bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal MRI signal intensity of the triangular fibrocartilage complex in asymptomatic wrists
Authors: Wang Zhixin , Chen Shanlin , Liu Bo , Qian Zhanhua , Zhu Jin , Wang Qianqian
Published: December 2022

We investigated abnormal MRI findings of the triangular fibrocartilage complex in 154 asymptomatic volunteers (21–79 years). Except prevalence, we focused on the morphological features of abnormal signals in relation to age. The majority of full-thickness tears were located in the articular disc (63 participants). The incidence of disc perforation with characteristics of ulnar impaction syndrome increased significantly with age. Asymptomatic full-thickness tears of the ulnar attachment were found in ten participants (seven over 60 years old). The proximal and distal laminae of the ulnar attachment could not be differentiated in 36 participants. In conclusion, MRI is of limited value for the elderly in diagnosing triangular fibrocartilage disorders. For young subjects, MRI is still valuable, especially in diagnosing ulnar detachment, although the ability to distinguish between proximal and distal laminae remains questionable. Disc perforations in volunteers mimicked ulnar impaction syndrome, therefore age, clinical signs and other factors should also be considered in clinical diagnosis.

Level of evidence: III
Clinical significance of acute exacerbation in interstitial lung disease with antineutrophil cytoplasmic antibody: an indicator of poor prognosis
Authors: Wu Tingting , Zhang Yun , Cen Zekai , Ying Yanan , Sun Chao , Lv Chengna , Ding Qunli
Published: December 2022

Background:

The association between interstitial lung disease (ILD) and antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) has been increasingly recognized in recent years. The clinical features and prognostic differences between AAV-associated ILD and isolated ANCA-positive idiopathic interstitial pneumonias (IIPs) remain unclear. The purpose of this study was to determine the clinical significance and prognosis of ANCA-positive ILD to further guide clinical management.

Methods:

This study retrospectively reviewed the data of 379 ILD patients with available ANCA results and ultimately analysed 49 ANCA-positive patients. AAV diagnosis was based on the 2012 revised Chapel Hill Consensus Conference (CHCC) criteria, and 33 of 49 patients were diagnosed with microscopic polyangiitis (MPA). The baseline clinical information and laboratory parameters were collected and analysed at each patient’s initial diagnosis.

Results:

Among 49 ANCA-positive ILD patients, the high-resolution computed tomography (HRCT) pattern was mainly usual interstitial pneumonia (UIP) (59.18%), followed by nonspecific interstitial pneumonia (NSIP) (26.53%). The C-reactive protein (CRP) level (43.89± 40.61 versus 18.74± 20.05, p = 0.028) and erythrocyte sedimentation rate (ESR) (71.97± 42.73 versus 40.69± 28.46, p = 0.011) were significantly higher in the MPA-ILD group than in the ANCA-IIP group. Haemoglobin (113.09 ± 24.47 versus 132.19± 13.34, p = 0.006) and albumin (32.95± 5.84 versus 36.52± 3.94, p = 0.032) levels were significantly lower. Survival was shorter among MPA-ILD patients than among ANCA-IIP patients [hazard ratio (HR) 3.38, 95% confidence interval (CI) 1.32–8.67, p = 0.040]. In the multivariable Cox analysis, a diagnosis of MPA (HR 3.91, 95% CI 1.07–14.08, p = 0.038) and acute exacerbation (AE) of ILD (HR 9.43, 95% CI 2.89–30.30, p < 0.001) were significantly independently associated with shorter survival in ANCA-positive ILD patients, and the NSIP pattern (HR 0.07, 95% CI 0.01–0.41, p = 0.003) was independently associated with prolonged survival.

Conclusion:

ANCA-ILD patients mostly have myeloperoxidase (MPO)-ANCA positivity and an MPA diagnosis. Survival was shorter among MPA-ILD patients than among ANCA-IIP patients. Respiratory failure and AE were associated with poorer prognosis. Early antifibrotic treatment may be a reasonable treatment option in fibrotic ILD patients with ANCA positivity.
Clinical Outcomes of the Lateral Trabecular Metal Total Ankle Replacement at a 5-Year Minimum Follow-up
Authors: Kim Jaeyoung , Gagne Oliver J. , Rajan Lavan , Caolo Kristin , Sofka Carolyn , Ellis Scott J. , Demetracopoulos Constantine A. , Deland Jonathan T.
Published: December 2022

Background

The Trabecular Metal (Zimmer Biomet, Warsaw, IN) total ankle arthroplasty (TAA) system uses a lateral approach with a fibular osteotomy to gain access to the tibiotalar joint and a sagittally curved tibial component. This is the first TAA system to laterally approach the ankle, and few studies have explored outcomes associated with this implant. This study aimed to report the 5-year clinical and radiographic outcomes as well as the survivorship of the implant.

