies referring to three AhR polymorphisms (rs2066853, rs7796976, and rs2074113) were identified, and 9557 cases and 10038 controls were included. There was no statistically significant association of AhR rs2066853 polymorphism with cancer risk in the overall population, and the negative results were repeated in subgroup analysis by the ethnicity and cancer type. Concerning AhR rs7796976 or rs2074113 polymorphism, no significant correlation was detected. Moreover, these non-significant findings were stable in sensitivity analysis, and the cumulative meta-analysis indicated a trend of no significant link between this three AhR polymorphisms and cancer risk as more data accumulated over time.

Conclusion

This meta-analysis provides evidence that the rs2066853, rs7796976, or rs2074113 polymorphism in AhR gene is not a susceptible predictor of cancer. Further clinical and functional investigation between AhR polymorphisms and cancer susceptibility are needed.
Evidence based models of care for the treatment of alcohol use disorder in primary health care settings: a systematic review
Authors: Rombouts Susan A. , Conigrave James H. , Saitz Richard , Louie Eva , Haber Paul , Morley Kirsten C.
Published: December 2020

Background

Pharmacological and behavioural treatments for alcohol use disorders (AUDs) are effective but the uptake is limited. Primary care could be a key setting for identification and continuous care for AUD due to accessibility, low cost and acceptability to patients.

We aimed to synthesise the literature regarding differential models of care for the management of AUD in primary health care settings.

Methods

We conducted a systematic review of articles published worldwide (1998-present) using the following databases; Medline, PsycINFO, Cochrane database of systematic reviews, Cochrane Central Register of Controlled Trials and Embase. The Grey Matters Tool guided the grey literature search. We selected randomised controlled trials evaluating the effectiveness of a primary care model in the management of AUD. Two researchers independently assessed and then reached agreement on the included studies. We used the Cochrane risk of bias tool 2.0 for the critical appraisal.

Results

Eleven studies (4186 participants) were included. We categorised the studies into ‘lower’ versus ‘higher’ intensity given the varying intensity of clinical care evaluated across the studies. Significant differences in treatment uptake were reported by most studies. The uptake of AUD medication was reported in 5 out of 6 studies that offered AUD medication. Three studies reported a significantly higher uptake of AUD medication in the intervention group. A significant reduction in alcohol use was reported in two out of the five studies with lower intensity of care, and three out of six studies with higher intensity of care.

Conclusion

Our results suggest that models of care in primary care settings can increase treatment uptake (e.g. psychosocial and/or pharmacotherapy) although results for alcohol-related outcomes were mixed. More research is required to determine which specific patient groups are suitable for AUD treatment in primary health care settings and to identify which models and components are most effective.

Trial Registration

PROSPERO: CRD42019120293.
Factors affecting prehospital delay in rural and urban patients with stroke: a prospective survey-based study in Southwest Germany
Authors: Ungerer Matthias N. , Busetto Loraine , Begli Nima H. , Riehle Katharina , Regula Jens , Gumbinger Christoph
Published: December 2020

Background

Reducing prehospital delay plays an important role in increasing the thrombolysis rate in patients with stroke. Several studies have identified predictors for presentation ≤4.5 h, but few compared these predictors in urban and rural communities. We aimed to identify predictors of timely presentation to the hospital and identify possible differences between the urban and rural populations.

Methods

From January to June 2017, we conducted a prospective survey of patients with stroke admitted to an urban comprehensive stroke centre (CSC) and a rural primary care centre (PCC). Predictors were identified using binary logistical regression. Predictors and patient characteristics were then compared between the CSC and PCC.

Results

Overall, 459 patients were included in our study. We identified hesitation before seeking help, awareness of the existence of a time-window, type of admission and having talked about stroke symptoms with friends/relatives who had previously had a stroke as the strongest predictors for presentation to the emergency room ≤4.5 h. Patients admitted to the rural PCC were more hesitant to seek help and less likely to contact emergency services, even though patients had comparable knowledge pertaining to stroke care concepts.

Conclusions

Patients from rural areas were more likely to be hesitant to seek help and contacted the EMS less frequently, despite similar self-awareness of having a stroke.

