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•A rare mutation in CXCR4 led to life-long autoimmunity and lymphoid hypertrophy in several members of a kindred.•Lack of characteristic features of WHIM syndrome led to greatly delayed diagnosis.

Hematologic neoplasms with germline predisposition have been increasingly recognized as a distinct category of tumors over the last few years. As such, this category was added to the World Health Organization (WHO) 4th edition as well as maintained in the WHO 5th edition and International Consensus Classification (ICC) 2022 classification systems. In practice, these tumors require a high index of suspicion and confirmation by molecular testing. Flow cytometry is a cost‐effective diagnostic tool that is routinely performed on peripheral blood and bone marrow samples. In this review, we sought to summarize the current body of research correlating flow cytometric immunophenotype to assess its utility in diagnosis of and clinical decision making in germline hematologic neoplasms. We also illustrate these findings using cases mostly from our own institution. We review some of the more commonly mutated genes, including CEBPA, DDX41, RUNX1, ANKRD26, GATA2, Fanconi anemia, Noonan syndrome, and Down syndrome. We highlight that flow cytometry may have a role in the diagnosis (GATA2, Down syndrome) and screening (CEBPA) of some germline predisposition syndromes, although appears to show nonspecific findings in others (DDX41, RUNX1). In many of the others, such as ANKRD26, Fanconi anemia, and Noonan syndrome, further studies are needed to better understand whether specific flow cytometric patterns are observed. Ultimately, we conclude that further studies such as large case series and organized data pipelines are needed in most germline settings to better understand the flow cytometric immunophenotype of these neoplasms.

Objective: To characterize the representation of Black and Hispanic cancer patients in tobacco treatment trials, and to offer recommendations for future research. Methods: We conducted two systematic searches of the literature (2018, 2021) using 5 databases (MEDLINE via EBSCO, Pubmed, PsycInfo, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (EMBASE)) to examine the prevalence of tobacco trials that included Black or Hispanic cancer patients. Two coders independently screened all articles at title, abstract, and full-text to identify eligible trials. Information about the proportion of Black and Hispanic patients included, trial design features, and whether the authors analyzed outcomes for Black and Hispanic patients were documented. Results: Of 4682 identified studies, only 10 published trials included and reported on the rates of Black or Hispanic cancer patients enrolled in their tobacco trial. The proportion of enrolled Black cancer patients ranged from 2 to 55.6%. Only our studies documented enrollment rates for Hispanics, and rates were less than 6%. None of the studies offered strategies to promote or the accrual of Black or Hispanic patients. Discussion: There remains a large gap in the literature regarding the reach and efficacy of tobacco treatment for Black and Hispanic cancer patients. Black and Hispanic cancer patients remain largely under-represented in tobacco cessation trials, limiting the applicability of existing, evidence-based treatments. To optimize intervention generalizability, future studies should emphasize the targeted recruitment and engagement of these patients in tobacco trials.

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This study evaluated the impact of training two practitioners to create and implement video-based intervention (VBI) to teach vocational skills to three autistic young adults in authentic workplace settings, via a multiple-probe single-case research design. A behavioral skills training (BST) package was used to train the practitioners to create and implement VBI. Practitioners’ fidelity of VBI creation and implementation was also evaluated via pretest-posttest. There was a functional relation between the practitioner-created and -implemented VBI and the autistic young adults’ vocational skill acquisition, with all three reaching 100% independent accuracy and demonstrating maintenance of the learned vocational skills. The practitioners also showed large increases in their fidelity of VBI creation and implementation from pretest to posttest, although their VBI creation performance decreased slightly at follow-up. All participants reported positive experiences with the VBI and rated it as socially valid.

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.

Inventory management is the core of supply and demand chain management. The economic order quantity (EOQ) model is the fundamental inventory management model that is assumed to bring only perfect items out of the ordered lot. A lot undergoes a single acceptance sampling plan with an imperfect inspection process before being placed in the inventory. The traditional inventory management process fails to address real-world situations where each type of product is handled in a unique way by manufacturers. This paper formulates an EOQ model in a fuzzy environment while considering: 1) shortages and backorders; 2) the chance of misclassification; 3) fuzziness in the model parameters. An optimisation problem is developed to maximise the total profit. The existence and uniqueness of the optimal solutions are proved with the help of a theorem established for concavity conditions of the total expected profit function. A sensitivity analysis study is also conducted to examine the effect of inspection error on order quantity, backorder level, and total profit. Finally, several numerical examples are presented to illustrate the model derived.

