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Ming Y Lim, Katarzyna JamiesonDepartment of Medicine, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USAAbstract: Acute myeloid leukemia (AML) is a hematopoietic stem cell disorder that affects approximately 14,000 persons each year in the US. AML occurs at all ages but the incidence increases with age with the median age at diagnosis being 67 years. Advances in the treatment of AML over the past decades have led to improved survival, albeit mostly in younger patients. The prognosis of older patients with this disease over the same time span has not changed much and remains dismal. This review focuses on the epidemiology and characteristics of AML in elderly patients, the rationale for treating elderly AML patients, and the currently available and potential future treatment options such as sapacitabine. Elderly AML patients treated with intensive chemotherapy have a higher mortality rate, and a lower rate of complete remission and overall survival when compared to the younger population. This is due to both the different biology of the disease and the number of patient-specific factors. However, elderly AML patients treated with aggressive chemotherapy can achieve durable remissions, which offer prolonged survival and improved quality of life. Recent data also indicates that elderly AML patients deemed unfit for intensive chemotherapy benefit from leukemia-specific attenuated dose chemotherapy compared to supportive care alone. This has led to renewed interest to look for anti-leukemic therapies designed specifically for older patients. Sapacitabine, a novel oral nucleoside analog, promises good efficacy, favorable toxicity profile, and ease of administration; all of which makes it very appealing. Results from pre-clinical and clinical studies have been very encouraging and sapacitabine is currently being evaluated in a Phase III study, of which the results are eagerly awaited.Keywords: AML, elderly, management, sapacitabine

A 38-year-old man presented with right knee pain and swelling following a football injury. Magnetic resonance (MR) imaging showed a complete anterior cruciate ligament (ACL) tear and lateral meniscal tears. The torn ACL was repaired with a graft obtained from the semitendinosus muscle, and the menisci were debrided. The mechanisms of injury to the ACL are varied and may be due to direct or indirect contact with the knee as well as with twisting injuries. Knowledge of the ACL's normal anatomy, together with MR imaging technique and understanding of the appearance of the lesion on MR examination, is crucial to aid in the identification of an ACL tear. Diagnosis of an ACL tear should be based on direct MR imaging signs, although indirect signs may be helpful, particularly in chronic tears. Other associated injuries to be aware of include meniscal and other ligamentous injuries. Normal ACL graft and post-ACL graft reconstruction complications are also briefly discussed. [ABSTRACT FROM AUTHOR]

Abstract Background To investigate whether expression of carbonic anhydrase XII (CA12) is associated with histologic grade of the tumors and radiotherapy outcomes of the patients with invasive cervical cancer. Methods CA12 expression was examined by immunohistochemical stains in cervical cancer tissues from 183 radiotherapy patients. Histological grading was classified as well (WD), moderately (MD) or poorly differentiated (PD). Oligonucleotide microarray experiment was performed using seven cervical cancer samples to examine differentially expressed genes between WD and PD cervical cancers. The association between CA12 and histological grade was analyzed by chi-square test. CA12 and histological grades were analyzed individually and as combined CA12 and histologic grade categories for effects on survival outcome. Results Immunohistochemical expression of CA12 was highly associated with the histologic grade of cervical cancer. Lack of CA12 expression was associated with PD histology, with an odds ratio of 3.9 (P = 0.01). Microarray analysis showed a fourfold reduction in CA12 gene expression in PD tumors. CA12 expression was marginally associated with superior disease-free survival. Application of the new combined categories resulted in further discrimination of the prognosis of patients with moderate and poorly differentiated tumor grade. Conclusions Our study indicates that CA12 may be used as a novel prognostic marker in combination with histologic grade of the tumors.

