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A study published in the journal Science explores the potential of a compound called MED6-189 as a new antimalarial drug candidate. The compound, which belongs to the kalihinol subfamily of sponge-derived natural products, demonstrated potent activity against drug-sensitive and drug-resistant strains of the malaria parasite. Through various experiments and analyses, researchers discovered that MED6-189 disrupts the apicoplast, a crucial organelle involved in parasite isoprenoid synthesis, and also interferes with lipid metabolism and vesicular trafficking. The compound showed promise in inhibiting parasite growth and clearing infections in both humanized mouse models and nonhuman primate parasites. The study suggests that MED6-189, along with other kalihinols and isocyanoterpene compounds, could be a promising lead drug for malaria treatment. [Extracted from the article]

The New York City Administration for Children's Services (ACS) instituted a neighborhood-based services system through the realignment of all foster care, preventive, and protective services along community district lines. ACS, with its community partners, also formed neighborhood-based networks to improve service coordination and collaboration among key community stakeholders and to shape a multisystem strategy tailored to each district informed by child welfare data. Based on analysis of neighborhood-specific census tract child welfare data, ACS initiated the Community Partnership to Strengthen Families project to address the disproportionate number of foster care placements originating from a small group of high-need communities, including Manhattan's Central Harlem. This article describes examples of specific strategies based on the Central Harlem experience. [ABSTRACT FROM AUTHOR]

Mitosis in eukaryotes involves reorganization of the nuclear envelope (NE) and microtubule-organizing centres (MTOCs). In Plasmodium , the causative agent of malaria, male gametogenesis mitosis is exceptionally rapid and divergent. Within 8 minutes, the haploid male gametocyte genome undergoes three replication cycles (1N to 8N), while maintaining an intact NE. Axonemes assemble in the cytoplasm and connect to a bipartite MTOC-containing nuclear pole and cytoplasmic basal body, producing eight flagellated gametes. The mechanisms coordinating NE remodelling, MTOC dynamics, and flagellum assembly remain poorly understood. Here, we identify the SUN1-ALLAN complex as a novel mediator of NE remodelling and bipartite MTOC coordination during Plasmodium male gametogenesis. SUN1, a conserved NE protein, localizes to dynamic loops and focal points near nuclear spindle poles. ALLAN, a divergent Allantoicase-like protein, has a location like that of SUN1 at nuclear MTOCs. SUN1 and ALLAN form a unique complex, detected by live-cell imaging, ultrastructural expansion microscopy, and interactomics. Deletion of either SUN1 or ALLAN gene disrupts nuclear MTOC organization, leading to basal body mis-segregation, defective spindle assembly, and impaired kinetochore attachment, but axoneme formation remains intact. Ultrastructural analysis revealed nuclear and cytoplasmic MTOC miscoordination, producing aberrant flagellated gametes lacking nuclear material. Sun1 deletion also alters parasite lipid composition, underscoring its role in NE homeostasis. These defects block parasite development in the mosquito and transmission, highlighting the essential functions of this complex. This study reveals a bipartite MTOC and a highly divergent mechanism of NE remodelling during Plasmodium male gametogenesis. The SUN1-ALLAN complex is an unusual adaptation of the LINC complex, in absence of canonical KASH-domain proteins in Plasmodium , providing new insights into the evolution of closed mitosis and highlighting potential targets for blocking malaria transmission.