Objectives: Blacks and Hispanics face a higher incidence rate of end-stage renal disease (ESRD) and tend to experience poorer access to quality health care compared with Whites. Income, education, and insurance coverage differentials are typically identified as risk factors, but neighborhood-level analyses may provide additional insights. We examine whether neighborhood racial composition contributes to racial/ethnic inequities in access to high-quality dialysis care in Chicago. Methods: Data are drawn from the United States Renal Data System merged to the ESRD Quality Incentive Program file and the American Community Survey (2005–2009) for facility and neighborhood characteristics (N= 2797). Outcomes included (1) spatial access (travel time to dialysis facilities) and (2) realized access (actual use of quality care). Neighborhood racial/ethnic composition was categorized into four types: predominantly White, Black, and Hispanic neighborhoods, and racially integrated neighborhoods. Results: Blacks lived closer to a dialysis facility but traveled the same distance to their own dialysis compared with Whites. Hispanics had longer travel time to any dialysis than Whites, and the difference between Hispanics and Whites became no longer significant after adjusting for neighborhood racial/ethnic composition. Blacks and Hispanics had better access to a high-quality facility if they lived in integrated neighborhoods (OR= 1.85 and 3.77, respectively, p< 0.01) or in neighborhoods with higher concentrations of their own race/ethnicity (OR= 1.68 for Blacks in Black neighborhoods and 1.92 for Hispanics in Hispanic neighborhoods, p< 0.05) compared with Whites in predominantly White neighborhoods. Conclusion: Expanding opportunities for Blacks and Hispanics to gain access to racially integrated and minority neighborhoods may help alleviate racial/ethnic inequities in access to quality care among kidney disease patients.

Coffee industry generates large amounts of organic waste such as spent coffee grounds (SCG) and green coffee beans press cake (PC). The extraction of oil and phenolic compounds from PC was evaluated by: 1) Soxhlet extraction system using ethanol and hexane as solvent; 2) Extraction in a fixed bed at 400 bar and 60 °C using as solvent supercritical CO2(scCO2), ethanol or a mixture scCO2/ethanol 90:10 w/w; and 3) sequential extraction in a fixed bed at 400 bar and 60 °C using scCO2followed by pressurized liquid extraction with ethanol, followed by water. PC showed a residual oil content around 6%, which was extracted with pure scCO2and with hexane. Multi-stage extractions provide a statistically equal total extraction yield (p≤ 0.05) to that obtained in a single step with ethanol, which was around 21%. However, ethanolic extract in one step presented about 96 mg CAE/g extract and the ethanolic and aqueous extracts obtained in the sequential stages showed 159 mg CAE/g and 146 mg CAE/g, respectively. The residue from the mechanical extraction of green coffee oil has an important oil content and the amount of phenolic compounds is greater than that from SCG.

Parents of three children with neurodevelopmental disorders and pica were taught to use a safety checklist to create pica-safe areas when transitioning to new locations. During baseline, no parent displayed pica-safe behavior, and their children attempted pica at moderate to high rates. After use of the checklist, parent pica-safe behavior increased, and instances of pica diminished to near zero. Results transferred to new contexts and additional substances associated with pica. Using the safety checklist appears to have aided parents in creating pica-safe environments to minimize pica.

Quality protein maize (QPM) has abundant γ‐zein, which crosslinks itself and other zeins through disulfide bonding. The work aims to develop zein bioplastics with better functionality by using QPM zein. Physical properties of cast QPM zein films from QPM maize were compared with zein films from regular maize types and commercial zein, all without added plasticizers. QPM zein contained 3.8% cysteine compared with 1.8%–2.7% in regular maize zeins and 1% in commercial zein and the QPM zein had a much higher proportion of γ‐zein. QPM zein films cast from glacial acetic acid (GAA) were opaque but absorbed the least liquid (≈16%) and swelled less (≈11%) after buffer immersion than the other zein films and aqueous ethanol‐cast films. Notably, the GAA‐cast QPM zein films became highly flexible after ambient storage, whereas the other zein films remained brittle. The low buffer uptake and swelling of QPM zein films is attributed to crosslinking involving the cysteine‐rich γ‐zein polypeptides. Their flexibility is attributed to better solubilization of the zein in GAA and water molecules bound to the γ‐zein polypeptides acting as a plasticizer. QPM zein can enable the formation of flexible zein bioplastics without added plasticizers.