Abstract Background The genus Brassica includes the most extensively cultivated vegetable crops worldwide. Investigation of the Brassica genome presents excellent challenges to study plant genome evolution and divergence of gene function associated with polyploidy and genome hybridization. A physical map of the B. rapa genome is a fundamental tool for analysis of Brassica "A" genome structure. Integration of a physical map with an existing genetic map by linking genetic markers and BAC clones in the sequencing pipeline provides a crucial resource for the ongoing genome sequencing effort and assembly of whole genome sequences. Results A genome-wide physical map of the B. rapa genome was constructed by the capillary electrophoresis-based fingerprinting of 67,468 Bacterial Artificial Chromosome (BAC) clones using the five restriction enzyme SNaPshot technique. The clones were assembled into contigs by means of FPC v8.5.3. After contig validation and manual editing, the resulting contig assembly consists of 1,428 contigs and is estimated to span 717 Mb in physical length. This map provides 242 anchored contigs on 10 linkage groups to be served as seed points from which to continue bidirectional chromosome extension for genome sequencing. Conclusion The map reported here is the first physical map for Brassica "A" genome based on the High Information Content Fingerprinting (HICF) technique. This physical map will serve as a fundamental genomic resource for accelerating genome sequencing, assembly of BAC sequences, and comparative genomics between Brassica genomes. The current build of the B. rapa physical map is available at the B. rapa Genome Project website for the user community.

People with bleeding disorders (PWBD) have been exposed to the risk of developing chronic viral hepatitis and cirrhosis after replacement therapy. At today, the advent of new pharmacological strategies for the control of hemostasis and the efficacious antiviral therapies against HCV and HBV have significantly reduced this risk. However, the real success for liver health in this clinical setting is based on other risk factors, among them, the severity of liver disease at time of HBV/HCV antiviral therapy and the exposure to highly prevalent factors of chronic liver damage (e.g.; metabolic dysfunction and/or alcohol) that can cause a residual risk of complications such as hepatocellular carcinoma, portal hypertension, liver insufficiency. With this background, a group of experts selected among hepatologists, PWBD treaters and patient representatives, produced this practical multisociety guidance for the protection of liver health and the prevention and management of liver complications in PWBD based on the most updated protocols of care., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: The association between the fecal microbiota and colorectal cancer (CRC) risk has been suggested in epidemiologic studies. However, data from large-scale population-based studies are lacking., Materials and Methods: In this case-control study, we recruited 283 CRC patients from the Center for Colorectal Cancer, National Cancer Center Hospital, Korea to perform 16S rRNA gene sequencing of fecal samples. A total of 283 age- and sex-matched healthy participants were selected from 890 cohort of healthy Koreans that are publicly available (PRJEB33905). The microbial dysbiosis index (MDI) was calculated based on the differentially abundant species. The association between MDI and CRC risk was observed using conditional logistic regression. Sparse Canonical Correlation Analysis was performed to integrate species data with microbial pathways obtained by PICRUSt2., Results: There is a significant divergence of the microbial composition between CRC patients and controls (PERMANOVA p=0.001). Those who were in third tertile of the MDI showed a significantly increased risk of CRC in the total population (OR: 6.93, 95% CI: 3.98-12.06, p-trend<0.001) compared to those in the lowest tertile. Similar results were found for men (OR: 6.28, 95% CI: 3.04-12.98-, p-trend<0.001) and women (OR: 7.39, 95% CI: 3.10-17.63, p-trend<0.001). Bacteroides coprocola and Bacteroides plebeius species and 12 metabolic pathways were interrelated in healthy controls that explain 91% covariation across samples., Conclusion: Dysbiosis in the fecal microbiota may be associated with an increased risk of CRC. Due to the potentially modifiable nature of the gut microbiota, our findings may have implications for CRC prevention among Koreans.