Background: The molecular architecture of acute myeloid leukemia (AML) is heterogeneous. Obesity has been identified as a risk factor for the development of AML. There remains a scarcity of data elucidating the specific genetic profile of AML in obese patients., Methods: We conducted a review of adult patients treated at our institution for newly diagnosed AML from January 1, 2017, to January 1, 2023. Obesity is defined as BMI > 30 kg/m 2 . Demographic, clinical, laboratory, and pathologic data were collected retrospectively. The primary outcome of interest was the molecular features of obese compared to non-obese AML patients. The secondary outcome was overall survival (OS). Inverse probability of treatment weights (IPTW) used to balance both groups on several confounding variables., Results: A total of 185 patients were included in the analysis. 90 (49%) were obese. Compared with non-obese patients, obese patients were younger and more likely to be females (55 vs. 63, p = 0.04, 55% vs. 38%, p value, p = 0.02, respectively). After matching on age, gender, and ethnicity, obese patients exhibit lower rates of total number of gene mutations (median 2.7 vs. 3.2, p = 0.05), significantly lower rates of mutations in transcriptional factor genes (15.7% vs. 33.2%, p = 0.01), and near-significant in spliceosome genes (12% vs. 22.3%, p = 0.08), and higher rates of NPM1 mutation (23.3% vs. 12.6%, p = 0.08). Median OS was not significantly different in the matched cohort., Conclusions: The molecular features of obese AML patients significantly differ from non-obese counterparts. These findings suggest distinct underlying mechanisms in leukemogenesis in obese patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The environmental challenges the human malaria parasite, Plasmodium falciparum , faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light into the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate that Pf MORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggest that Pf MORC binds to not only sub-telomeric regions and genes involved in antigenic variation but may also play a role in modulating stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation of Pf MORC impairs key histone marks and induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm that Pf MORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies., Competing Interests: Declarations of Interest The authors declare no competing interests.

Little is known about the dietary knowledge (DK) and eating habits (EHs) of patients with type 2 diabetes (T2D) in Lebanon. Therefore, the aim of this study was to assess the DK and EH of the population with T2D and determine their associated factors. A cross-sectional survey enrolling 351 patients with T2D was carried out, using the snowball sampling technique. The survey used the UK Diabetes and Diet Questionnaire and the Dietary Knowledge questionnaire to assess participants' EH including the frequency of consumption of certain foods and their knowledge of food groups and food choices. While a higher DK index indicated better knowledge, a higher EH index indicated less healthy EH. Independent sample T -test and Mann-Whitney test were used for dichotomous variables, and ANOVA and Kruskal-Wallis tests were used for polytomous variables. Correlation analysis tested the association between two continuous variables. Two multiple linear regression models were used to identify factors associated with DK and EH. Overall, 67% of participants had good or adequate DK, and around 25% and 75% of them had healthy and less healthy EH, respectively. Better knowledge was significantly related to occupation, BMI, presence of comorbidities, and HbA1c testing during the last 3 months. Higher family income, physical activity, family history of diabetes, receiving help in medication administration from family or friends, and higher DK level were factors associated with healthier EH. Nutrition education and awareness campaigns aimed at patients and their families are needed to empower patients with adequate DK and skills to facilitate the adoption of healthy EH., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Myriam Abboud et al.)

Plasmodium falciparum , the human malaria parasite, infects two hosts and various cell types, inducing distinct morphological and physiological changes in the parasite in response to different environmental conditions. These variations required the parasite to adapt and develop elaborate molecular mechanisms to ensure its spread and transmission. Recent findings have significantly improved our understanding of the regulation of gene expression in P. falciparum . Here, we provide an up-to-date overview of technologies used to highlight the transcriptomic adjustments occurring in the parasite throughout its life cycle. We also emphasize the complementary and complex epigenetic mechanisms regulating gene expression in malaria parasites. This review concludes with an outlook on the chromatin architecture, the remodeling systems, and how this 3D genome organization is critical in various biological processes.

Background: The prevalence of eosinophilic asthma in Lebanon, one of the most severe phenotypes among severe asthma, is not known. This study aimed at determining the prevalence of the eosinophilic phenotype defined as an eosinophil count ≥ 300 cells/mm 3 among severe asthma patients in Lebanon., Methods: The Lebanese Chapter of the PREPARE study was a national, multicenter, cross-sectional observational study. Patients aged ≥ 12 years with severe asthma were identified and prospectively enrolled during clinic visits and completed the Global Initiative for Asthma (GINA) assessment of asthma control questionnaire. Patients' health characteristics were collected from medical records and blood samples were obtained for measurement of serum IgE levels and blood eosinophils count., Results: Overall, 101 patients (with mean age of 46.3 ± 17.0 years and 73.27% females) with severe asthma were included and, among them, 37% had eosinophilic phenotype, 67.3% had atopic phenotype with IgE > 100 IU/mL and 25.7% patients had overlapping atopic and eosinophilic phenotypes. Close to 80% had late-onset asthma, beyond 12 years of age, and around 85% had at least one severe exacerbation in the 12 months prior to study enrolment. The majority of participants [64.4%] had uncontrolled asthma, 24.7% had partially controlled symptoms and 10.9% had controlled symptoms. 19.8% of participants were on chronic oral corticosteroids, 78.2% had short course treatment of corticosteroids and all were prescribed a combination of inhaled corticosteroids and long-acting beta-agonist., Conclusions: The majority of patients with severe asthma were uncontrolled of which 37% present with an eosinophilic phenotype, which should be taken into consideration for better management of these patients in view of the novel phenotype-specific therapeutic options., (© 2023. Canadian Society of Allergy & Clinical Immunology.)

