bluuebunny/crossref_metadata_2025 huggingface dataset:
Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms
Authors: Gotlib Jason
Published: December 2022

The historically poor prognosis of patients with advanced systemic mastocytosis (AdvSM) and primary eosinophilic neoplasms has shifted to increasingly favorable outcomes with the discovery of druggable targets. The multikinase/KIT inhibitor midostaurin and the highly selective KIT D816V inhibitor avapritinib can elicit marked improvements in measures of mast cell (MC) burden as well as reversion of MC-mediated organ damage (C-findings) and disease symptoms. With avapritinib, the achievement of molecular remission of KIT D816V and improved survival compared with historical therapy suggests a potential to affect disease natural history. BLU-263 and bezuclastinib are KIT D816V inhibitors currently being tested in trials of AdvSM. In the new World Health Organization and International Consensus Classifications, the category of “myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions” is inclusive of rearrangements involving PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1. While the successful outcomes with imatinib in FIP1L1::PDGFRA-positive cases and PDGFRB-rearranged neoplasms have become the “poster children” of these disorders, the responses of the other TK-driven neoplasms to small-molecule inhibitors are more variable. The selective FGFR inhibitor pemigatinib, approved in August 2022, is a promising therapy in aggressive FGFR1-driven diseases and highlights the role of such agents in bridging patients to allogeneic transplantation. This review summarizes the data for these approved and investigational agents and discusses open questions and future priorities regarding the management of these rare diseases.
No crystal stair: supporting fertility care and the pursuit of pregnancy in women with sickle cell disease
Authors: Pecker Lydia H. , Nero Alecia , Christianson Mindy
Published: December 2022

Growing recognition that the ovary is an end organ in sickle cell disease (SCD), advances in SCD treatment and cure, and innovations in assisted reproductive technologies invite progressive challenges in fertility care for women with SCD. The reproductive life span of women with SCD may be reduced because ovarian reserve declines more rapidly in people with SCD compared to unaffected people. Some young women have diminished ovarian reserve, a risk factor for infertility. Referrals for fertility preservation may be offered and anticipatory guidance about when to seek infertility care provided. For a subset of people with SCD, this information is also applicable when pursuing in vitro fertilization with preimplantation genetic testing to avoid implantation of an embryo with SCD. Here we explore the dimensions of SCD-related fertility care illustrated by the case of a 28-year-old woman with hemoglobin SS disease who initially presented for a hematology consultation for preconception counseling. This case highlights the complexity of preconception SCD management and care and the need to partner with patients to help align pregnancy hopes with SCD treatment and the many associated uncertainties.
Genetics of severe congenital neutropenia as a gateway to personalized therapy
Authors: Donadieu Jean , Bellanné-Chantelot Christine
Published: December 2022

Severe congenital neutropenias (SCNs) are rare diseases, and to date about 30 subtypes have been described according to their genetic causes. Standard care aims to prevent infections and limit the risk of leukemic transformation; however, several subtypes may have additional organ dysfunction(s), requiring specialized care. Granulocyte colony-stimulating factor and hematopoietic stem cell transplantation are now the bedrock of standard care. Better understanding of SCN mechanisms now offers the possibility of adapted therapy for some entities. An inhibitor of sodium glucose cotransporter, an antidiabetic drug, may attenuate glycogen storage disease type Ib and glucose-6-phosphatase catalytic subunit 3 neutropenias by clearing 1,5-anhydroglucitol, the precursor of the phosphate ester responsible for these SCNs. Chemokine receptor CXCR4 inhibitors contribute to reversing the leukocyte defect in warts, hypoglobulinemia, infections, and myelokathexis syndrome. All these new approaches use oral drugs, which notably improve quality of life. Additionally, improved research into clonal evolution has highlighted some ways to potentially prevent leukemia, such as stimulating somatic genetic rescue, a physiological process that might limit the risk of leukemic transformation.
Modern management of Fanconi anemia
Authors: Dufour Carlo , Pierri Filomena
Published: December 2022