Introduction: Infectious diseases (ID) consultations have been demonstrated to improve patient outcomes in the treatment of severe infections. However, ID consultation is often unavailable to patients that live in rural communities. Little is known regarding the treatment of infections in rural hospitals with no coverage from an ID specialist. We characterized the outcomes of patients cared for in hospitals without coverage from an ID physician. Methods: Patients aged 18 years or older admitted to eight community hospitals without access to ID consultation during a 6.5-month period were assessed. All patients had received at least three days of continuous antimicrobial therapy. The primary outcome was the need for transfer to a tertiary facility for ID services. The secondary outcome was the characterization of antimicrobials received. Antimicrobial courses were evaluated independently by two board-certified ID physicians. Results: 3706 encounters were evaluated. Transfers for ID consultation occurred in 0.01% of patients. The ID physician would have made modifications in 68.5% of patients. Areas for improvement included treatment of chronic obstructive pulmonary disease exacerbations, broad-spectrum treatment of skin and soft tissue infection, long courses of azithromycin, and management of Staphylococcus aureusbacteremia, including choice and length of therapy, as well as obtaining echocardiography. Patients evaluated received 22,807 days of antimicrobial therapy. Conclusions: Patients hospitalized in community hospitals are rarely transferred for ID consultation. Our work demonstrates a need for ID consultation in community hospitals, identifying opportunities to enhance patient care by modifying antimicrobial regimens to improve antimicrobial stewardship and avoid inappropriate antimicrobials. Efforts to expand the ID workforce to include coverage at rural hospitals will likely improve antibiotic utilization.

Standardized letters of recommendation (SLOR) are hypothesized to decrease bias and provide consistent domains for evaluation. However, their ability to differentiate among applicants is unknown. The utilization and functionality of SLOR and the impact of SLOR domain rating on matching for colon and rectal surgery (CRS) residency applicants have yet to be assessed.

Acceptance sampling plans are widely used inspection policies for the quality assurance models in supply chain management systems. In this paper, the authors propose a decision-making model to obtain the optimal decision about a lot undergoing an acceptance sampling plan. In the first stage, the proportion of defectives is assumed to follow the Poisson distribution. Bayesian inference is used to model the decision outcomes of the sampling plan, which are acceptance, rejection or further inspection policies. The decision tree method along with backward induction is used in the second stage to determine the expected cost of various decisions about the lot. An optimal decision on a lot is evaluated based on minimal rejections allowed such that the cost incurred is minimum. The efficiency of the proposed model is compared with sampling models under identical conditions and numerical examples are provided to illustrate the application of the decision model.

People living with dementia almost universally experience behavioral and psychological symptoms of dementia at some point throughout the course of their illness. Behavioral and psychological symptoms of dementia (BPSD) are a result of complex interpersonal, intrapersonal, and environmental interactions—such symptoms include depression, aggression, anxiety, sleep disturbances, irritability, hallucinations, delusions, and agitation. While antipsychotics are often administered to address BPSD, behavioral modifications and nonpharmacological interventions are preferred first-line treatments. The Staff Training in Assisted Living Residences (STAR) program was designed and employed in community-based assisted living communities and later adapted for VA-based nursing homes, Community Living Centers (STAR-VA). STAR-VA is an interdisciplinary approach to managing challenging BPSD with the goal of decreasing distress behaviors and improving quality of care. A limitation of STAR-VA is its focus on long-term care, not acute care settings that often first encounter veterans with BPSD. Providing nonpharmacological, person-centered dementia care in the acute care setting remains a challenge due to the fast-paced environment, high staff turnover, and limited training and resources focused on providing high-quality dementia care. As such, the project team assessed the feasibility of implementing the STAR-VA framework onto one acute care unit. To illustrate the success of our implementation, we will present a case example where STAR-VA framework was applied to a veteran admitted onto the acute care unit.