Methods

Over a 3-year period, 2 fellowship-trained foot and ankle surgeons used this implant system to treat 38 end-stage arthritic ankles. Reoperation and revision data were collected from all patients (100%) as part of the local prospective database. Patients completed the Foot and Ankle Outcome Score (FAOS) questionnaire preoperatively and at each annual follow-up visit; scores for a minimum of 5 years were available for 28 (73.7%) patients. A radiographic analysis compared postoperative coronal and sagittal alignment in weightbearing radiographs at a minimum of 5 years with that at 3 months postoperatively, as well as cyst or lucency formation, which was available for 21 patients (55.3%).

Results

At 5 years, there were 3 revisions (7.9%) and 9 reoperations (23.7%). Reoperations included 4 fibular hardware removal and 5 medial gutter debridement procedures. The FAOS significantly improved for all domains (P < .05). Implant positioning did not significantly change between 3 months and 5 years postoperatively.

Conclusion

Our 5-year results in this small series using this unique prosthesis showed good overall survivorship (92.1%) and a reoperation rate of 23.7%, along with clinically significant improvement in patient-reported outcomes.

Levels of Evidence:

Level IV: Retrospective case series
Experimental investigation of blast mitigation of pre-fractal obstacles
Authors: Isaac Obed Samuelraj , Alshammari Omar Ghareeb , Clarke Samuel David , Rigby Samuel Edward
Published: December 2022

Obstacles arranged into a pre-fractal shape (Sierpinski carpet) were tested for their blast attenuation abilities using 250 g PE4 at three different scaled distances ( Z = 1.87, 2.24, 2.99 m/kg1/3). Three pre-fractal iterations were tested, as well as free-field tests for comparative purposes. Reductions in peak overpressure up to 26% and peak specific impulse up to 19% were observed, attributed to a mechanism known as ‘trapping’. This mechanism is characterised by a reduction in the ability of a blast wave to advect downstream, with corresponding increases in pressure observed within the bounds of the pre-fractal obstacle. Attenuation magnitudes and areas of reduced pressure and impulse were found to be drastically different with each pre-fractal iteration, with a transition from shadowing to wave trapping as the obstacles more closely resembled true fractals. A linear dependence on a newly-defined obstruction factor ( OF) was found for arrival time, overpressure and impulse at the sensor locations, suggesting that the attenuation of a pre-fractal obstacle is inherently determinable. The results indicate that the mechanism of blast mitigation of pre-fractal obstacles is fundamentally different from singular or arrays of regular obstacles, and could be exploited further to develop novel protective structures with enhanced blast attenuation.
Harlequin ichthyosis newborn: A case report
Authors: Nikbina Maryam , Sayahi Masoumeh
Published: December 2022

Harlequin ichthyosis is a rare and severe genetic skin disorder that occurs within the developing foetus. Harlequin ichthyosis is the most severe and devastating form of autosomal recessive congenital ichthyoses. It is caused by mutations in the lipid transporter adenosine triphosphate binding cassette A 12. Here, we reported a case of harlequin ichthyosis with no family history. No abnormalities were detected in prenatal sonography. A 24-year-old pregnant woman with premature rupture of membrane and labour pain was referred to a hospital in Shoushtar city, Iran. The mother delivered a male baby with harlequin ichthyosis. The infant baby died on the 5th day. Harlequin ichthyosis is associated with adenosine triphosphate binding cassette A 12 gene mutation; therefore, genetic screening and counselling for susceptible parents should be taken into account. Prenatal diagnosis of harlequin ichthyosis principally via sonographic techniques is important in managing the disorder.
A case of tumor-induced osteomalacia masked by acute kidney injury
Authors: Kanduri Swetha Rani , Kovvuru Karthik , Wickman Terrance J , Velez Juan Carlos Q
Published: December 2022

Introduction:

Hypophosphatemia in patients with tumor-induced osteomalacia (TIO) is due to abnormal excess production of fibroblast growth factor 23 (FGF-23) causing urinary phosphate wasting. However, in patients with coexisting acute kidney injury (AKI), hypophosphatemia may not be apparent as AKI reduces filtration and excretion of phosphate.

Case report:

We describe a case of 36-year-old woman who presented with right-sided abdominal pain. Initial laboratory testing revealed non oliguric AKI with creatinine (Cr) of 2.0 mg/dL (baseline 1.2 mg/dL), low phosphate (1.8 mg/dL), and normal parathyroid (PTH) levels. Hypophosphatemia in the setting of AKI and normal PTH raised suspicion for renal phosphate wasting disorder independent of PTH, triggering an order for FGF-23 level. Further into hospital stay, the AKI worsened (Cr rose to 7.2 mg/dL) and phosphate levels increased to 6.7 mg/dL casting doubt on the initial suspicion. However, FGF-23 level resulted at 12,715 RU/mL, strongly suggesting TIO. Random liver biopsy was obtained as part of TIO work up due to liver ultrasound findings of hepatomegaly, diffuse parenchymal heterogenicity mimicking steatosis and potential ill-defined mass. Liver specimen showed tumor cells positive for CD56 and Ki-67, indicating high-grade metastatic neuro endocrine tumor which was the likely source of FGF-23. Patient rapidly deteriorated and opted for comfort measures.