Purpose: To synthesize the current literature regarding patients with inherited bleeding disorders and suggest comprehensive evaluation and preoperative recommendations for these patients before undergoing corneal refractive surgery., Methods: The literature search was conducted through PubMed, Embase, and Google Scholar databases for publications through January 4, 2024 for reports of ocular bleeding manifestations in patients with inherited bleeding disorders and reports of patients without a history of bleeding disorders who had intraoperative or postoperative hemorrhagic complications with corneal refractive surgery. Additional cases from the literature and a retrospective chart review at a corneal practice were obtained describing patients with inherited bleeding disorders who underwent corneal refractive surgery., Results: Four articles were found detailing ocular bleeding manifestations in patients with inherited bleeding disorders who underwent ocular surgery other than corneal refractive surgery. Thirty articles were found detailing intraoperative and postoperative bleeding manifestations in patients without a history of inherited bleeding disorders who underwent corneal refractive surgery. Eight cases (3 patients from the literature search and 5 patients from a retrospective chart review) were found regarding patients with inherited bleeding disorders who underwent corneal refractive surgery., Conclusions: For corneal refractive surgery with topical anesthesia, the perioperative risk and need for any hemostasis intervention in individuals with an inherited bleeding disorder depends on the type of disorder, status of preoperative factor level concentrations, or a prior history of bleeding. If required, clotting factor optimization should be tailored to each candidate on a case-by-case basis., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The fecal microbiota of two healthy adults was cultivated in a medium containing commercial fructooligosaccharides [FOS; 1-kestose (GF 2 ), nystose (GF 3 ), and 1 F -fructofuranosylnystose (GF 4 )]. Initially, the proportions of lactobacilli in the two feces samples were only 0.42% and 0.17%; however, they significantly increased to 7.2% and 4.8%, respectively, after cultivation on FOS. Most FOS-utilizing isolates could utilize only GF 2 ; however, Lacticaseibacillus paracasei strain Lp02 could fully consume GF 3 and GF 4 too. The FOS operon (fosRABCDXE) was present in Lc. paracasei Lp02 and another Lc. paracasei strain, KCTC 3510 T , but fosE was only partially present in the non-FOS-degrading strain KCTC 3510 T . In addition, the top six upregulated genes in the presence of FOS were fosABCDXE, particularly fosE. FosE is a β-fructosidase that hydrolyzes both sucrose and all three FOS. Finally, a genome-based analysis suggested that fosE is mainly observed in Lc. paracasei, and only 13.5% (61/452) of their reported genomes were confirmed to include it. In conclusion, FosE allows the utilization of FOS, including GF 3 and GF 4 as well as GF 2 , by some Lc. paracasei strains, suggesting that this species plays a pivotal role in FOS utilization in the human gut., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

A young woman in her early 30s presented with a right thyroid mass and progressive hoarseness due to a right vocal cord palsy. The preoperative fine-needle aspiration cytology was classified as Bethesda V and she underwent a total thyroidectomy and neck dissection. Intraoperatively, the thyroid mass was adherent to the oesophagus, trachea and encasing the right recurrent laryngeal nerve which was sacrificed. Final histopathology diagnosed a rare subtype of thyroid cancer known as intrathyroidal thymic carcinoma (ITC). She was then sent for adjuvant radiotherapy after a multidisciplinary tumour board discussion. This case report highlights the difficulty in preoperative diagnosis of ITC and the importance of immunohistochemical staining in clinching the diagnosis. In view of its rarity, there have been no published consensus on the treatment of ITC, hence we would like to share some learning points through a comprehensive literature review., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy., Methods: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed., Results: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria., Conclusions: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models., Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index., Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm., Results: In our cohort ( n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively., Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare., (© 2024 The Author(s).)

Objective: The standard treatment for regional failure in nasopharyngeal carcinoma (NPC) is the radical neck dissection (RND). Our study sought to determine if magnetic resonance imaging (MRI) may accurately predict nodal involvement to allow selected levels of neck dissection to be preserved., Study Design and Setting: We analysed retrospectively all NPC patients in our centre undergoing neck dissections as salvage therapy for nodal recurrence. Nodal involvement based on the preoperative MRI was assessed and compared with postoperative histopathology., Methods: This is a retrospective study conducted on patients in our centre with recurrent NPC from February 2002 to February 2017. Patients were identified from the database of the otolaryngology oncology division at our institution. Of these, 28 patients met all our inclusion and exclusion criteria. We calculated sensitivity and specificity as well as average number of nodes per patient., Results: In our study, we calculated the false negative and false positive rates of preoperative MRI neck by levels. Overall sensitivity of MRI picking up disease by level was 76% and specificity was 86%., Conclusion: Based on our study, we will be missing a total of 10 (7.1%) diseased neck levels in eight (28.5%) patients. MRI alone, therefore, does not provide enough information to allow safe selective preservation of neck levels in surgical salvage of neck recurrences in NPC.