Educational campaigns should focus on addressing these disparities in rural populations. Affected patients should also be encouraged to talk about their symptoms and take part in educational campaigns.
A study of medication errors during the prescription stage in the pediatric critical care services of a secondary-tertiary level public hospital
Authors: Brennan-Bourdon Lorena Michele , Vázquez-Alvarez Alan O. , Gallegos-Llamas Jahaira , Koninckx-Cañada Manuel , Marco-Garbayo José Luis , Huerta-Olvera Selene G.
Published: December 2020

Background

Medication Errors (MEs) are considered the most common type of error in pediatric critical care services. Moreover, the ME rate in pediatric patients is up to three times higher than the rate for adults. Nevertheless, information in pediatric population is still limited, particularly in emergency/critical care practice. The purpose of this study was to describe and analyze MEs in the pediatric critical care services during the prescription stage in a Mexican secondary-tertiary level public hospital.

Methods

A cross-sectional study to detect MEs was performed in all pediatric critical care services [pediatric emergency care (PEC), pediatric intensive care unit (PICU), neonatal intensive care unit (NICU), and neonatal intermediate care unit (NIMCU)] of a public teaching hospital. A pharmacist identified MEs by direct observation as the error detection method and MEs were classified according to the updated classification for medication errors by the Ruíz-Jarabo 2000 working group. Thereafter, these were subclassified in clinically relevant MEs.

Results

In 2347 prescriptions from 301 patients from all critical care services, a total of 1252 potential MEs (72%) were identified, and of these 379 were considered as clinically relevant due to their potential harm. The area with the highest number of MEs was PICU (n = 867). The ME rate was > 50% in all pediatric critical care services and PICU had the highest ME/patient index (13.1). The most frequent MEs were use of abbreviations (50.9%) and wrong speed rate of administration (11.4%), and only 11.7% of the total drugs were considered as ideal medication orders.

Conclusion

Clinically relevant medication errors can range from mild skin reactions to severe conditions that place the patient’s life at risk. The role of pharmacists through the detection and timely intervention during the prescription and other stages of the medication use process can improve drug safety in pediatric critical care services.
The forehead is a better site than the sternum to check transcutaneous bilirubin during phototherapy in sick infants
Authors: Jeon Jaesung , Lim Gina , Oh Ki Won , Lee Na Mi , Park Hye Won , Chung Mi Lim
Published: December 2020

Background

To confirm the accuracy of transcutaneous bilirubin (TcB) in the neonatal intensive care unit both with and without phototherapy, and compare forehead and sternum as the TcB assessment site.

Methods

We simultaneously assessed the total serum bilirubin (TSB) and TcB at the forehead and sternum, using a JM-103 bilirubinometer. We analyzed the correlation between the TSB and TcB assessed at the forehead and sternum, with measurements classified as ‘without phototherapy’ (before phototherapy and > 24 hours after phototherapy discontinuation) and ‘with phototherapy’ (after 24 hours of phototherapy).

Results

There were 1,084 paired forehead and sternum TcB measurements, with the corresponding TSB measurement, from 384 infants. Their mean gestational age of 35.4 ± 3.2 weeks (62% were preterm) and a mean birth weight of 2434 ± 768 grams, and TSB was 6.61 ± 3.56 mg/dL. Without phototherapy, TcB values at the forehead and sternum were correlated well to the TSB value (r = 0.925 and 0.915, respectively). With phototherapy, TcB values at the forehead and sternum were significantly correlated with the TSB value, but TcB at the forehead (r = 0.751) was a better match to the TSB than was TcB at the sternum (r = 0.668). Additionally, Bland-Altman plots showed a greater degree of underestimation of the TSB by TcB at the sternum with phototherapy.

Conclusions

TcB was more accurate in infants not receiving phototherapy. During phototherapy, it is better to assess TcB at the forehead rather than at the sternum.
Effect of thermal therapy and exercises on acute low back pain: a protocol for a randomized controlled trial
Authors: Côté-Picard Claudia , Tittley Jean , Mailloux Catherine , Perreault Kadija , Mercier Catherine , Dionne Clermont E. , Roy Jean-Sébastien , Massé-Alarie Hugo
Published: December 2020

Background

Low back pain (LBP) is the first cause of years lived with disability worldwide. This is due to the development of chronic pain. Thus, it is necessary to identify the best therapeutic approaches in the acute phase of LBP to limit the transition to chronic pain. Superficial heat presents the highest level of evidence for short-term reduction in pain and disability in acute LBP. Physical activity is also recommended to avoid transition to chronic LBP, but there is a lack of evidence to determine its effect to reduce acute LBP. Also, the long-term effects of these interventions are unknown. This is a protocol for a randomized controlled trial (RCT) to determine the short and long-term effects of wearable continuous low-level thermal therapy, in combination with exercises or not, on disability and pain.