In this review, we present a clinical case report and discussion to outline the importance of long-term specific Fanconi anemia (FA) monitoring, and we discuss the main aspects of the general management of patients with FA and clinical complications. While several nontransplant treatments are currently under evaluation, hematopoietic stem cell transplantation (HSCT) remains the only therapeutic option for bone marrow failure (BMF). Although HSCT outcomes in patients with FA have remarkably improved over the past 20 years, in addition to the mortality intrinsic to the procedure, HSCT increases the risk and accelerates the appearance of late malignancies. HSCT offers the best outcome when performed in optimal conditions (moderate cytopenia shifting to severe, prior to transfusion dependence and before clonal evolution or myelodysplasia/acute myeloid leukemia); hence, an accurate surveillance program is vital. Haploidentical HSCT offers very good outcomes, although long-term effects on malignancies have not been fully explored. A monitoring plan is also important to identify cancers, particularly head and neck carcinomas, in very early phases. Gene therapy is still experimental and offers the most encouraging results when performed in early phases of BMF by infusing high numbers of corrected cells without genotoxic effects. Patients with FA need comprehensive monitoring and care plans, coordinated by centers with expertise in FA management, that start at diagnosis and continue throughout life. Such long-term follow-up is essential to detect complications related to the disease or treatment in this setting.
Dyskeratosis congenita and telomere biology disorders
Authors: Savage Sharon A.
Published: December 2022

Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.
New strategies for mismatched unrelated donor (MMUD) hematopoietic cell transplant (HCT)
Authors: Arslan Shukaib , Al Malki Monzr M.
Published: December 2022

With increasing numbers of patients with hematologic malignancies requiring allogeneic hematopoietic cell transplant (HCT), including minority racial and ethnic groups, the limited availability of matched related donors and matched unrelated donors remains a significant obstacle. Hence, the use of alternative donors such as haploidentical and mismatched unrelated donors (MMUDs) is on the rise. Herein, we present case studies to outline a rational and stepwise approach with a focus on the use of MMUD for HCT in patients with hematologic malignancies. We also review novel approaches used to reduce the incidence of severe graft-versus-host disease and improve HCT outcomes in patients undergoing MMUD HCT.
Novel platelet products including cold-stored platelets
Authors: Devine Dana V.
Published: December 2022

This article reviews 3 products: pathogen-inactivated platelets, cold-stored platelets, and cryoplatelets. These are all coming to a transfusion service near you in the next few years. The article reviews the limitations of these new products and highlights the gaps in our understanding of their place in patient treatment.
Thrombocytopenia and liver disease: pathophysiology and periprocedural management
Authors: Lim Hana I. , Cuker Adam
Published: December 2022

Abnormal bleeding in patients with liver disease may result from elevated portal pressure and varix formation, reduced hepatic synthesis of coagulation proteins, qualitative platelet dysfunction, and/or thrombocytopenia. Major mechanisms of thrombocytopenia in liver disease include splenic sequestration and impaired platelet production due to reduced thrombopoietin production. Alcohol and certain viruses may induce marrow suppression. Immune thrombocytopenia (ITP) may co-occur in patients with liver disease, particularly those with autoimmune liver disease or chronic hepatitis C. Drugs used for the treatment of liver disease or its complications, such as interferon, immunosuppressants, and antibiotics, may cause thrombocytopenia. Periprocedural management of thrombocytopenia of liver disease depends on both individual patient characteristics and the bleeding risk of the procedure. Patients with a platelet count higher than or equal to 50 000/µL and those requiring low-risk procedures rarely require platelet-directed therapy. For those with a platelet count below 50 000/µL who require a high-risk procedure, platelet-directed therapy should be considered, especially if the patient has other risk factors for bleeding, such as abnormal bleeding with past hemostatic challenges. We often target a platelet count higher than or equal to 50 000/µL in such patients. If the procedure is elective, we prefer treatment with a thrombopoietin receptor agonist; if it is urgent, we use platelet transfusion. In high-risk patients who have an inadequate response to or are otherwise unable to receive these therapies, other strategies may be considered, such as a trial of empiric ITP therapy, spleen-directed therapy, or transjugular intrahepatic portosystemic shunt placement.
Risk factors and screening for neurocognitive impacts of therapy
Authors: Krull Kevin R.
Published: December 2022

Long-term survivors of pediatric hematologic malignancies are at elevated risk for neurocognitive impairment. Such impairment manifests in different ways at different times during survivorship, with deficits in processing speed, attention, and memory often appearing before deficits in executive function, intelligence, and academics. Survivors exposed to therapies that directly target the central nervous system (CNS), as is the case in acute lymphoblastic leukemia, may demonstrate subtle deficits during frontline therapy, and these deficits may grow and evolve over time. Survivors who do not receive CNS-directed therapies (eg, Hodgkin lymphoma) are also at elevated risk for neurocognitive impairment, although the influence on brain function is indirect through cancer therapy impact on systemic organ function vital to brain health (eg, cardiopulmonary morbidity). Over the course of the survivor's life span, the presence and impact of neurocognitive deficits will be determined by a complex interaction between premorbid development and environment, cancer therapy and clinical care, and posttreatment recovery and health. The timing and type of these treatment and health events will dictate the approach to screening and monitoring for neurocognitive impairment.
Evidence-Based Minireview: Full dose, modified dose, or no anticoagulation for patients with cancer and acute VTE and thrombocytopenia
Authors: Patell Rushad , Zwicker Jeffrey I.
Published: December 2022