Introduction: Guidelines on the management of pregnant individuals with von Willebrand disease (VWD) at the time of delivery recommend that von Willebrand factor (VWF) and factor VIII:C (FVIII:C) levels be ≥50% to prevent postpartum haemorrhage (PPH). Yet, high PPH rates persist despite these levels or with prophylactic factor replacement therapy to achieve these levels., Aims: The current practice at our centre has been to target peak plasma VWF and FVIII:C levels of ≥100 IU/dL at time of delivery. The objective of this study was to describe obstetric outcomes in pregnant individuals with VWD who were managed at our centre., Methods: Demographics and outcomes on pregnant individuals with VWD who delivered between January 2015 and April 2023 were collected., Results: Forty-seven singleton deliveries (among 41 individuals) resulting in 46 live births and one foetal death were included. Twenty-one individuals had at least one prior birth by the start date of this study, of which 11 (52.4%) self-reported a history of PPH. Early PPH occurred in 12.8% (6/47) of deliveries. Two individuals required blood transfusion, of which one also had an unplanned hysterectomy and transfer to ICU. There were no thrombotic events reported., Conclusion: The strategy of targeting higher peak plasma VWF and FVIII:C levels (≥100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery-associated bleeding complications in VWD patients. Yet, the rate of early PPH remains unsatisfactory compared to the non-VWD population., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Abstract: Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by arterial, venous, or microvascular thrombosis, pregnancy morbidities, or nonthrombotic manifestations in patients with persistently positive antiphospholipid antibodies. These antibodies bind cellular phospholipids and phospholipid-protein complexes resulting in cellular activation and inflammation that lead to the clinical features of APS. Our evolving understanding of APS has resulted in more specific classification criteria. Patients meeting these criteria should be treated during pregnancy according to current guidelines. Yet, despite treatment, those positive for lupus anticoagulant have at least a 30% likelihood of adverse pregnancy outcomes. Patients with recurrent early miscarriage or fetal death in the absence of preeclampsia or placental insufficiency may not meet current classification criteria for APS. Patients with only low titer anticardiolipin or anti-β(2)-glycoprotein I antibodies or immunoglobulin M isotype antibodies will not meet current classification criteria. In such cases, clinicians should implement management plans that balance potential risks and benefits, some of which involve emotional concerns surrounding the patient's reproductive future. Finally, APS may present in pregnancy or postpartum as a thrombotic microangiopathy, a life-threatening condition that may initially mimic preeclampsia with severe features but requires a very different treatment approach., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Gene therapy is now a reality for individuals with haemophilia, yet little is known regarding the quality-of-life impact of factor correction. As few data exist, and recognizing the analogy to liver transplantation (OLTX), we identified OLTX+ and OLTX- men in the ATHNdataset to compare post-OLTX factor VIII and IX on quality of life (QoL) by Haem-A-QoL and PROMIS-29., Methods: OLTX- were matched to OLTX+ by age, race, and haemophilia type and severity. Deidentified demographic data, including post-transplant factor levels, genotype and target joint disease were analysed by descriptive statistics. Haem-A-Qol and PROMIS-29 were compared in OLTX+ and OLTX- by student's t-test and univariate regression models., Results: Of 86 people with haemophilia A (HA) or haemophilia B (HB) cared for at 10 haemophilia treatment centers (HTCs), 21 (24.4%) OLTX+ and 65 (75.6%) OLTX- were identified. OLTX+ and OLTX- had a similar frequency of target joint disease (p = .806), HA genotypes, null versus non-null (p = .696), and HIV infection (p = .316). At a median 9.2 years post-OLTX, median FVIII, .63 IU/mL [IQR 0.52-0.97] and FIX, .91 IU/mL [IQR .63-1.32], Haem-A-QoL, PROMIS-29, and HOT scores were comparable. Severe HA/HB had lower post-OLTX 'dealing with haemophilia' scores (p = .022) and higher 'sports and leisure' (p = .010) and 'view of yourself' scores (p = .024) than OLTX+ non-severe participants. Non-caucasian OLTX+ had significantly lower scores in sports and leisure (p = .042), future expectations (p = .021) and total score (p = .010)., Conclusion: Nine years after OLTX, QoL is comparable to OLTX-, but significantly better in OLTX+ with severe than non-severe disease and in caucasians than non-caucasians., (© 2023 John Wiley & Sons Ltd.)