Methods/design

Sixty-nine participants with acute LBP will be randomly assigned to one of three intervention programs: 1) thermal therapy, 2) thermal therapy + exercises, and 3) control. The interventions will be applied for 7 continuous days. The primary outcome will be disability and secondary outcomes will be pain intensity, pain-related fear, self-efficacy, number of steps walked and perception of change. The evaluators will be blinded to the interventions, and participants will be blinded to other groups’ interventions. Primary and secondary outcomes will be compared between intervention groups.

Discussion

This study will provide new evidence about acute LBP treatments, to limit transition to chronicity. This will be the first study to measure the long-term effects of wearable continuous low-level thermal therapy, combined or not to exercises.

Trial registration

This RCT has been retrospectively registered on ClinicalTrials.gov (NCT03986047) on June 14th, 2019.
Multiple micronutrient supplementation improves growth and reduces the risk of anemia among infants in Gaza Strip, Palestine: a prospective randomized community trial
Authors: Albelbeisi Ali , Shariff Zalilah Mohd , Mun Chan Yoke , Rahman Hejar Abdul , Abed Yehia
Published: December 2020

Background

Infants and young children 6–24 months of age are the most nutritionally vulnerable groups, as their needs for vitamins and minerals are high relative to the amount of food they consume. This study determines the effect of Micronutrient Powder Supplementation (MNP) on growth and hemoglobin of infants in Gaza Strip, Palestine.

Method

This was a two-arm parallel-group randomized controlled trial conducted in two health care clinics of the United Nations Relief and Work Agency (UNRWA) at the Middle Area governorate of Gaza Strip, Palestine. A total of 200 healthy infants aged 6-month-old were recruited and randomized to receive 3 sachets/week of MNP for 12 months alongside with the National Micronutrient Supplement (NMS) (n = 100) or NMS alone (n = 100). Weight, length, blood hemoglobin, and dietary intakes were measured at 6, 9, 12, 15, 18, and 21 (3 months after the end of intervention) months of age. Analysis was by intention to treat.

Results

The experimental group had a higher concentration of hemoglobin at 12 and 15 months than did the control group, and a significant difference (p <  0.05) was observed at 15 months only. Significantly greater weight, length, weight-for-age, length-for-age, and weight-for-length z-scores were observed in the experimental group than that in the control group at 12 and 15 months (p <  0.05). The prevalence of anemia (18% vs. 52%) and stunting (1% vs. 11%) were higher in the control than the experimental group, respectively. After controlling for sex, similar findings were reported.

Conclusions

Addition of MNP to the existing NMS program improved the nutritional status of young children. The potential benefits of MNP supplementation on physical growth and hemoglobin should be considered in the existing NMS program.

Trial registration

ISRCTN57594793; Date of registration: 20-03-2018 (Retrospectively registered).
CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy
Authors: Cherry Jonathan D. , Meng Gaoyuan , Daley Sarah , Xia Weiming , Svirsky Sarah , Alvarez Victor E. , Nicks Raymond , Pothast Morgan , Kelley Hunter , Huber Bertrand , Tripodis Yorghos , Alosco Michael L. , Mez Jesse , McKee Ann C. , Stein Thor D.
Published: December 2020

Background

Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown.

Methods

Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer’s disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aβ42 were compared to CCL2 levels to examine possible mechanistic pathways.

Results

An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aβ42 in AD and CTE. Although levels of Aβ42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ42 trended toward an inverse relationship with CCL2 suggesting possible gender associations.

Conclusion

Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.
Safety and efficacy of a novel cephalomedullary nail in femoral shaft fractures: a retrospective observational cohort in 33 patients
Authors: De Leon Jorge C. , Tye Cooper B. , Breinholt Connor S. , Dang Khang H. , Karia Ravi A.
Published: December 2020

Background

Despite advances in femoral shaft fracture fixation, the nonunion rate remains relatively high; and there is limited data on the efficacy and failure rate of specific implants. A novel cephalomedullary nail provides the ability to treat femur shaft fractures in isolation, with associated ipsilateral femur injuries, and provides various options for proximal and distal fixation exists on the market; but literature remains limited on the safety and efficacy of this implant. The aim of this study is to evaluate the early failure rate of this cephalomedullary nail, while comparing the nonunion rate to what is currently presented in the literature. This study is the first of its kind in evaluation of a specific implant for treatment of femoral shaft fractures and ipsilateral pathology.

Methods

Patients over 18 years of age, with traumatic femur shaft fractures, treated with this particular cephalomedullary nail and available for a minimum of 3-month follow-up were included for analysis. Data was collected by retrospective chart review and review of existing radiographs. Demographic data, injury details, AO/OTA fracture classification, and implant details were recorded for each patient. Primary outcome measured was implant failures (screw or nail breakage). Secondary outcomes measured included malunion, nonunion, deep infection, post-operative complications, and need for reoperation.