Conclusion:

TIO typically manifests with overt hypophosphatemia. This case highlights the fact that decreased glomerular filtration rate may mask the degree of urinary phosphate wasting resulting in normal to high serum phosphate level. This warrants high index of suspicion to diagnose an underlying phosphate wasting disorder in the setting of normal to high serum phosphate levels and reduced kidney function.
Arthroscopic Removal of the Polyethylene Glenoid Component After Total Shoulder Arthroplasty: A Systematic Review
Authors: Ozdag Yagiz , Baylor Jessica , Hayes Daniel , Grandizio Louis C
Published: December 2022

Purpose

To identify prior studies of arthroscopic glenoid component removal after total shoulder arthroplasty (TSA) and understand indications, techniques and patient outcomes.

Methods

A search of the English language literature on arthroscopic removal of the glenoid component (ARGC) after TSA published between 2005 and 2021 was performed from MEDLINE and EMBASE databases. Articles with ARGC after TSA were identified and we recorded article characteristics as well as patient demographics and outcomes contained within the studies.

Results

A total of six publications (two case reports and four retrospective case series) detailing the outcome of ARGC performed on twenty-five shoulders were identified. The average time from index procedure to glenoid removal was 117 months and mean age at time of ARGC was 75 years. Although patient reported outcomes measures (PROMs) varied in type and reporting style, all articles reported improvements in PROMs. Twenty patients in this systematic review were evaluated for post-operative complications and the complication rate was found to be 15% (n = 3). There were 2 cases (18%) of superior migration of the humeral head relative to the glenoid and no reported cases of anterior or posterior humeral head subluxation. Two of 25 patients (8%) underwent subsequent open revision procedures.

Conclusions

The limited number of publications in this systematic review demonstrates that ARGC after TSA can result in improvements in both pain and PROMs. This less-invasive arthroscopic technique may be an alternative to open revision for lower demand patients; however, future prospective, comparative studies are necessary to better define indications.
Current Diagnosis of Achalasia: Beyond Standard High-Resolution Manometry
Authors: Parsa Nasim , Vela Marcelo F.
Published: December 2022

Achalasia is a rare esophageal motility disorder characterized by incomplete relaxation of the lower esophageal sphincter and absence of normal peristalsis. A precise diagnosis is crucial to successful treatment, and over the past few years significant advances have been made in how achalasia is diagnosed. Although high resolution manometry (HRM) is generally considered the gold standard diagnostic modality, manometric findings can be inconclusive and in some cases patients may not tolerate the procedure. Therefore, the addition of provocative maneuvers during HRM, and the use of timed barium esophagram and the functional lumen imaging probe (FLIP) are all important tools that have improved our ability to accurately diagnose achalasia. In this review, we go over the current approach to the diagnosis of achalasia.
Cloned antibodies from patients with HIT provide new clues to HIT pathogenesis
Authors: Zhu Wen , Zheng Yongwei , Yu Mei , Wu Yaling , Wei Jianhui , Zhou Lu , Fu Guoping , Schneider Nicholas , Jones Curtis , Irani Mehraboon , Padmanabhan Anand , Aster Richard , Wang Demin , Wen Renren
Published: December 2022

Heparin-induced thrombocytopenia (HIT) is a serious adverse drug reaction characterized by antibodies that recognize platelet factor 4/heparin complexes (PF4/H) and activate platelets to create a prothrombotic state. Although a high percentage of heparin-treated patients produce antibodies to PF4/H, only a subset also makes antibodies that are platelet activating (PA). A close correlation between PA antibodies and the likelihood of experiencing HIT has been demonstrated in clinical studies, but how PA (presumptively pathogenic) and nonactivating (NA) (presumptively benign) antibodies differ from each other at the molecular level is unknown. To address this issue, we cloned 7 PA and 47 NA PF4/H-binding antibodies from 6 patients with HIT and characterized their structural and functional properties. Findings showed that PA clones differed significantly from NA clones in possessing 1 of 2 heavy chain complementarity-determining region 3 (HCDR3) motifs, RX1-2R/KX1-2R/H (RKH) and YYYYY (Y5), in an unusually long complementarity-determining region 3 (≥20 residues). Mutagenic studies showed that modification of either motif in PA clones reduced or abolished their PA activity and that appropriate amino acid substitutions in HCDR3 of NA clones can cause them to become PA. Repertoire sequencing showed that the frequency of peripheral blood IgG+ B cells possessing RKH or Y5 was significantly higher in patients with HIT than in patients without HIT given heparin, indicating expansion of B cells possessing RKH or Y5 in HIT. These findings imply that antibodies possessing RKH or Y5 are relevant to HIT pathogenesis and suggest new approaches to diagnosis and treatment of this condition.
RUNX1 isoform disequilibrium promotes the development of trisomy 21–associated myeloid leukemia
Authors: Gialesaki Sofia , Bräuer-Hartmann Daniela , Issa Hasan , Bhayadia Raj , Alejo-Valle Oriol , Verboon Lonneke , Schmell Anna-Lena , Laszig Stephanie , Regényi Enikő , Schuschel Konstantin , Labuhn Maurice , Ng Michelle , Winkler Robert , Ihling Christian , Sinz Andrea , Glaß Markus , Hüttelmaier Stefan , Matzk Sören , Schmid Lena , Strüwe Farina Josepha , Kadel Sofie-Katrin , Reinhardt Dirk , Yaspo Marie-Laure , Heckl Dirk , Klusmann Jan-Henning
Published: December 2022