The complex life cycle of Plasmodium falciparum requires coordinated gene expression regulation to allow host cell invasion, transmission, and immune evasion. Increasing evidence now suggests a major role for epigenetic mechanisms in gene expression in the parasite. In eukaryotes, many lncRNAs have been identified to be pivotal regulators of genome structure and gene expression. To investigate the regulatory roles of lncRNAs in P. falciparum we explore the intergenic lncRNA distribution in nuclear and cytoplasmic subcellular locations. Using nascent RNA expression profiles, we identify a total of 1768 lncRNAs, of which 718 (~41%) are novels in P. falciparum. The subcellular localization and stage-specific expression of several putative lncRNAs are validated using RNA-FISH. Additionally, the genome-wide occupancy of several candidate nuclear lncRNAs is explored using ChIRP. The results reveal that lncRNA occupancy sites are focal and sequence-specific with a particular enrichment for several parasite-specific gene families, including those involved in pathogenesis and sexual differentiation. Genomic and phenotypic analysis of one specific lncRNA demonstrate its importance in sexual differentiation and reproduction. Our findings bring a new level of insight into the role of lncRNAs in pathogenicity, gene regulation and sexual differentiation, opening new avenues for targeted therapeutic strategies against the deadly malaria parasite., (© 2023. Springer Nature Limited.)

The human malaria parasites, including Plasmodium falciparum, persist as a major cause of global morbidity and mortality. The recent stalling of progress toward malaria elimination substantiates a need for novel interventions. Controlled gene expression is central to the parasite's numerous life cycle transformations and adaptation. With few specific transcription factors (TFs) identified, crucial roles for chromatin states and epigenetics in parasite transcription have become evident. Although many chromatin-modifying enzymes are known, less is known about which factors mediate their impacts on transcriptional variation. Like those of higher eukaryotes, long noncoding RNAs (lncRNAs) have recently been shown to have integral roles in parasite gene regulation. This review aims to summarize recent developments and key findings on the role of lncRNAs in P. falciparum., Competing Interests: Declaration of interests The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood., Materials and Methods: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan-Meier method, respectively., Results: A total of 87 MIBC patients were included. The median age was 66 (39-84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 ( p = 0.006), non-responders ( p = 0.002), and at stage ≥ 3 ( p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance., Conclusion: CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product─along with a hypothesis about a biosynthetic relationship to related family members─inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis -to- trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama-Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C-N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.

Pathogenic protists are a group of organisms responsible for causing a variety of human diseases including malaria, sleeping sickness, Chagas disease, leishmaniasis, and toxoplasmosis, among others. These diseases, which affect more than one billion people globally, mainly the poorest populations, are characterized by severe chronic stages and the lack of effective antiparasitic treatment. Parasitic protists display complex life-cycles and go through different cellular transformations in order to adapt to the different hosts they live in. Autophagy, a highly conserved cellular degradation process, has emerged as a key mechanism required for these differentiation processes, as well as other functions that are crucial to parasite fitness. In contrast to yeasts and mammals, protist autophagy is characterized by a modest number of conserved autophagy-related proteins (ATGs) that, even though, can drive the autophagosome formation and degradation. In addition, during their intracellular cycle, the interaction of these pathogens with the host autophagy system plays a crucial role resulting in a beneficial or harmful effect that is important for the outcome of the infection. In this review, we summarize the current state of knowledge on autophagy and other related mechanisms in pathogenic protists and their hosts. We sought to emphasize when, how, and why this process takes place, and the effects it may have on the parasitic cycle. A better understanding of the significance of autophagy for the protist life-cycle will potentially be helpful to design novel anti-parasitic strategies.