Results

Of the 33 patients included for analysis, 1 patient went on to non-union. There were no cases of implant failure. The single nonunion was a high-energy mechanism, open fracture, and higher level AO/OTA classification. The remaining 32 reached radiographic union at 3 months.

Conclusion

The nonunion rate of this novel cephalomedullary nail is comparable to what is reported in the literature. This nail is a safe and effective implant to treat femoral shaft fractures with a variety of ipsilateral femoral shaft injuries and reliably leads fracture union. Further studies are needed analyzing implant failure and comparing specific implants.
Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis
Authors: De Meyer Steffi , Schaeverbeke Jolien M. , Verberk Inge M. W. , Gille Benjamin , De Schaepdryver Maxim , Luckett Emma S. , Gabel Silvy , Bruffaerts Rose , Mauroo Kimberley , Thijssen Elisabeth H. , Stoops Erik , Vanderstichele Hugo M. , Teunissen Charlotte E. , Vandenberghe Rik , Poesen Koen
Published: December 2020

Background

Blood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages.

Methods

In this prospective cross-sectional study, we quantified plasma Aβ1–42/Aβ1–40ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ1–42/Aβ1–40to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer’s disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms.

Results

ELISA and SIMOA plasma Aβ1–42/Aβ1–40detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72–0.84; SIMOA: AUC 0.79, 95% CI 0.73–0.85), and both increased the performance of a basic demographic model including only age andAPOE-ε4genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ1–42/Aβ1–40correlated similarly with amyloid-PET for both platforms (Spearmanρ = − 0.32,p <  0.0001), yet correlations with CSF Aβ1–42/t-tau were stronger for ELISA (ρ = 0.41,p = 0.002) than for SIMOA (ρ = 0.29,p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ1–42and Aβ1–40measured by SIMOA consistently underestimating those measured by ELISA.

Conclusions

ELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ1–42/Aβ1–40, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment.

Trial registration

EudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014,https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE).
Impact of percutaneous embolization versus subinguinal microsurgical ligation on semen parameters in primary varicocele patients: comparative study
Authors: Nasser Haytham M. , Hussein Ahmed , Behairy Gad M. , Abdo Mostafa
Published: December 2020

Background

Varicocele is an abnormally dilated pampiniform plexus of the veins within the spermatic cord and is considered the most common correctable cause of male factor infertility. Many approaches are described for treatment either surgical (tradition inguinal, subinguinal, and laparoscopic) or non-surgical percutaneous embolization. During the period from August 2017 to December 2018, we prospectively analyzed the preoperative and post-operative alteration of semen parameters (at 3 and 9 months) of the data collected from 63 patients with clinically evident varicocele referred to our tertiary hospital. Patients were divided into two groups: group 1, thirty-three patients who underwent subinguinal microsurgical ligation, and group 2, thirty patients who underwent percutaneous embolization.

Results

Sixty-three patients enrolled in this study were divided in two groups: group 1, patients who underwent surgery, and group 2, patients who underwent embolization; the mean age is 24.6 ± 1.27 years in group 1 and 23.7 ± 2 years in group 2; there was no statistically significant difference between the two groups as regards BMI, diabetes, hypertension, and smoking. Bilaterality was present in 15.2% of group 1 patients and 10% in group 2 patients (P value 0.06). Most of the patients were classified as grades 2 and 3 with no statistical significance regarding severity of the disease. Preoperative semen parameters for patients including sperm count, motility, and abnormal forms showed no statistically significant difference between the two groups. Post-intervention semen analysis was done twice during follow-up after 3 months and 9 months from the date of intervention. After 3 months, the semen parameters were improved in both groups in spite of the higher sperm count in group 2 but with no statistical significance. After 9 months follow-up, semen analysis showed persistent increase in sperm mobility in group 1 patients in comparison to group 2 patients. Both groups had better improvement in count of normal form with no statistical significant change.

Conclusion

Improvement of semen parameters while treating primary varicocele by either subinguinal microsurgery approach or percutaneous embolization shows equivalent outcomes.
Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study
Authors: Lehn-Stefan Angela , Peter Andreas , Machann Jürgen , Schick Fritz , Randrianarisoa Elko , Heni Martin , Wagner Robert , Birkenfeld Andreas L , Fritsche Andreas , Häring Hans-Ulrich , Staiger Harald , Stefan Norbert
Published: December 2020

Objective

Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis.

Methods

Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT).

Results

Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ –.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05).

Conclusions

Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.