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR–CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA therapy
Authors: Schnegg-Kaufmann Annatina S. , Thoms Julie A. I. , Bhuyan Golam Sarower , Hampton Henry R. , Vaughan Lachlin , Rutherford Kayleigh , Kakadia Purvi M. , Lee Hui Mei , Johansson Emma M. V. , Failes Timothy W. , Arndt Greg M. , Koval Jason , Lindeman Robert , Warburton Pauline , Rodriguez-Meira Alba , Mead Adam J. , Unnikrishnan Ashwin , Davidson Sarah , Polizzotto Mark N. , Hertzberg Mark , Papaemmanuil Elli , Bohlander Stefan K. , Faridani Omid R. , Jolly Christopher J. , Zanini Fabio , Pimanda John E.
Published: December 2022

Myelodysplastic neoplasms (MDSs) and chronic myelomonocytic leukemia (CMML) are clonal disorders driven by progressively acquired somatic mutations in hematopoietic stem cells (HSCs). Hypomethylating agents (HMAs) can modify the clinical course of MDS and CMML. Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated HSCs. However, in patients with established disease it is unclear whether (1) HSCs with multiple mutations progress through differentiation with comparable frequency to their less mutated counterparts or (2) improvements in peripheral blood counts following HMA therapy are driven by residual wild-type HSCs or by clones with particular combinations of mutations. To address these questions, the somatic mutations of individual stem cells, progenitors (common myeloid progenitors, granulocyte monocyte progenitors, and megakaryocyte erythroid progenitors), and matched circulating hematopoietic cells (monocytes, neutrophils, and naïve B cells) in MDS and CMML were characterized via high-throughput single-cell genotyping, followed by bulk analysis in immature and mature cells before and after AZA treatment. The mutational burden was similar throughout differentiation, with even the most mutated stem and progenitor clones maintaining their capacity to differentiate to mature cell types in vivo. Increased contributions from productive mutant progenitors appear to underlie improved hematopoiesis in MDS following HMA therapy.
Knowledge to date on secondary malignancy following hematopoietic cell transplantation for sickle cell disease
Authors: Fitzhugh Courtney D.
Published: December 2022

Allogeneic hematopoietic cell transplantation, gene therapy, and gene editing offer a potential cure for sickle cell disease (SCD). Unfortunately, myelodysplastic syndrome and acute myeloid leukemia development have been higher than expected after graft rejection following nonmyeloablative conditioning and lentivirus-based gene therapy employing myeloablative busulfan for SCD. Somatic mutations discovered in 2 of 76 patients who rejected their grafts were identified at baseline at much lower levels. While a whole-genome sequencing analysis reported no difference between patients with SCD and controls, a study including whole-exome sequencing revealed a higher prevalence of clonal hematopoiesis in individuals with SCD compared with controls. Genetic risk factors for myeloid malignancy development after curative therapy for SCD are currently being explored. Once discovered, decisions could be made about whether gene therapy may be feasible vs allogeneic hematopoietic cell transplant, which results in full donor chimerism. In the meantime, care should be taken to perform a benefit/risk assessment to help patients identify the best curative approach for them. Long-term follow-up is necessary to monitor for myeloid malignancies and other adverse effects of curative therapies for SCD.
Thrombocytopenia in pregnancy
Authors: Pishko Allyson M. , Marshall Ariela L.
Published: December 2022

Hematologists are often consulted for thrombocytopenia in pregnancy, especially when there is a concern for a non-pregnancy-specific etiology or an insufficient platelet count for the hemostatic challenges of delivery. The severity of thrombocytopenia and trimester of onset can help guide the differential diagnosis. Hematologists need to be aware of the typical signs of preeclampsia with severe features and other hypertensive disorders of pregnancy to help distinguish these conditions, which typically resolve with delivery, from other thrombotic microangiopathies (TMAs) (eg, thrombotic thrombocytopenic purpura or complement-mediated TMA). Patients with chronic thrombocytopenic conditions, such as immune thrombocytopenia, should receive counseling on the safety and efficacy of various medications during pregnancy. The management of pregnant patients with chronic immune thrombocytopenia who are refractory to first-line treatments is an area that warrants further research. This review uses a case-based approach to discuss recent updates in diagnosing and managing thrombocytopenia in pregnancy.
Expanding the platelet inventory to mitigate the impact of severe shortages
Authors: Stubbs James R. , Shaz Beth H. , Vassallo Ralph R. , Roback John D.
Published: December 2022

The platelet collection and distribution system, based on volunteer nonremunerated donors, apheresis platelet collections, and primarily 1-directional distribution of platelets for up to 5-day room temperature storage at hospitals, typically performs well and provides therapeutic support for hundreds of thousands of patients annually. However, direct and indirect effects of the coronavirus disease 2019 pandemic, particularly during the Omicron wave, produced dramatic systemic failures and severe shortages. We propose 4 initiatives to reinforce the existing platelet pipeline and buffer the platelet supply against future unexpected disruptions.
Gene therapy for hemophilia
Authors: Nathwani Amit C.
Published: December 2022