Co-incident venous thromboembolism and thrombocytopenia are frequent in patients with active malignancies. The optimal approach for anticoagulation in patients with cancer and thrombocytopenia is not established. Different strategies are often utilized including dose-reduced anticoagulation dictated by degree of thrombocytopenia or transfusing platelets in order to facilitate therapeutic anticoagulation. This minireview provides an overview of the data and we outline our approach toward anticoagulation in patients with venous thromboembolism and thrombocytopenia in the setting of cancer.
Detecting clusters of transcription factors based on a nonhomogeneous poisson process model
Authors: Wu Xiaowei , Liu Shicheng , Liang Guanying
Published: December 2022

Background

Rapidly growing genome-wide ChIP-seq data have provided unprecedented opportunities to explore transcription factor (TF) binding under various cellular conditions. Despite the rich resources, development of analytical methods for studying the interaction among TFs in gene regulation still lags behind.

Results

In order to address cooperative TF binding and detect TF clusters with coordinative functions, we have developed novel computational methods based on clustering the sample paths of nonhomogeneous Poisson processes. Simulation studies demonstrated the capability of these methods to accurately detect TF clusters and uncover the hierarchy of TF interactions. A further application to the multiple-TF ChIP-seq data in mouse embryonic stem cells (ESCs) showed that our methods identified the cluster of core ESC regulators reported in the literature and provided new insights on functional implications of transcrisptional regulatory modules.

Conclusions

Effective analytical tools are essential for studying protein-DNA relations. Information derived from this research will help us better understand the orchestration of transcription factors in gene regulation processes.
Pro-MAP: a robust pipeline for the pre-processing of single channel protein microarray data
Authors: Mowoe Metoboroghene Oluwaseyi , Garnett Shaun , Lennard Katherine , Talbot Jade , Townsend Paul , Jonas Eduard , Blackburn Jonathan Michael
Published: December 2022

Background

The central role of proteins in diseases has made them increasingly attractive as therapeutic targets and indicators of cellular processes. Protein microarrays are emerging as an important means of characterising protein activity. Their accurate downstream analysis to produce biologically significant conclusions is largely dependent on proper pre-processing of extracted signal intensities. However, existing computational tools are not specifically tailored to the nature of these data and lack unanimity.

Results

Here, we present the single-channel Protein Microarray Analysis Pipeline, a tailored computational tool for analysis of single-channel protein microarrays enabling biomarker identification, implemented in R, and as an interactive web application. We compared four existing background correction and normalization methods as well as three array filtering techniques, applied to four real datasets with two microarray designs, extracted using two software programs. The normexp, cyclic loess, and array weighting methods were most effective for background correction, normalization, and filtering respectively.

Conclusions

Thus, here we provided a versatile and effective pre-processing and differential analysis workflow for single-channel protein microarray data in form of an R script and web application (https://metaomics.uct.ac.za/shinyapps/Pro-MAP/.) for those not well versed in the R programming language.
The combination of lactate level, lactate clearance and APACHE II score better predicts short-term outcomes in critically Ill patients: a retrospective cohort study
Authors: Cao Yongmei , Yao Sijia , Shang Jiawei , Ping Feng , Tan Qin , Tian Zijun , Huang Weifeng , Li Yingchuan
Published: December 2022

Background

The mortality rate is high in critically ill patients due to the difficulty of diagnosis and treatment. Thus, it is very important to explore the predictive value of different indicators related to prognosis in critically ill patients.

Methods

This was a retrospective cohort study of patients in the intensive care unit (ICU) of the Sixth People’s Hospital in Shanghai, China. A total of 1465 ICU patients had lactate values > 2.1 mmol/L at least once within 24 h of ICU admission, and arterial blood gas was monitored more than twice during the ICU stay.

Results

The predictive value of lactate clearance at 24 h was not high, and the sensitivity and specificity were lower. The predictive value of the lactate level at baseline and the APACHE II score was higher than that of lactate clearance at 24 h in critically ill patients. The predictive value of the lactate level at baseline combined with the APACHE II score was higher than that of the lactate level at baseline or the APACHE II score alone. In addition, the predictive value of lactate clearance at 24 h combined with the APACHE II score was also significantly higher than that of lactate clearance at 24 h or the APACHE II score alone. In particular, the area under the ROC curve reached 0.900, the predictive value was markedly higher than that of the ROC alone, and the sensitivity and specificity were better when these three indicators were combined.