As the proportion of older people in the world's population steadily increases, there is an urgent need to identify ways to support healthy aging. The gut microbiome has been proposed to be involved in aging-related diseases and has become an attractive target for improving health in older people. Herein, we cover the relationship between the gut microbiome and chronological age in adults, and then, we discuss the gut microbiome features associated with frailty, as a hallmark of unhealthy aging in older people. Furthermore, we describe the effects of microbiome-targeted interventions, such as dietary patterns and consumption of probiotics, prebiotics, and synbiotics, on modulating the gut microbiome composition and further promoting healthy aging. Further studies are needed to explore the underlying mechanisms of gut microbiome-induced aging complications and to develop personalized microbiome-based strategies for reducing the severity of frailty or preventing the onset of frailty in older adults.

Background: Heparin-induced thrombocytopenia (HIT) is a relatively uncommon condition characterized by 2 exceedingly common phenomena in hospitalized patients: thrombocytopenia and heparin exposure. Consequently, HIT is frequently overdiagnosed and inappropriately treated. These issues are the focus of many quality improvement (QI) initiatives., Objectives: In this scoping review, we identified and characterized all published QI studies on improving the diagnosis and management of HIT., Methods: We conducted a systematic literature search through April 2022 for studies reporting on QI interventions regarding the diagnosis, treatment, and/or prevention of HIT., Results: Thirty studies were included in the final review. Studies were separated into 5 groups based on the focus of the interventions: increasing HIT recognition, reducing HIT incidence, reducing HIT overdiagnosis, promoting safer HIT management, and creating HIT task forces. Nine studies focused on the implementation of 4Ts score calculator into electronic medical record orders for HIT testing, while only 1 evaluated the impact of reducing unfractionated heparin use in favor of low-molecular-weight heparin. Six studies focused on the implementation of direct thrombin inhibitor management protocols, while none evaluated the use of alternative anticoagulants in HIT management., Conclusion: The bulk of published HIT QI research focused on reducing overdiagnosis and promoting safer direct thrombin inhibitor therapy, while minimal attention has been devoted to HIT prevention and the use of evidence-based alternative HIT therapies., (© 2023 The Author(s).)

Background: Universal Health Coverage (UHC) has received much attention and many countries are striving to achieve it. The Southeast Asian region, in particular, comprises many developing countries with limited resources, exacerbating challenges around attaining UHC. This paper aims to specifically explore the health financing challenges these countries face in achieving UHC via a systematic review approach and formulate recommendations that will be useful for policymakers., Methods: The systematic review followed the guidelines as recommended by PRISMA. The narrative synthesis approach was used for data synthesis, followed by identifying common themes., Results: The initial search returned 160 articles, and 32 articles were included after the screening process. The identified challenges in health financing towards achieving UHC in the Southeast Asian region are categorised into six main themes, namely (1) Unsustainability of revenue-raising methods, (2) Fragmented health insurance schemes, (3) Incongruity between insurance benefits and people's needs, (4) Political and legislative indifference, (5) Intractable and rapidly rising healthcare cost, (6) Morally reprehensible behaviours., Conclusions: The challenges identified are diverse and therefore require a multifaceted approach. Regional collaborative efforts between countries will play an essential role in the progress towards UHC and in narrowing the inequity gap. At the national level, individual countries must work towards sustainable health financing strategies by leveraging innovative digital technologies and constantly adapting to dynamic health trends., Registration: This study is registered with PROSPERO, under registration number CRD42022336624., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Predicted