Kinesins are microtubule (MT)-based motors important in cell division, motility, polarity, and intracellular transport in many eukaryotes. However, they are poorly studied in the divergent eukaryotic pathogens Plasmodium spp., the causative agents of malaria, which manifest atypical aspects of cell division and plasticity of morphology throughout the life cycle in both mammalian and mosquito hosts. Here, we describe a genome-wide screen of Plasmodium kinesins, revealing diverse subcellular locations and functions in spindle assembly, axoneme formation, and cell morphology. Surprisingly, only kinesin-13 is essential for growth in the mammalian host while the other 8 kinesins are required during the proliferative and invasive stages of parasite transmission through the mosquito vector. In-depth analyses of kinesin-13 and kinesin-20 revealed functions in MT dynamics during apical cell polarity formation, spindle assembly, and axoneme biogenesis. These findings help us to understand the importance of MT motors and may be exploited to discover new therapeutic interventions against malaria., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Multiple myeloma (MM) is the second most common hematological malignancy, accounting for 1% of all cancers, with median age of diagnosis between 66-70 years. MM remains incurable despite advances in treatment over time. Lenalidomide is an important medication used in induction therapy for MM and is also used for maintenance therapy for standard risk patients. With its increasing use, data is emerging about its use being associated with increased risk of secondary primary malignancies (SPM), especially when used as maintenance therapy., Case Series: In this case series, we describe three patients with refractory MM treated with lenalidomide maintenance who later developed sALL. All had a common presentation of pancytopenia. They developed cytopenias while being on lenalidomide which was refractory to lenalidomide cessation, prompting bone marrow biopsy., Management and Outcome: Lenalidomide was subsequently stopped, and patients were treated for secondary B-ALL. However, all passed away either due to relapse of disease or complications arising from treatment., Discussion: The mechanism of lenalidomide associated SPMs is not well understood however its incidence is well documented. At least 13 cases of ALL (predominantly B-cell ALL) following Immunomodulator imide drugs (IMiDs) have been reported in literature. An analysis of a larger cohort of patients is required to determine causality of lenalidomide with sALL. However, benefits of maintenance lenalidomide in patients with MM outweighs the risk of developing SPMs. Albeit persistent pancytopenia on lenalidomide therapy should be evaluated with bone marrow biopsy since it could be caused by secondary B -cell ALL.

Background: The prognostic value of the KRAS proto-oncogene mutation in colorectal cancer has been debated. Herein, we analyzed the National Cancer Database (NCDB) to assess the role of KRAS mutation as a prognostic marker in patients with locally advanced rectal cancer (LARC)., Methods: We identified LARC patients treated with neoadjuvant chemoradiation from 2004-2015 excluding those with stage I/IV disease and unknown KRAS status. Multivariable logistic regression identified variables associated with KRAS positivity. Propensity adjusted univariable and multivariable analyses identified predictors of survival., Results: Of the 784 eligible patients, 506 were KRAS-negative (KRAS -) and 278 were KRAS-positive (KRAS +). Median survival was 63.6 months and 76.3 months for KRAS + and KRAS - patients respectively, with propensity adjusted 3 and 5-year survival of 79.9% vs. 83.6% and 56.7% vs. 61.9% respectively (HR 1.56, p 1.074-2.272). Male sex, no insurance, and KRAS + disease were associated with poorer survival on unadjusted and propensity adjusted multivariable analyses., Conclusions: Our analysis of KRAS + LARC suggest that KRAS + disease is associated with poorer overall survival. Given the inherent limitations of retrospective data, prospective validation is warranted., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A minority of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) undergo surgery before the initiation of systemic therapy. The aim of this study is to explore the characteristics of patients undergoing surgery prior to systemic therapy (surgfirst), the predictors for surgfirst, and the survival outcomes., Methods: The National Cancer Database was queried for patients with DLBCL diagnosed between 2006 and 2015, and we performed a subgroup analysis of patients that received surgfirst. Time-to-initial therapy (TTI) was defined as the time in days (d) from diagnosis to systemic therapy. Overall survival was measured from the day of diagnosis in terms of months (m)., Results: Factors associated with lower likelihood of surgfirst were non-Hispanic Black race (p-value<0.005), rural location (p-value<0.005), treatment at academic center (p-value<0.005), Medicaid insurance (p-value=0.01), comorbidity score >=3 (p-value 0.007), year of diagnosis, advanced stages of disease, and presence of B-symptoms. The TTI of systemic therapy was delayed in the surgfirst group - 34 (IQR 22-52) days vs. 23 (IQR 13-38) days, p-value<0.005. The five-year overall survival was 62.7% (95% CI 62.1-63.2%) vs. 58.3% (95% CI 57.7-60.0%) - HR 0.87 (95% CI 0.85-0.89), p-value<0.005. The factors associated with higher mortality were advanced comorbidities, lower educational status, disease primarily located in the bone, brain, and spinal cord, advanced clinical stage, presence of B-symptoms, and advanced age., Conclusion: Despite the delay in systemic therapy, we could not identify a detrimental impact of surgfirst on survival. This needs to be confirmed in large-scale multicenter studies. We identified clinical and socioeconomic factors that affect treatment selection and survival., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Vusqa et al.)