Conclusions

The combination of lactate level, lactate clearance and APACHE II score better predicts short-term outcomes in critically ill patients.
A successful case of electrical storm rescue after acute myocardial infarction
Authors: Liu Bin , Xie Bo , Chen Xun , Zhu Ke , Wang Cheng-Ming , Guo Shu-Hong
Published: December 2022

Background

Electrical storm (ES) is a heterogeneous clinical emergency that can present with malignant ventricular arrhythmias such as ventricular fibrillation (VF), ventricular tachycardia (VT), requiring the need for cardiac defibrillation. ES is a life-threatening condition with a high mortality rate. Successfully managing ES in the setting of acute myocardial infarction (MI) is expected to be known by physicians on call to reduce in-hospital mortality.

Case presentation

A 57-year-old man presenting with acute onset chest pain was found to have an infero-posterior ST-segment elevation myocardial infarction (STEMI) complicated by acute right ventricular MI secondary to total occlusion of the proximal right coronary artery (RCA). The patient developed ES in the form of recurrent VF that was managed successfully with electrical defibrillation, antiarrhythmic therapy with amiodarone and esmolol, endotracheal intubation, sedation, electrolyte replacement, volume resuscitation, comfort care, psychological intervention, and percutaneous coronary intervention (PCI) of the occluded epicardial artery. With these interventions used in quick succession and with the aspiration of a massive RCA thrombus, the patient was reversed to hemodynamic stability, did not have further episodes of VF, and survived the index hospitalization.

Conclusion

ES is a rare but fatal complication of acute MI. Residents on night shifts should be better prepared and equipped to deal with this rare condition. We hope our successful experience can benefit physicians on call who take care of acute MI patients that deteriorate with ES.
Outcome of burn injury and associated factor among patient visited at Addis Ababa burn, emergency and trauma hospital: a two years hospital-based cross-sectional study
Authors: Mulatu Damena , Zewdie Ayalew , Zemede Biruktawit , Terefe Bewuketu , Liyew Bikis
Published: December 2022

Background

Burn is one of the critical health problems worldwide. Developing countries with sub-Saharan and Asian populations are affected more. Its mortality and non-fatal complications depend on several factors including age, sex, residency, cause, the extent of the burn, and time and level of care given.

Objective

The purpose of this study was to assess the outcome of burn injury and its associated factor among patients who visited Addis Ababa burn emergency and trauma hospital.

Methods

The institutional-based, retrospective cross-sectional study design was conducted from April 1, 2019, to March 30, 2021. After checking the data for its consistency the data were entered and analyzed by using SPSS version 25. A total of 241 patients who had visited Addis Ababa burn, emergency and trauma Hospitals after sustained burn injury were recruited through convenience sampling method for final analysis. Model goodness-of-fit was checked by Hosmer and Lemeshow test (0.272). After checking multi-collinearity both the bi-variable and multivariable logistic regression model was fitted and variables having ap-value less than or equal to 0.05 at 95% CI in the multivariable analysis were considered statistically significant.

Result

Adults (age 15 to 60 years) are the most affected groups accounting for 55.2% followed by pediatric age groups (age <15 years) (43.6%) and the elderly (age > 60 years) (1.2%). Scald burn was the major cause accounting for 39 % followed by Flame burn (33.6%), Electrical burn (26.6%), and chemical burn (0.8%). The mean TBSA% was 15.49%, ranging from1% to 64%. Adult males are more affected by electrical burns while adult females and the elderly encounter flame burn. 78.4% of patients were discharged without complications, 14.9% were discharged with complications and 6.6% died. The commonest long-term complication is the amputation of the extremity (19, 7.9%). Age greater than 60 years and TBSA% greater than 30% is a strong predictors of mortality with odds of 2.2 at 95% CI of [1.32, 3.69] and 8.7 at 95% CI of [1.33, 57.32] respectively.

Conclusion and recommendation

The mortality rate show decrement from previous studies. Overall scald burn is common in all age groups but electrical burns and flame burns affected more adult and elderly age groups. Extremities were by far, the commonest affected body parts. The extent of burn injury and the age of the patient independently predict mortality. Early intervention will reduce mortality and complications.
Prognostic value of a nomogram based on peripheral blood immune parameters in unresectable hepatocellular carcinoma after intensity-modulated radiotherapy
Authors: Li Jian-Xu , He Mei-Ling , Qiu Mo-Qin , Yan Liu-Ying , Long Mei-Ying , Zhong Jian-Hong , Zhang Rui-Jun , Liang Chun-Feng , Pang Ya-Dan , He Jun-Kun , Chen Qian-Qian , Weng Jin-Xia , Liang Shi-Xiong , Xiang Bang-De
Published: December 2022

Background

For patients with unresectable hepatocellular carcinoma (uHCC), intensity-modulated radiotherapy (IMRT) has become one of the options for clinical local treatment. Immune parameters, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and systemic immune inflammatory (SII), predict survival in various cancers. This study aimed to determine whether peripheral immune parameters can predict survival in patients with uHCC undergoing IMRT and establish a clinically useful prognostic nomogram for survival prediction.