climate change-induced increases in heat waves and hypoxic events will have profound effects on fishes, yet the capacity of parents to alter offspring phenotype via non-genetic inheritance and buffer against these combined stressors is not clear. This study tested how prolonged adult zebrafish exposure to combined diel cycles of thermal stress and hypoxia affect offspring early survival and development, parental investment of cortisol and heat shock proteins (HSPs), larval offspring stress responses, and both parental and offspring heat and hypoxia tolerance. Parental exposure to the combined stressor did not affect fecundity, but increased mortality, produced smaller embryos and delayed hatching. The combined treatment also reduced maternal deposition of cortisol and increased embryo hsf1, hsp70a, HSP70, hsp90aa and HSP90 levels. In larvae, basal cortisol levels did not differ between treatments, but acute exposure to combined heat stress and hypoxia increased cortisol levels in control larvae with no effect on larvae from exposed parents. In contrast, whereas larval basal hsf1, hsp70a and hsp90aa levels differed between parental treatments, the combined acute stressor elicited similar transcriptional responses across treatments. Moreover, the combined acute stressor only induced a marked increase in HSP47 levels in the larvae derived from exposed parents. Finally, combined hypoxia and elevated temperatures increased both thermal and hypoxia tolerance in adults and conferred an increase in offspring thermal but not hypoxia tolerance. These results demonstrate that intergenerational acclimation to combined thermal stress and hypoxia elicit complex carryover effects on stress responsiveness and offspring tolerance with potential consequences for resilience., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Aim: To evaluate the association between trajectories of glycated haemoglobin (HbA1c) and potentially avoidable hospitalisations (PAH)., Methods: We performed a cohort study in a tertiary hospital in Singapore among adult type 2 diabetes patients with ≥ 3 HbA1c tests over two years. Then, we followed up for one year after the last HbA1c reading to determine the PAH outcome. Glycaemic control was analysed by (1) HbA1c trajectories through group-based trajectory modelling, and (2) mean HbA1c. PAH was defined using the Agency of Healthcare Research and Quality criteria, categorising as overall, diabetes, acute, and chronic-composites., Results: A total of 14,923 patients (mean age: 62.9 ± 12.8 years; 55.2% men) were included. Four HbA1c trajectories were observed; low-stable (n = 9854, 66.0%), moderate-stable (n = 3125, 20.9%), high-decrease (n = 1017, 6.8%) and high-persistent (n = 927, 6.2%). Compared to the low-stable trajectory, one-year risk ratio (RR) and 95% confidence interval (CI), respectively for moderate-stable, high-decrease and high-persistent trajectories were as follows: (1) overall PAH: 1.15 (1.00-1.31), 1.53 (1.31-1.80), 1.96 (1.58-2.43); (2) diabetes PAH: 1.30 (1.04-1.64), 1.98 (1.55-2.53), 2.24 (1.59-3.15); (3) acute PAH: 1.14 (0.90-1.44), 1.29 (0.95-1.77), 1.75 (1.17-2.62); and (4) chronic PAH: 1.21 (1.02-1.43), 1.62 (1.34-1.97), 2.14 (1.67-2.75). Mean HbA1c was significantly associated with overall and chronic-composites of PAH whilst evidence of a non-linear relationship with diabetes-composite of PAH was noted., Conclusion: Patients with high-decrease trajectory had a risk lower than those with persistently-high HbA1c, highlighting that a greater risk of hospitalisation conferred by poor glycaemic control is potentially reversible. Determining HbA1c trajectories could help to identify the high-risk individuals for targeted and intensive management to improve care and reduce hospitalisations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Drug-induced TMA (DI-TMA) is a thrombotic microangiopathy (TMA) caused by certain drugs, usually managed by drug discontinuation and supportive measures. Data on the use of complement-inhibition with eculizumab in DI-TMA is scarce, and its benefit in cases of severe or refractory DI-TMA is unclear. We conducted a comprehensive search in PubMed, Embase and MEDLINE databases (2007-2021). We included articles that reported on DI-TMA patients treated with eculizumab and its clinical outcomes. All other causes of TMA were excluded. We evaluated the outcomes of hematologic recovery, renal recovery, and a composite of both (complete TMA recovery). 