The human malaria parasite, Plasmodium falciparum, is a unicellular protozoan responsible for over half a million deaths annually. With a complex life cycle alternating between human and invertebrate hosts, this apicomplexan is notoriously adept at evading host immune responses and developing resistance to all clinically administered treatments. Advances in omics-based technologies, increased sensitivity of sequencing platforms and enhanced CRISPR based gene editing tools, have given researchers access to more in-depth and untapped information about this enigmatic micro-organism, a feat thought to be infeasible in the past decade. Here we discuss some of the most important scientific achievements made over the past few years with a focus on novel technologies and platforms that set the stage for subsequent discoveries. We also describe some of the systems-based methods applied to uncover gaps of knowledge left through single-omics applications with the hope that we will soon be able to overcome the spread of this life-threatening disease., Competing Interests: Conflict of interest 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.

Background: Disparities driven by socioeconomic factors have been shown to impact outcomes for cancer patients. We sought to explore this relationship among patients with multiple myeloma (MM) who were not considered for hematopoietic stem cell transplant in the first-line setting and how it varied over time., Methods: We queried the National Cancer Database for patients diagnosed with MM between 2004 and 2016 and included only those who received systemic therapy as the first-line treatment. Enrollment rates for therapy were calculated as receipt of systemic therapy as the incident event of interest (numerator) over time to initiation of therapy (denominator) and used to calculate incident rate ratios that were further analyzed using Poisson regression analysis. A multivariate Cox proportional hazards model was constructed for survival analysis, and differences were reported as hazard ratios (HRs)., Results: We identified 56,102 patients for enrollment analysis and 50,543 patients for survival analysis. Therapy enrollment in a multivariate model was significantly impacted by race and sex (p < .005). Advanced age, earlier year of diagnosis, lack of insurance or Medicaid, and higher comorbidity were associated with poor survival (HR > 1), whereas female sex, non-Hispanic black race, higher income, and treatment at an academic center were associated with improved survival (HR < 1)., Conclusion: Disparities in treatment of MM exist and are caused by a complex interplay of multiple factors, with socioeconomic factor playing a significant role. Studies exploring such determinants may help in equitable distribution of resources to overcome such differences., 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 © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

A 23-year-old Caucasian woman, presented with recurrent fevers, elevated liver function tests and pancytopenia. Her labs at presentation were white blood cells 1.5 ×10 9 /L, haemoglobin 8 g/L, platelets 59 k/mcl, lactate dehydrogenase (LDH) over 2000 U/L, aspartate aminotransferase 593 U/L, alanine aminotransferase 1321 U/L, alkaline phosphatase 223 U/L and ferritin 7665 µg/L. Epstein-Barr virus (EBV) IgM and IgG antibodies were positive in serum. A soluble interleukin 2 receptor was elevated at 2458. A bone marrow biopsy revealed scattered macrophages containing erythrocytes and other cellular elements. Immunohistochemistry for CD68 highlighted macrophages with erythrophagocytosis and in situ hybridisation was positive for EBV. She met the diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH). She was initially treated with broad spectrum antibiotics which were eventually discontinued once the diagnosis was established. Over a period of 2-3 weeks her fever, transaminitis, ferritin and LDH improved spontaneously. She continued to improve clinically and was subsequently discharged. HLH is an aggressive, life-threatening hyper-inflammatory syndrome which, if not promptly recognised and treated, can be fatal. Treatment involves etoposide-based chemotherapy and possible stem-cell transplantation. This patient showed signs of improvement spontaneously and a decision was made to not treat her. This was a rare case of EBV-associated HLH which resolved spontaneously without any intervention. This young patient was not subjected to unnecessary chemotherapy. So far only few cases of spontaneous resolution of EBV-associated HLH have been reported., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