The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular diagnostic for hemophilia, followed by the development of recombinant clotting factor replacement therapy. Now gene therapy beckons on the back of decades of research that has brought us to the final stages of the approval of 2 products in Europe and United States, thus heralding a new era in the treatment of the hemophilias. Valoctocogene roxaparvovec, the first gene therapy for treatment of hemophilia A, has been granted conditional marketing authorization in Europe. Another approach (etranacogene dezaparvovec, AMT-061) for hemophilia B is also under review by regulators. There are several other gene therapy approaches in earlier stages of development. These approaches entail a one-off infusion of a genetically modified adeno-associated virus (AAV) engineered to deliver either the FVIII or FIX gene to the liver, leading to the continuous endogenous synthesis and secretion of the missing coagulation factor into the circulation by the hepatocytes, thus preventing or reducing bleeding episodes. Ongoing observations show sustained clinical benefit of gene therapy for >5 years following a single administration of an AAV vector without long-lasting or late toxicities. An asymptomatic, self-limiting, immune-mediated rise in alanine aminotransferase is commonly observed within the first 12 months after gene transfer that has the potential to eliminate the transduced hepatocytes in the absence of treatment with immunosuppressive agents such as corticosteroids. The current state of this exciting and rapidly evolving field, as well as the challenges that need to be overcome for the widespread adaptation of this new treatment paradigm, is the subject of this review.
Diagnostic pitfalls and conundrums in type 1 von Willebrand disease
Authors: Sidonio Robert F. , Lavin Michelle
Published: December 2022

Most people with von Willebrand disease (VWD) have a partial quantitative deficiency of plasma von Willebrand factor (VWF) or type 1 VWD. In contrast to type 2 and type 3 VWD, laboratory assays will not always establish the diagnosis in type 1 VWD. This is because plasma VWF levels in type 1 VWD, especially those with levels closer to 50 IU/dL, overlap with the general population. Assessment is further complicated by increased plasma VWF levels in response to physiologic stressors or aging. Diagnosis of those with type 1 VWD with plasma VWF levels 30 to 50 IU/dL (previously referred to as “low VWF”) requires expert assessment of bleeding phenotype as well as an understanding of the limitations of both bleeding assessment tools (BATs) and laboratory testing. Using the available evidence and highlighting research gaps, we discuss common dilemmas facing providers relating to assessment of adolescents, transition from pediatrics to adult care, and older individuals with type 1 VWD.
What have we learned about the patient's experience of von Willebrand disease? A focus on women
Authors: VanderMeulen Heather , Arya Sumedha , Nersesian Sarah , Philbert Natalie , Sholzberg Michelle
Published: December 2022

Von Willebrand disease (VWD), the most common inherited bleeding disorder (IBD), disproportionately affects females, given the hemostatic challenges they may encounter throughout their lifetimes. Despite this, research about VWD remains grossly underrepresented, particularly compared to hemophilia, which is historically diagnosed in males. Structural sexism, stigmatization of menstrual bleeding, delayed diagnosis, and a lack of timely access to care result in an increased frequency of bleeding events, iron deficiency, iron deficiency anemia, and a decreased quality of life. However, we are only beginning to recognize and acknowledge the magnitude of the burden of this disease. With an increasing number of studies documenting the experiences of women with IBDs and recent international guidelines suggesting changes to optimal management, a paradigm shift in recognition and treatment is taking place. Here, we present a fictional patient case to illustrate one woman's history of bleeding. We review the evidence describing the impact of VWD on quality of life, normalization of vaginal bleeding, diagnostic delays, and the importance of access to multidisciplinary care. Furthermore, we discuss considerations around reproductive decision-making and the intergenerational nature of bleeding, which often renders patients as caregivers. Through incorporating the patient perspective, we argue for an equitable and compassionate path to overcome decades of silence, misrecognition, and dismissal. This path moves toward destigmatization, open dialogue, and timely access to specialized care.
To prophylax or not, and how much and how long? Controversies in VTE prevention for medical inpatients, including COVID-19 inpatients
Authors: Spyropoulos Alex C.
Published: December 2022