The inherited thrombocytopenia syndromes are a group of disorders characterized primarily by quantitative defects in platelet number, though with a variety demonstrating qualitative defects and/or extrahematopoietic findings. Through collaborative international efforts applying next-generation sequencing approaches, the list of genetic syndromes that cause thrombocytopenia has expanded significantly in recent years, now with over 40 genes implicated. In this review, we focus on what is known about the genetic etiology of inherited thrombocytopenia syndromes and how the field has worked to validate new genetic discoveries. We highlight the important role for the clinician in identifying a germline genetic diagnosis and strategies for identifying novel causes through research-based endeavors.

Therapy-related myeloid neoplasm (t-MN) arising in patients with prior cytotoxic treatments is considered a distinct entity due to its unfavorable prognosis. Latencies between the initial cytotoxic therapy and the occurrence of t-MNs vary but usually fall between 1 and 10 years. t-MNs with unusually short or long latencies are not well characterized. It is unclear if they are biologically similar to the ones with ordinary latencies and should be kept in the t-MN entity. We compiled a cohort of t-MN cases including short (<1 year), ordinary (1–10 years), and extended (>10 years) latencies from two tertiary medical centers. Both the t-MNs with ordinary and extended latencies showed high likelihood of high-risk genetic abnormalities and demonstrated no significant survival differences. But the t-MNs with extended latencies were more likely associated with history of multiple cancers (p= 0.007) and were younger at the time of cytotoxic treatments (p< 0.001) when compared to the t-MNs with ordinary latencies. The t-MN with short latencies appears to be a very rare and highly heterogeneous group. In summary, the genetic composition appears similar in the t-MNs with ordinary and extended latencies. However, the association between the t-MN with extended latencies and history of multiple cancers raises a possibility that cancer predisposition may contribute to the accumulation of genetic abnormalities in these patients. Investigation into potential germline mutations in the t-MN patients with extended latencies may provide important information for related family members.

Therapy-related myeloid neoplasm (t-MN) arising in patients with prior cytotoxic treatments is considered a distinct entity due to its unfavorable prognosis. Latencies between the initial cytotoxic therapy and the occurrence of t-MNs vary but usually fall between 1 and 10 years. t-MNs with unusually short or long latencies are not well characterized. It is unclear if they are biologically similar to the ones with ordinary latencies and should be kept in the t-MN entity. We compiled a cohort of t-MN cases including short (<1 year), ordinary (1–10 years), and extended (>10 years) latencies from two tertiary medical centers. Both the t-MNs with ordinary and extended latencies showed high likelihood of high-risk genetic abnormalities and demonstrated no significant survival differences. But the t-MNs with extended latencies were more likely associated with history of multiple cancers (p= 0.007) and were younger at the time of cytotoxic treatments (p< 0.001) when compared to the t-MNs with ordinary latencies. The t-MN with short latencies appears to be a very rare and highly heterogeneous group. In summary, the genetic composition appears similar in the t-MNs with ordinary and extended latencies. However, the association between the t-MN with extended latencies and history of multiple cancers raises a possibility that cancer predisposition may contribute to the accumulation of genetic abnormalities in these patients. Investigation into potential germline mutations in the t-MN patients with extended latencies may provide important information for related family members.

FIP1L1-RARA–a ssociated neoplasm is a very rare and aggressive disease, with only 3 previously reported cases in the literature. Here, we describe a 9-month-old boy who presented with a FIP1L1-RARA fusion–associated myelodysplastic/myeloproliferative neoplasm-like overlap syndrome, with similarities and distinct features to both acute promyelocytic leukemia and juvenile myelomonocytic leukemia. Using a combined approach of chemotherapy, differentiating agents, and allogeneic hematopoietic stem cell transplant (allo-HCT), this patient remains in remission 20 months after allo-HCT. To our knowledge, this is only the second published pediatric case involving this condition and the only case with a favorable long-term outcome. Given the aggressive disease described in the previously published case report, as well as the successful treatment course described, the combinatorial use of chemotherapy, differentiation therapy, and allo-HCT for treatment of FIP1L1-RARA fusion–associated myeloid neoplasms should be considered.