A leukemoid reaction is typically defined as white blood cell (WBC) count >50×10 9 /L, predominantly neutrophil precursors, that are not due to tumour involvement in the bone marrow and not derived from clones. Leukemoid reactions associated with malignancy, known as paraneoplastic leukemoid reactions, are less common and are most notably seen with non-small cell lung cancer. A 64-year-old woman presented with right leg painful ulceration. On examination, she had multiple venous stasis ulcers more severe on the right, with no palpable pulses in her lower extremities. Her WBC count was 124×10 9 /L and platelets were 517×10 9 /L. Arterial dopplers showed limb-threatening arterial insufficiency which prompted right femoral endarterectomy. Few months earlier she was diagnosed with metastatic lung adenocarcinoma to the bone and she had leukemoid reaction with WBC 43.920× 10 9 /L with 90% neutrophils. Repeat imaging showed progression of her malignancy and she passed shortly after. Inflammation is a key element of carcinogenesis and cancer progression. Among the different tumours, lung cancer is a non-haematologic malignancy that is most closely associated with leucocytosis. Some studies have found that leucocytosis was significantly associated with metastasis and shorter survival irrespective of other factors such as age or sex. The mechanism remains unclear however elevated levels of granulocyte colony-stimulating factor (CSF), granulocyte macrophage-CSF and interleukin 6 have been linked to this phenomena. The degree of leucocytosis seen in our patient is suggestive of CSF production leading to a paraneoplastic leukemoid reaction., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Gene families underlie genetic innovation and phenotypic diversification. However, our understanding of the early genomic and functional evolution of tandemly arranged gene families remains incomplete as paralog sequence similarity hinders their accurate characterization. The Drosophila melanogaster-specific gene family Sdic is tandemly repeated and impacts sperm competition. We scrutinized Sdic in 20 geographically diverse populations using reference-quality genome assemblies, read-depth methodologies, and qPCR, finding that ∼90% of the individuals harbor 3-7 copies as well as evidence of population differentiation. In strains with reliable gene annotations, copy number variation (CNV) and differential transposable element insertions distinguish one structurally distinct version of the Sdic region per strain. All 31 annotated copies featured protein-coding potential and, based on the protein variant encoded, were categorized into 13 paratypes differing in their 3' ends, with 3-5 paratypes coexisting in any strain examined. Despite widespread gene conversion, the only copy present in all strains has functionally diverged at both coding and regulatory levels under positive selection. Contrary to artificial tandem duplications of the Sdic region that resulted in increased male expression, CNV in cosmopolitan strains did not correlate with expression levels, likely as a result of differential genome modifier composition. Duplicating the region did not enhance sperm competitiveness, suggesting a fitness cost at high expression levels or a plateau effect. Beyond facilitating a minimally optimal expression level, Sdic CNV acts as a catalyst of protein and regulatory diversity, showcasing a possible evolutionary path recently formed tandem multigene families can follow toward long-term consolidation in eukaryotic genomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: Patients with advanced cancers are among the most vulnerable group of patients. We sought to analyze the impact of Affordable Care Act (ACA) on the interaction of socioeconomic factors with treatment and survival in patients with metastatic colorectal cancers., Methods: National Cancer Database (NCDB) was queried for patients with Stage-IV colon(CCa) and rectal cancers(R-Ca) diagnosed 2004-2015 and excluded those who did not receive any therapies within 6 months of diagnosis. Enrollment-rates were calculated as receipt of primary therapy as the incident-event (numerator) over time-to-initiation of therapy (denominator) and used to calculate incident-rate ratios that was analyzed using Poisson regression analysis- reported as enrollment-rate ratios (ER, <1 indicating lower enrollment rate). Multivariate Cox-proportional hazard model was performed for survival analysis and reported as calculate Hazard Ratios (HR)., Results: For CCa, enrollment to primary therapies was significantly associated (p-value < 0.05) with gender, race, insurance status, educational status and treatment facility. The HR for non-Hispanic Blacks (NHB) vs. Whites (NHW) improved from 1.1(1.03-1.11),p-value<0.005 to no-significant difference post-ACA. For R-Ca, the enrollment rates were favorable for NHB vs. NHW and ER improved from 1.15(1.0-1.32),p-value = 0.054) to 1.29(1.06-1.58),p-value = 0.013 post-ACA. Despite this, the HR for mortality were unfavorable - 1.19(1.06-1.33),p-value = 0.003 that persisted through the post-ACA period. The HR was favorable for the insured group in both cancer groups (0.84 for R-Ca,0.86 for CCa) and for high-income vs. low-income group-0.90(0.87-0.94),p-value < 0.005 in CCa., Conclusion: The ACA appears to have had a positive impact overall but further research and ongoing interventions are warranted to mitigate disparities in this population., 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 © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The flagship member of the antiplasmodial isocyanoterpenes, 7,20-diisocyanoadociane (DICA), was synthesized from dehydrocryptone in 10 steps, and in 13 steps from commercially available material. Our previous formal synthesis was reengineered, leveraging only productive transformations to deliver DICA in fewer than half the number of steps of our original effort. Important contributions, in addition to the particularly concise strategy, include a solution to the problem of axial nucleophilic methylation of a late-stage cyclohexanone, and the first selective synthesis and antiplasmodial evaluation of the DICA stereoisomer with both isonitriles equatorial., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This article presents a high-level overview of the complex issues, opportunities, and challenges involved in improving child safety and preventing child maltreatment fatalities. It emphasizes that improving measurement and classification is critical to understanding and preventing child maltreatment fatalities. It also stresses the need to reframe child maltreatment interventions from a public health perspective. The article draws on the lessons learned from state-of-the-art safety engineering innovations, research, and other expert recommendations presented in this special issue that can inform future policy and practice direction in this important area.