35 studies fulfilled our search criteria, which included 69 individual cases of DI-TMA treated with eculizumab. Most cases were secondary to chemotherapeutic agents, and the most implicated drugs were gemcitabine (42/69), carfilzomib (11/69), and bevacizumab (5/69). The median number of eculizumab doses given was 6 (range 1-16). 55/69 (80 %) patients achieved renal recovery, after 28-35 days (5-6 doses). 13/22 (59 %) patients were able to discontinue hemodialysis. 50/68 (74 %) patients achieved complete hematologic recovery after 7-14 days (1-2 doses). 41/68 (60 %) patients met criteria for complete TMA recovery. Eculizumab was safely tolerated in all cases, and appeared to be effective in achieving both hematologic and renal recovery in DI-TMA refractory to drug discontinuation and supportive measures, or with severe manifestations associated with significant morbidity or mortality. Our findings suggest that eculizumab may be considered as a potential treatment for severe or refractory DI-TMA that does not improve after initial management, although larger studies are needed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MYL has received honorarium for participation in advisory boards from Takeda, Dova Pharmaceuticals and Forma Therapeutics. MYA has received honorarium for participation in advisory boards from Sanofi., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The oral microbiome is an important component of the microbiome in the human body. Although the association of the oral microbiome with various diseases, including periodontitis and cancer, has been reported, information on how the oral microbiome is related to health-related indicators in healthy populations is still insufficient. In this study, we examined the associations of the oral microbiome with 15 metabolic and 19 complete blood count (CBC)-based markers in 692 healthy Korean individuals. The richness of the oral microbiome was associated with four CBC markers and one metabolic marker. Compositional variation in the oral microbiome was significantly explained by four markers: fasting glucose, fasting insulin, white blood cell count, and total leukocyte count. Furthermore, we found that these biomarkers were associated with the relative abundances of numerous microbial genera, such as Treponema , TG5 , and Tannerella . By identifying the relationship between the oral microbiome and clinical biomarkers in a healthy population, our study presents a direction for future studies on oral microbiome-based diagnosis and interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lim, Kim and Nam.)

Introduction: Reproductive-age women with bleeding disorders (BDs) are underdiagnosed and understudied, despite their increased risk for adverse health outcomes and pregnancy complications., Aim: This study examines pregnancy outcomes and obstetric complications of Utah women with BDs., Methods: This retrospective cohort study utilized linked birth records and clinical billing data from two large Utah healthcare systems. Utah residents who had their first birth at > 20 weeks gestation (2008-2015) and who received non-emergent care within either system before delivery were included (n = 61 226). Multivariable logistic regression models were used to examine relationships between BDs and neonatal and obstetric outcomes., Results: A total of 295 women (.48%) were included in the BD study population. Women with BDs had significantly increased odds of preterm birth (aOR 1.85, 95% CI 1.32-2.60), Caesarean delivery (aOR 1.38, 95% CI 1.06-1.79), postpartum blood transfusion (aOR 2.55, 95% CI 1.05-6.22), unplanned postpartum hysterectomy (aOR 33.96, 95% CI 7.30-157.89) and transfer to an intensive care unit (aOR 18.18, 95% CI 7.17-46.08). All of the women with BDs who experienced these serious complications were not diagnosed with a BD until the year of their first birth. Additionally, those with BDs were more likely to experience maternal and infant mortality., Conclusion: Women with BDs had an increased risk for preterm birth, Caesarean delivery, blood transfusion, unplanned hysterectomy, intensive care unit admission, maternal and infant mortality. Those who were not diagnosed with a BD before the year of their first birth were at an increased risk for serious pregnancy complications., (© 2022 John Wiley & Sons Ltd.)