Methods

The clinical data of 309 HCC patients were retrospectively analyzed and randomly divided into training (n = 216) and validation (n = 93) cohorts. PLR, NLR and SII were collected before and after IMRT. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors affecting survival, which were used to generate a nomogram.

Results

The median survival was 16.3 months, and significant increases in PLR, NLR, and SII were observed after IMRT (P < 0.001). High levels of immune parameters were associated with poor prognosis (P < 0.001); enlarged spleen, Barcelona clinic liver cancer stage (B and C), post-SII, and delta-NLR were independent risk factors for survival and were included in the nomogram, which accurately predicted 3- and 5-year survival. The nomogram was well verified in the validation cohort.

Conclusions

High levels of immune parameters are associated with poor prognosis in uHCC patients receiving IMRT. Our nomogram accurately predicts the survival of patients with uHCC receiving IMRT.
Can frailty in conjunction with FRAX identify additional women at risk of fracture - a longitudinal cohort study of community dwelling older women
Authors: Bartosch Patrik , Malmgren Linnea
Published: December 2022

Background

Fracture risk assessment is still far from perfect within the geriatric population. The overall aim of this study is to better identify older women at risk for fractures, using a quantitative measure of frailty in conjunction with the web-based Fracture Risk Assessment Tool (FRAX®).

Methods

This study was performed in the Osteoporosis Risk Assessment (OPRA) cohort of n = 1023, 75-year-old women followed for 10-years. A frailty index (FI) of ‘deficits in health’ was created, and FRAX 10-year probability for major osteoporotic and hip fractures was calculated and bone mineral density measured. Incident fractures were continuously registered for 10-years. Receiver Operating Characteristic (ROC) curves were used to compare FI, FRAX and the combination FI + FRAX as instruments for risk prediction. Discriminative ability was estimated by comparing Area Under the Curve (AUC). In addition, using guidelines from the Swedish Osteoporosis Foundation, a category of low risk women who would not have been recommended for pharmacological treatment (non-treatment group) was identified, categorized by frailty status and for relative risk analysis, hazard ratios (HR) and 95% confidence intervals were calculated using Cox proportional hazard regressions.

Results

For hip fracture, FRAX and frailty performed almost equally (HIP AUC 10y: 0.566 vs. 0.567, p = 0.015 and p = 0.013). Next, FI was used in conjunction with FRAX; proving marginally better than either score alone (AUC 10y: 0.584, p = 0.002). Comparable results were observed for osteoporotic fracture.

In the non-treatment group (564 women), being frail was associated with higher 10y hip fracture risk (HR 2.01 (1.13–3.57)), although failing to reach statistical significance for osteoporotic fracture (HR 1.40 (0.97–2.01).

The utility of measuring frailty was also demonstrated when using T-score as an index of bone density to define fracture risk. Among n = 678 non-osteoporotic women, frailty added to the 10-year fracture risk (Hip; HR 2.22 (1.35–3.71); Osteoporotic fracture; HR 1.57 (1.15–2.14)).

Conclusions

While the addition of frailty to FRAX marginally improved fracture prediction, applying a frailty measurement to a group of ‘low risk’ women, identified a set of individuals with high actual hip fracture risk that would not be prioritized for pharmacological treatment. Further cost-benefit analysis studies are needed to formally test potential benefit.
PerBrain: a multimodal approach to personalized tracking of evolving state-of-consciousness in brain-injured patients: protocol of an international, multicentric, observational study
Authors: Willacker L. , Raiser T. M. , Bassi M. , Bender A. , Comanducci A. , Rosanova M. , Sobel N. , Arzi A. , Belloli L. , Casarotto S. , Colombo M. , Derchi C. C. , Fló Rama E. , Grill E. , Hohl M. , Kuehlmeyer K. , Manasova D. , Rosenfelder M. J. , Valota C. , Sitt J. D.
Published: December 2022

Background

Disorders of consciousness (DoC) are severe neurological conditions in which consciousness is impaired to various degrees. They are caused by injury or malfunction of neural systems regulating arousal and awareness. Over the last decades, major efforts in improving and individualizing diagnostic and prognostic accuracy for patients affected by DoC have been made, mainly focusing on introducing multimodal assessments to complement behavioral examination. The present EU-funded multicentric research project “PerBrain” is aimed at developing an individualized diagnostic hierarchical pathway guided by both behavior and multimodal neurodiagnostics for DoC patients.