The field of thromboprophylaxis for acutely ill medical patients, including those hospitalized for COVID-19, is rapidly evolving both in the inpatient setting and the immediate post–hospital discharge period. Recent data reveal the importance of incorporating holistic thromboembolic outcomes that encompass both venous thromboembolism (VTE) and arterial thromboembolism, as thromboprophylaxis with low-dose direct oral anticoagulants has been shown to reduce major and fatal vascular events, especially against a background of dual pathway inhibition with aspirin. In addition, recent post hoc analyses from randomized trial data have established 5 key bleeding-risk factors that, if removed, reveal a low-bleeding- risk medically ill population and, conversely, key individual risk factors, such as advanced age, a past history of cancer or VTE, an elevated D-dimer, or the use of a validated VTE risk score—the IMPROVE VTE score using established cutoffs—to predict a high-VTE-risk medically ill population that benefits from extended postdischarge thromboprophylaxis. Last, thromboprophylaxis of a high-thrombotic-risk subset of medically ill patients, those with COVID-19, is rapidly evolving, both during hospitalization and post discharge. This article reviews 3 controversial topics in the thromboprophylaxis of hospitalized acutely ill medical patients: (1) clinical relevance of key efficacy and safety outcomes incorporated into randomized trials but not incorporated into relevant antithrombotic guidelines on the topic, (2) the use of individual risk factors or risk models of low-bleeding-risk and high-thrombotic-risk subgroups of medically ill inpatients that benefit from extended thromboprophylaxis, and (3) thromboprophylaxis of hospitalized COVID-19 patients, including extended postdischarge thromboprophylaxis.
Galantamine attenuates autoinflammation in a mouse model of familial mediterranean fever
Authors: Mughrabi Ibrahim T. , Ochani Mahendar , Tanovic Mirza , Wang Ping , Diamond Betty , Sherry Barbara , Pavlov Valentin A. , Ozen Seza , Kastner Daniel L. , Chae Jae Jin , Al-Abed Yousef
Published: December 2022

Background

Autoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine.

Methods

We tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Multiple chronic disease markers were evaluated in animals that received long-term galantamine treatment compared to vehicle.

Results

Long-term treatment with galantamine attenuated the associated splenomegaly and anemia which are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch.

Conclusions

These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases.
Mid-term results of subcapital realignment of chronic slipped capital femoral epiphysis using surgical hip dislocation: a prospective case series
Authors: Abosalem Ahmed Abdelazim , Sakr Samy Abdel-Hady , Mesregah Mohamed Kamal , Zayda Ahmed Ibrahim
Published: December 2022

Background

Slipped capital femoral epiphysis (SCFE) requires surgical treatment when diagnosed. The surgical management of moderate to severe SCFE remains an area of controversy among pediatric orthopedic surgeons. The severity of slippage, the viability of the femoral epiphysis, and the method of surgical management determine the long-term clinical and radiographical outcome. This study sought to evaluate the mid-term results of subcapital realignment of chronic stable slipped femoral epiphysis with open physis using surgical hip dislocation.

Materials and methods

This study was a prospective case series of adolescents with moderate or severe degrees of chronic SCFE who had undergone subcapital osteotomy using the surgical hip dislocation technique. The Harris Hip Score (HHS) was used to assess functional outcomes at 6 years of follow-up. A HHS of ≥ 80 points was considered satisfactory. Postoperative radiological outcomes were evaluated using epiphyseal-shaft angles and alpha angles. Postoperative complications were observed.

Results

This study included 40 patients, 32 (80%) males and 8 (20%) females, with a mean age of 14.1 ± 1.8 years. There was a statistically significant improvement in the mean HHS from 45 ± 12.3 preoperatively to 91.8 ± 11.6 points at 6 years of follow-up. The mean epiphyseal-shaft angle reduced from 60.5 ± 15.3° preoperatively to 10.3 ± 2.4° postoperatively, P < 0.001. The mean alpha angle reduced from 72.5 ± 10.1° preoperatively to 40.4 ± 6.4°, P < 0.001. Four (10%) patients showed femoral head avascular necrosis (AVN).

Conclusions

Subcapital realignment of chronic SCFE can achieve satisfactory clinical and radiological outcomes, but femoral head AVN remains a risk.

Level of evidence Level IV.
EasySMPC: a simple but powerful no-code tool for practical secure multiparty computation
Authors: Wirth Felix Nikolaus , Kussel Tobias , Müller Armin , Hamacher Kay , Prasser Fabian
Published: December 2022

Background

Modern biomedical research is data-driven and relies heavily on the re-use and sharing of data. Biomedical data, however, is subject to strict data protection requirements. Due to the complexity of the data required and the scale of data use, obtaining informed consent is often infeasible. Other methods, such as anonymization or federation, in turn have their own limitations. Secure multi-party computation (SMPC) is a cryptographic technology for distributed calculations, which brings formally provable security and privacy guarantees and can be used to implement a wide-range of analytical approaches. As a relatively new technology, SMPC is still rarely used in real-world biomedical data sharing activities due to several barriers, including its technical complexity and lack of usability.

Results

To overcome these barriers, we have developed the tool EasySMPC, which is implemented in Java as a cross-platform, stand-alone desktop application provided as open-source software. The tool makes use of the SMPC method Arithmetic Secret Sharing, which allows to securely sum up pre-defined sets of variables among different parties in two rounds of communication (input sharing and output reconstruction) and integrates this method into a graphical user interface. No additional software services need to be set up or configured, as EasySMPC uses the most widespread digital communication channel available: e-mails. No cryptographic keys need to be exchanged between the parties and e-mails are exchanged automatically by the software. To demonstrate the practicability of our solution, we evaluated its performance in a wide range of data sharing scenarios. The results of our evaluation show that our approach is scalable (summing up 10,000 variables between 20 parties takes less than 300 s) and that the number of participants is the essential factor.