Cancer affects older adults with varying levels of frailty, but cancer treatment is extrapolated from clinical trials involving predominantly young and robust subjects. Recent geriatric oncology randomised controlled trials (RCT) report that geriatric assessment leading to frailty-guided intervention reduces treatment-related toxicity whilst maintaining survival and improving quality of life (QoL). However, these positive results have not have been consistently reported in the literature. We postulate that the impact of geriatric interventions has been underestimated in these studies with the inclusion of subjects receiving palliative-intent chemotherapy in whom dose reduction is common. Integrating supportive care with current geriatric oncology models may improve the QoL of older adults undergoing treatment. However, no studies as yet have examined such integrated geriatric and supportive models of care. The Geriatric Oncology SuPportive clinic for Elderly (GOSPEL) study is a single-centre, open-label, analyst-blinded RCT evaluating the impact of comprehensive geriatric and supportive care on QoL of older adults with cancer undergoing curative treatment. Older adults aged above 65, with a Geriatric-8 score ≤ 14, with plans for high dose radiotherapy and/or curative chemotherapy will be recruited. The primary QoL outcome is measured using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-ELD14 mobility scale at 12 weeks. Secondary outcomes include overall and disease-free survival, treatment-related adverse events, and hospital admissions. We pre-powered this study to recruit 200 subjects based on the minimally clinically important difference for EORTC QLQ-ELD14 to achieve 80% statistical power (alpha 0.05), assuming 25% attrition. Outcomes will be analysed using intention-to-treat. Intervention consists of multi-domain comprehensive geriatric and supportive care assessments from a multidisciplinary team targeting unmet needs. These include functional decline, falls, incontinence, cognitive impairment, multi-morbidity, polypharmacy, and symptom relief, as well as social and psycho-spiritual concerns. Standard care entails routine oncological management with referral to geriatrics based on the discretion of the primary oncologist. Recruitment has been ongoing since August 2020. Results from the GOSPEL study will increase understanding of the impact of integrated geriatric and supportive care programs in older adults with cancer receiving curative treatment. Trial registration: This study is registered under ClinicalTrials.gov (ID NCT04513977)., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The most common thrombotic microangiopathy (TMA) of pregnancy is the well-recognized syndrome of preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. However, rare TMAs, including thrombotic thrombocytopenic purpura, complement-mediated hemolytic-uremic syndrome, and catastrophic antiphospholipid syndrome, may occur during pregnancy or postpartum and present with features similar to those of preeclampsia with severe features. Early recognition and treatment of these infrequently encountered conditions are key for avoiding serious maternal morbidities with long-term sequelae and possible maternal or fetal death. Differentiating between preeclampsia with severe features and these rare TMAs is diagnostically challenging as there is significant overlap in their clinical and laboratory presentation. Given the rarity of these TMAs, high-quality evidence-based recommendations on diagnosis and management during pregnancy are lacking. Using current objective information and recommendations from working groups, this report provides practical clinical approaches to diagnose and manage these rare TMAs. This report also discusses how to manage individuals with a history of these rare TMAs who are planning to conceive. To optimize favorable outcomes, a multidisciplinary approach including obstetricians, maternal-fetal medicine specialists, hematologists, and nephrologists alongside close clinical and laboratory monitoring is vital., Competing Interests: Financial Disclosure Ming Yeong Lim received payment for participation in advisory boards from Takeda, Dova Pharmaceuticals, and Forma Therapeutics. D. Ware Branch received payment as a Member of the UCB Women with Inflammatory Disease Advisory Board in September of 2020. He received payment for Grand Rounds at the University of Iowa (Obstetric antiphospholipid syndrome: A tale of two patients. October 27, 2020). He also received payment for Obstetric antiphospholipid syndrome: Diagnosis, treatment, controversies. American Society for Clinical Laboratory Service Region VIII Annual Seminar, October 20, 2020. Dr. Branch also disclosed receiving payment for the following: Swanson, Martin & Bell, medical expert consultancy, check issued September 21, 2020; Association of Idaho Rheumatologists, Obstetric antiphospholipid syndrome. December 4, 2021; Bendin Sumrall & Ladner medical expert consultancy; Michigan Professional Insurance Exchange medical expert consultancy; Grand Rounds, Cornell University/Hospital for Special Surgery Division of Rheumatology, Obstetric antiphospholipid syndrome: A tale of three patients, May 26, 2021; Bendin Sumrall & Ladner medical expert consultancy; Gershon, Willoughby & Getz medical expert consultancy; Snow, Christensen & Matineau medical expert consultancy; Grand Rounds, Cornell University/Hospital for Special Surgery Division of Rheumatology, Obstetric antiphospholipid syndrome: A tale of three patients, May 26, 2021; Grand Rounds, University of New York, Stonybrook, November 3, 2021. Mouhamed Yazan Abou-Ismail did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)