Methods

In this project, each enrolled patient undergoes repetitive behavioral, clinical, and neurodiagnostic assessments according to a patient-tailored multi-layer workflow. Multimodal diagnostic acquisitions using state-of-the-art techniques at different stages of the patients’ clinical evolution are performed. The techniques applied comprise well-established behavioral scales, innovative neurophysiological techniques (such as quantitative electroencephalography and transcranial magnetic stimulation combined with electroencephalography), structural and resting-state functional magnetic resonance imaging, and measurements of physiological activity (i.e. nasal airflow respiration). In addition, the well-being and treatment decision attitudes of patients’ informal caregivers (primarily family members) are investigated. Patient and caregiver assessments are performed at multiple time points within one year after acquired brain injury, starting at the acute disease phase.

Discussion

Accurate classification and outcome prediction of DoC are of crucial importance for affected patients as well as their caregivers, as individual rehabilitation strategies and treatment decisions are critically dependent on the latter. The PerBrain project aims at optimizing individual DoC diagnosis and accuracy of outcome prediction by integrating data from the suggested multimodal examination methods into a personalized hierarchical diagnosis and prognosis procedure. Using the parallel tracking of both patients’ neurological status and their caregivers’ mental situation, well-being, and treatment decision attitudes from the acute to the chronic phase of the disease and across different countries, this project aims at significantly contributing to the current clinical routine of DoC patients and their family members.

Trial registration

ClinicalTrials.gov, NCT04798456. Registered 15 March 2021 – Retrospectively registered.
Prolonged neurologic deficits with brain MRI changes following ECT in an adolescent with a CACNA1a-related disorder; a case report
Authors: Vithayathil Joseph , Freeman Colbey , Jacobwitz Marin , Schwartz Erin Simon , Agarwal Sonika
Published: December 2022

Background

Electroconvulsive therapy is used to treat depression and schizophrenia with infrequent use in pediatric patients. We report a case of an adolescent with autism spectrum disorder and acute catatonia that presented with status epilepticus (SE) and prolonged neurologic deficits with unilateral left cerebral edema on imaging following unilateral electroconvulsive therapy (ECT) on the right side, subsequently found to have a CACNA1a pathogenic variant. This case highlights a potential adverse effect of ECT in patients with CACNA1a related disorders.

Case

The patient received unilateral ECT to the right side and subsequently had an episode of SE with right-sided hemiplegia for 72 h prior to regaining some function with persistent mild right-hand weakness that persisted for at least 1–2 weeks. A brain MRI 2 days after ECT was unremarkable, but a repeat MRI on day four of admission showed left hemisphere cortical diffusion restriction, increased perfusion and T2 prolongation suggestive of cortical edema. They had whole exome genetic testing sent after discharge that showed a known pathogenic CACNA1a variant (p.I1709T). CACNA1a encodes the P/Q type calcium channels and deleterious variants in this gene result in a channelopathy associated with a spectrum of neurodevelopmental disorders that include autism spectrum disorder, hemiplegic migraine with unilateral cerebral edema, epileptic encephalopathies, or episodic ataxia syndromes.

Conclusion

A literature review of ECT and neurologic deficits showed that most neurologic deficits resolve within 30 min of ECT. Case reports of prolonged deficits are rare and there are no prior reports of acute MRI changes related to ECT. Thus, the acute deterioration and MRI findings in this patient are likely related to the underlying CACNA1a channelopathy disorder with ECT as a precipitating event. This case report suggests care should be taken when using ECT in patients with pathogenic variants in CACNA1a. Furthermore, it reinforces the utility and importance of expanded genetic testing in patients with neurodevelopmental disorders as findings can provide valuable information that can guide treatment decisions.
Partnership, living arrangements, and low birth weight: evidence from a population-based study on Spanish mothers
Authors: Dello Iacono Chiara , Requena Miguel , Stanek Mikolaj
Published: December 2022

Background

Birth weight is considered a crucial indicator of individual and population health, as it determines a newborn’s growth and development. An extensive body of research has explored various determinants of perinatal health, including the impact of living arrangements. This population-based study analyzes the relationship between mothers’ partnership status and household structure and children’s low birth weights. It addresses two basic research objectives: on one hand, how living/not living in a couple affects birth weight; on the other, how partnership status impact on birthweight when mothers live in extended households with other non-nuclear members.

Methods

A novel database provided by the Spanish Office for National Statistics (INE), which links the 2011 census with births registered from 2011 to 2015 (sample size 22,433) is used. Llogistic regression models are estimated tto obtain adjusted odds ratios (OR) for the relative effects of living arrangements and other covariates such as characteristics of births and mothers’ socioeconomic profiles, on birth weight.