Conclusions

We have developed an easy-to-use “no-code solution” for performing secure joint calculations on biomedical data using SMPC protocols, which is suitable for use by scientists without IT expertise and which has no special infrastructure requirements. We believe that innovative approaches to data sharing with SMPC are needed to foster the translation of complex protocols into practice.
Transcriptome analysis and cytochrome P450 monooxygenase reveal the molecular mechanism of Bisphenol A degradation by Pseudomonas putida strain YC-AE1
Authors: Eltoukhy Adel , Jia Yang , Lamraoui Imane , Abo-Kadoum M. A. , Atta Omar Mohammad , Nahurira Ruth , Wang Junhuan , Yan Yanchun
Published: December 2022

Background

Bisphenol A (BPA) is a rapid spreading organic pollutant that widely used in many industries especially as a plasticizer in polycarbonate plastic and epoxy resins. BPA reported as a prominent endocrine disruptor compound that possesses estrogenic activity and fulminant toxicity. Pseudomonas putida YC-AE1 was isolated in our previous study and exerted a strong degradation capacity toward BPA at high concentrations; however, the molecular degradation mechanism is still enigmatic.

Results

We employed RNA sequencing to analyze the differentially expressed genes (DEGs) in the YC-AE1 strain upon BPA induction. Out of 1229 differentially expressed genes, 725 genes were positively regulated, and 504 genes were down-regulated. The pathways of microbial metabolism in diverse environments were significantly enriched among DEGs based on KEGG enrichment analysis. qRT-PCR confirm the involvement of BPA degradation relevant genes in accordance with RNA Seq data. The degradation pathway of BPA in YC-AE1 was proposed with specific enzymes and encoded genes. The role of cytochrome P450 (CYP450) in BPA degradation was further verified. Sever decrease in BPA degradation was recorded by YC-AE1 in the presence of CYP450 inhibitor. Subsequently, CYP450bisdB deficient YC-AE1 strain △ bisdB lost its ability toward BPA transformation comparing with the wild type. Furthermore, Transformation of E. coli with pET-32a-bisdAB empowers it to degrade 66 mg l−1 of BPA after 24 h. Altogether, the results showed the role of CYP450 in biodegradation of BPA by YC-AE1.

Conclusion

In this study we propose the molecular basis and the potential role of YC-AE1cytochrome P450 monooxygenase in BPA catabolism.
Sodium formononetin-3'-sulphonate alleviates cerebral ischemia–reperfusion injury in rats via suppressing endoplasmic reticulum stress-mediated apoptosis
Authors: Bai Yue , He Zhiwei , Duan Weisong , Gu He , Wu Kefeng , Yuan Wei , Liu Wenkang , Huang Huaipeng , Li Yanan
Published: December 2022

Background

Sodium formononetin-3ʹ-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia‐reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis.

Results

The cerebral lesions of middle cerebral artery occlusion (MCAO) model in SD rats were aggravated after 24 h of reperfusion, including impaired neurological function, increased infarct volume, intensified inflammatory response and poor cell morphology. After intervention, the edaravone (EDA, 3 mg/kg) group and Sul-F high-dose (Sul-F-H, 80 mg/kg) group significantly alleviated I/R injury via decreasing neurological score, infarct volume and the serum levels of inflammatory factors (TNF-α, IL-1β and IL-6), as well as alleviating pathological injury. Furthermore, the ER stress level and apoptosis rate were elevated in the ischemic penumbra of MCAO group, and were significantly blocked by EDA and Sul-F-H. In addition, EDA and Sul-F-H significantly down-regulated the ER stress related PERK/eIF2α/ATF4 and IRE1 signal pathways, which led to reduced cell apoptosis rate compared with the MCAO group. Furthermore, there was no difference between the EDA and Sul-F-H group in terms of therapeutic effect on cerebral I/R injury, indicating a therapeutic potential of Sul-F for ischemic stroke.

Conclusions

Sul-F-H can significantly protects against cerebral I/R injury through inhibiting ER stress-mediated apoptosis in the ischemic penumbra, which might be a novel therapeutic target for ischemic stroke.
Comprehensive identification and expression analyses of the SnRK gene family in Casuarina equisetifolia in response to salt stress
Authors: Ai Di , Wang Yujiao , Wei Yongcheng , Zhang Jie , Meng Jingxiang , Zhang Yong
Published: December 2022

Background

Sucrose nonfermenting-1 (SNF1)-related protein kinases (SnRKs) play crucial roles in plant signaling pathways and stress adaptive responses by activating protein phosphorylation pathways. However, there have been no comprehensive studies of the SnRK gene family in the widely planted salt-tolerant tree species Casuarina equisetifolia. Here, we comprehensively analyze this gene family in C. equisetifolia using genome-wide identification, characterization, and profiling of expression changes in response to salt stress.