FIP1L1-RARA–a ssociated neoplasm is a very rare and aggressive disease, with only 3 previously reported cases in the literature. Here, we describe a 9-month-old boy who presented with a FIP1L1-RARAfusion–associated myelodysplastic/myeloproliferative neoplasm-like overlap syndrome, with similarities and distinct features to both acute promyelocytic leukemia and juvenile myelomonocytic leukemia. Using a combined approach of chemotherapy, differentiating agents, and allogeneic hematopoietic stem cell transplant (allo-HCT), this patient remains in remission 20 months after allo-HCT. To our knowledge, this is only the second published pediatric case involving this condition and the only case with a favorable long-term outcome. Given the aggressive disease described in the previously published case report, as well as the successful treatment course described, the combinatorial use of chemotherapy, differentiation therapy, and allo-HCT for treatment of FIP1L1-RARAfusion–associated myeloid neoplasms should be considered.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Severe congenital neutropenia is an inborn disorder of granulopoiesis. Approximately one third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase that is implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket. Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis. These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Severe congenital neutropenia is an inborn disorder of granulopoiesis. Approximately one third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB(caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPBencodes an adenosine triphosphatase that is implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPBare associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPBvariants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket. Both genetic loss of CLPBand expression of CLPBvariants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis. These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPBvariants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPBvariants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.

The shortage of reliable primary taxonomic data limits the description of biological taxa and the understanding of biodiversity patterns and processes, complicating biogeographical, ecological, and evolutionary studies. This deficit creates a significant taxonomic impediment to biodiversity research and conservation planning. The taxonomic impediment and the biodiversity crisis are widely recognized, highlighting the urgent need for reliable taxonomic data. Over the past decade, numerous countries worldwide have devoted considerable effort to Target 1 of the Global Strategy for Plant Conservation (GSPC), which called for the preparation of a working list of all known plant species by 2010 and an online world Flora by 2020. Brazil is a megadiverse country, home to more of the world's known plant species than any other country. Despite that, Flora Brasiliensis, concluded in 1906, was the last comprehensive treatment of the Brazilian flora. The lack of accurate estimates of the number of species of algae, fungi, and plants occurring in Brazil contributes to the prevailing taxonomic impediment and delays progress towards the GSPC targets. Over the past 12 years, a legion of taxonomists motivated to meet Target 1 of the GSPC, worked together to gather and integrate knowledge on the algal, plant, and fungal diversity of Brazil. Overall, a team of about 980 taxonomists joined efforts in a highly collaborative project that used cybertaxonomy to prepare an updated Flora of Brazil, showing the power of scientific collaboration to reach ambitious goals. This paper presents an overview of the Brazilian Flora 2020 and provides taxonomic and spatial updates on the algae, fungi, and plants found in one of the world's most biodiverse countries. We further identify collection gaps and summarize future goals that extend beyond 2020. Our results show that Brazil is home to 46,975 native species of algae, fungi, and plants, of which 19,669 are endemic to the country. The data compiled to date suggests that the Atlantic Rainforest might be the most diverse Brazilian domain for all plant groups except gymnosperms, which are most diverse in the Amazon. However, scientific knowledge of Brazilian diversity is still unequally distributed, with the Atlantic Rainforest and the Cerrado being the most intensively sampled and studied biomes in the country. In times of “scientific reductionism”, with botanical and mycological sciences suffering pervasive depreciation in recent decades, the first online Flora of Brazil 2020 significantly enhanced the quality and quantity of taxonomic data available for algae, fungi, and plants from Brazil. This project also made all the information freely available online, providing a firm foundation for future research and for the management, conservation, and sustainable use of the Brazilian funga and flora.

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1–5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.

A common feature of both congenital and acquired forms of bone marrow failure is an increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Indeed, the development of MDS or AML is now the major cause of mortality in patients with congenital neutropenia. Thus, there is a pressing clinical need to develop better strategies to prevent, diagnose early, and treat MDS/AML in patients with congenital neutropenia and other bone marrow failure syndromes. Here, we discuss recent data characterizing clonal hematopoiesis and progression to myeloid malignancy in congenital neutropenia, focusing on severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome. We summarize recent studies showing excellent outcomes after allogenic hematopoietic stem cell transplantation for many (but not all) patients with congenital neutropenia, including patients with SCN with active myeloid malignancy who underwent transplantation. Finally, we discuss how these new data inform the current clinical management of patients with congenital neutropenia.