Results

Differences in low-birth-weight rates may be attributed to the dissimilar socio-demographic characteristics of the groups of mothers in the different coresidential situations. Although our models revealed that the impact of the covariates on birth weight was similar to that shown by previous studies, this was not the case for the effect of the main explanatory variable. Contrary to expectations, the presence/absence of a male partner in nuclear or in extended households does not reveal significant protection against low birth weight. Children born in households in which the male partner was absent were not more likely to have a low birth weight. On the other hand, analyzing the possible protective effect of extended households, we did not detect significant differences in the likelihood of low birth weight between single mothers without and with non-nuclear coresidents in their households.

Conclusions

Our analysis provides novel evidence regarding the effect of partnership status and household type on perinatal health in Spain. First, contrary to what has been observed in previous studies in Spain and elsewhere, our study shows that living without a partner has no effect on low birth weight. Second, we reveal that households including non-nuclear coresidents are associated with low birth weight suggesting that even in a basically familist societal context such as the Spanish one, the extended family does not fully protect against poor perinatal outcomes.
Time to first antenatal care booking and its determinants among pregnant women in Ethiopia: survival analysis of recent evidence from EDHS 2019
Authors: kitaw Tegene Atamenta , Haile Ribka Nigatu
Published: December 2022

Background

Antenatal care is one of the components of the maternal and child continuum of care. Timely booking ANC during pregnancy is of utmost importance to guarantee the best possible health outcomes for women and children. Inappropriate timing of the first ANC booking is associated with poor pregnancy outcomes, including perinatal death, stillbirth, and early neonatal death. According to WHO focused ANC recommendation, every mother should start booking ANC within the first 12 weeks of gestational age. However, in developing countries, including Ethiopia, many pregnant mothers were not booking ANC at the recommended time. Thus, this study aims to assess the time to first ANC booking and its determinants in Ethiopia.

Methods

A survival analysis was conducted to determine time to first ANC booking among 3917 weighted study subjects. The data were extracted from EDHS 2019 using STATA version 17 software. A Kaplan Meier survivor curve was computed to estimate the time of first ANC booking. A Long-rank test was used to compare the difference in survival curves. Weibull Inverse Gaussian shared frailty model was used to identify significant predictors. On multivariable analysis, variables having a p-value of ≤ 0.05 are considered statistically significant.

Results

The overall median survival time was four months. The significant determinant of time to first ANC booking are residence (rural [ϕ = 1.111, 95CI: 1.060, 1.164), mother educational level (primary education [ϕ = 0.945, 95CI: 0.915, 0.977], secondary and above educational [ϕ = 0.857, 95CI: 0.819, 0.896]) and wealth index (middle [0.948 (ϕ = 0.948, 95CI: 0.911, 0.986) and rich [ϕ = 0.904, 95CI: 0.865, 0.945])

Conclusion

The median time for first ANC booking is 4 month, which is higher than the WHO recommended time. The timing of the first ANC booking in Ethiopia was mainly influenced by the residence of women, mother educational level, and wealth index. It is strongly recommended to expose mothers to educational materials and other awareness-creation campaigns, as well as to support disadvantaged women, such as the uneducated, poor, and those living in rural or remote areas.
PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry
Authors: Pagadala Meghana S. , Linscott Joshua A. , Talwar James V. , Seibert Tyler M. , Rose Brent , Lynch Julie , Panizzon Matthew , Hauger Richard , Hansen Moritz H. , Sammon Jesse D. , Hayn Matthew H. , Kader Karim , Carter Hannah , Ryan Stephen T.
Published: December 2022

Background

Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance.

Methods

African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis.

Results

We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60–0.63] and 0.65 [0.64–0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry.

Conclusions

African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies.
Case presentation of 8-year follow up of recurrent malignant duodenal Insulinoma and lymph node metastases and literature review of malignant Insulinoma management
Authors: Walker Michelle P. , Shenoy Vikram , Metz David C. , Stanley Charles A. , Fraker Douglas , Chandrasekhara Vinay , Amaro Anastassia
Published: December 2022

Background

Insulinoma is an uncommon insulin-secreting neuroendocrine tumor that presents with severe recurrent hypoglycemia. Although cases of extrapancreatic insulinomas have been reported, the majority of insulinomas occur in the pancreas. The number of reported cases of ectopic insulinomas with follow-up assessments is limited and they do not report disease recurrence. The current report presents the first documented case of recurrent extrapancreatic insulinoma with 8 years of follow-up, provides relevant literature review, and proposes surveillance and treatment strategies.