Results

A total of 26 CeqSnRK genes were identified, which were divided into three subfamilies (SnRK1, SnRK2, and SnRK3). The intron–exon structures and protein‑motif compositions were similar within each subgroup but differed among groups. Ka/Ks ratio analysis indicated that the CeqSnRK family has undergone purifying selection, and cis-regulatory element analysis suggested that these genes may be involved in plant development and responses to various environmental stresses. A heat map was generated using quantitative real‑time PCR (RT-qPCR) data from 26 CeqSnRK genes, suggesting that they were expressed in different tissues. We also examined the expression of all CeqSnRK genes under exposure to different salt concentrations using RT-qPCR, finding that most CeqSnRK genes were regulated by different salt treatments. Moreover, co-expression network analysis revealed synergistic effects among CeqSnRK genes.

Conclusions

Several CeqSnRK genes (CeqSnRK3.7, CeqSnRK3.16, CeqSnRK3.17) were up-regulated following salt treatment. Among them, CeqSnRK3.16 expression was significantly up-regulated under various salt treatments, identifying this as a candidate gene salt stress tolerance gene. In addition, CeqSnRK3.16 showed significant expression change correlations with multiple genes under salt stress, indicating that it might exhibit synergistic effects with other genes in response to salt stress. This comprehensive analysis will provide a theoretical reference for CeqSnRK gene functional verification and the role of these genes in salt tolerance.
Coronary calcium density in relation to coronary heart disease and cardiovascular disease in adults with diabetes or metabolic syndrome: the Multi-ethnic Study of Atherosclerosis (MESA)
Authors: Zhao Yanglu , Malik Shaista , Criqui Michael H. , Allison Matthew A. , Budoff Matthew J. , Sandfort Veit , Wong Nathan D.
Published: December 2022

Background

Coronary artery calcium (CAC) density is inversely associated with coronary heart disease (CHD) and cardiovascular disease (CVD) risk. We examined this relation in those with diabetes mellitus (DM) or metabolic syndrome (MetS).

Methods

We studied 3,818 participants with non-zero CAC scores from the Multiethnic Study of Atherosclerosis and classified them as DM, MetS (without DM) or neither DM/MetS. Risk factor-adjusted CAC density was calculated and examined in relation to incident CHD and CVD events over a median follow-up of 15 years among these three disease groups.

Results

Adjusted CAC density was 2.54, 2.61 and 2.69 among those with DM, MetS or neither DM/MetS. Hazard ratios (HRs) for CHD per 1 SD increase of CAC density was 0.91 (95% CI: 0.72–1.16), 0.70 (95% CI: 0.56–0.87) and 0.79 (95% CI: 0.66–0.95) for those with DM, MetS or neither DM/MetS groups and were 0.77 (95% CI: 0.64–0.94), 0.83 (95% CI: 0.70–0.99) and 0.82 (95% CI: 0.71–0.95) for CVD, respectively. Adjustment for CAC density increased the HRs of CAC volume for CHD/CVD events. Compared to prediction models with or without single CAC measures, c-statistics of models with CAC volume and density were the highest ranging 0.67–0.72.

Conclusion

CAC density is lower among patients with DM or MetS than those with neither DM/MetS and is inversely associated with future CHD/CVD risk among them. Including CAC density in risk assessment among those with MetS may improve prediction of CHD and CVD.
Care and support networks of community-dwelling frail individuals in North West London: a comparison of patient and healthcare workers’ perceptions
Authors: Sunkersing David , Martin Finbarr C. , Sullivan Paul , Bell Derek
Published: December 2022

Background

Evidence suggests that successful assessment and care for frail individuals requires integrated and collaborative care and support across and within settings. Understanding the care and support networks of a frail individual could therefore prove useful in understanding need and designing support. This study explored the care and support networks of community-dwelling older people accessing a falls prevention service as a marker of likely frailty, by describing and comparing the individuals’ networks as perceived by themselves and as perceived by healthcare providers involved in their care.

Methods

A convenience sample of 16 patients and 16 associated healthcare professionals were recruited from a community-based NHS ‘Falls Group’ programme within North-West London. Individual (i.e., one on one) semi-structured interviews were conducted to establish an individual’s perceived network. Principles of quantitative social network analysis (SNA) helped identify the structural characteristics of the networks; qualitative SNA and a thematic analysis aided data interpretation.

Results

All reported care and support networks showed a high contribution level from family and friends and healthcare professionals. In patient-reported networks, ‘contribution level’ was often related to the ‘frequency’ and ‘helpfulness’ of interaction. In healthcare professional reported networks, the reported frequency of interaction as detailed in patient records was used to ascertain ‘contribution level’.

Conclusion

This study emphasises the importance of the role of informal carers and friends along with healthcare professionals in the care of individuals living with frailty. There was congruence in the makeup of ‘patient’ and ‘provider’ reported networks, but more prominence of helper/carers in patients’ reports. These findings also highlight the multidisciplinary makeup of a care and support network, which could be targeted by healthcare professionals to support the care of frail individuals.
A comparison of clinical development pathways to advance tuberculosis regimen development
Authors: Chang V. , Phillips P. P. J. , Imperial M. Z. , Nahid P. , Savic R. M.
Published: December 2022

Background

Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial.

Methods

Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs.

Results

Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥ 95% of trial simulations and reliably stop suboptimal regimens in ≥ 90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥ 8.5 years for standard sequential approach).

Conclusions

In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.