This article highlights current models used in child protection to assess safety and risk, and discusses implications for child maltreatment fatalities. The authors advance that current risk and safety practice approaches were not designed to accurately estimate the likelihood of low base-rate phenomena and have not been empirically tested in their ability to predict or prevent severe or fatal child maltreatment. They advance that, regardless of the ultimate effectiveness of safety and risk tools, competent assessment and decision-making in child protection depend on sound professional judgment and a comprehensive systemic approach that transcends the use of specific tools.

This article describes the efforts and special initiatives of New York City's Administration for Children's Services to improve services to immigrant and English language learner populations. Children's Services convened an immigration issues advisory subcommittee, created special tools for child welfare staff, collaborated with legal agencies to assist foster children with immigration status adjustments, improved agency data collection, and launched an agency-wide training initiative on immigration issues. The challenges encountered by Children's Services offer important insight for child welfare agencies in other jurisdictions designing strategies to strengthen their services for immigrant communities.

From January 1986 to June 1994, 252 cases of closed liver trauma were treated in an emergency setting. Non surgical conservative management, after a complete imaging work-up including CT scan in all cases, was applied in 142 cases (56.3%) with no hemodynamic complication. The spontaneous outcome in these cases was quite favourable in 131 (92.2%); all lesions had disappeared in 4 to 36 weeks. Complications were observed in only 6 cases: 2 intrahepatic abscesses managed with percutaneous drainage were not further complicated, 1 biliari fistula required surgical exploration, 1 intrahepatic bilioma was drained percutaneously, 1 disinsertion of the gallbladder was treated by laparoscopy and 1 operation for bleeding was required 48 hours after the trauma in 1 case. No deaths could be directly imputed to the liver trauma, 5 patients died from neurological causes. Non-surgical conservative treatment combined with strict prolonged surveillance is a reliable management option for patients with closed liver trauma.