Case presentation

We describe an insulinoma localized in the duodenal wall of a 36-year-old female who presented in 2013 with weight gain and Whipple’s triad and was successfully managed with duodenotomy and enucleation. She presented again in 2017 with recurrent Whipple’s triad and was found to have metastatic disease localized exclusively to peripancreatic lymph nodes. Primary pancreatic insulinoma was not evident and her hypoglycemia resolved following lymph node dissection. Eight years after initial presentation continuous glucose monitoring (CGM) showed a trend for euglycemia, and PET-CT Gallium 68 DOTATATE scan evaluation indicated absence of recurrent disease.

Conclusion

Insulinomas are rare clinical entities and extrapancreatic insulinomas are particularly uncommon. Follow-up evaluation and treatment strategies for ectopic insulinoma recurrence presents a significant clinical challenge as the condition has hitherto remained undescribed in the literature. Available evidence in the literature indicates that lymph node metastases of intrapancreatic insulinomas likely do not change prognosis. Given the absence of long-term data informing the management and monitoring of patients with extrapancreatic insulinoma, we suggest patient education for hypoglycemic symptoms, monitoring for hypoglycemia with CGM, annual imaging, and a discussion with patients regarding treatment with octreotide or alternative somatostatin receptor analog therapies.
Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study
Authors: Hataya Yuji , Okubo Marie , Hakata Takuro , Fujimoto Kanta , Iwakura Toshio , Matsuoka Naoki
Published: December 2022

Background

The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test.

Methods

We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 μg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 μg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 μg/dL and peak ACTH increase <two-fold were assigned to the pituitary disorder (PD) group (n = 15). Inter-group comparisons were performed based on clinical characteristics.

Results

In the CRH challenge test, the peak plasma ACTH levels were significantly lower in the unexplainable-HD group than in the NR group, despite more than two-fold increase compared to basal levels. The increase in serum cortisol was significantly higher in the unexplainable-HD group than in the explainable-HD and PD groups. Although patients in the unexplainable-HD group showed a clear ACTH response in the insulin tolerance test, some patients had peak serum cortisol levels of < 18 μg/dL. Furthermore, attenuated diurnal variations and low normal levels of urinary free cortisol were observed. Most patients in the unexplainable-HD group were young women with chronic fatigue. However, supplementation with oral hydrocortisone at physiological doses reduced fatigue only in some patients.

Conclusions

Patients with unexplainable HD diagnosed by the CRH challenge test had hypothalamic–pituitary–adrenal (HPA) axis dysfunction and some patients had mild central adrenal insufficiency. Hydrocortisone supplementation reduced fatigue only in some patients, suggesting that HPA axis dysfunction may be a physiological adaptation. Further investigation of these patients may help elucidate the pathophysiology of myalgic encephalitis/chronic fatigue syndrome.
Starting a Swedish national quality registry for orthognathic surgery: a tool for auditing fundamentals of care
Authors: Sjöström Mats , Lund Bodil , Sunzel Bo , Bengtsson Martin , Magnusson Mikael , Rasmusson Lars
Published: December 2022

Background

National quality registries (NQRs) provide open data for user-directed acquisition. National Quality Registry (NQR) data are often used to analyze the rates of treatment success and adverse events for studies that aim to improve treatment quality and patient satisfaction. Thus, NQRs promote the goal of achieving evidence-based therapies. However, the scientific literature seldom focuses on the complex process of initiating, designing, and implementing an NQR. Starting an NQR may be particularly challenging in a setting where specialized care is decentralized, such as orthognathic surgery in Sweden. The present study describes the initiation and early phases of a new NQR for orthognathic surgery in Sweden.

Methods

The initial inventory phase included gaining knowledge on regulations, creating economic plans, and identifying pitfalls in existing NQRs. Next, a crude framework for the registry was achieved. Outcome measures were selected with a nation-wide questionnaire, followed by a Delphi-like process for selecting parameters to include in the NQR. Our inclusive process comprised a stepwise introduction, feedback-based modifications, and preparatory educational efforts. Descriptive data were collected, based on the first 2 years (2018–2019) of registry operation.

Results

Two years after implementation, 862 patients that underwent 1320 procedures were registered. This number corresponded to a 91% coverage rate. Bimaxillary treatments predominated, and the most common were a Le Fort I osteotomy combined with a bilateral sagittal split osteotomy (n = 275). Reoperations were conducted in 32 patients (3.6%), and the rate of patient satisfaction was 95%.

Conclusions

A National Quality Registry should preferentially be started and maintained by an appointed task force of active clinicians. A collaborative, transparent, inclusive process may be an important factor for achieving credibility and high coverage, particularly in a decentralized setting.