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  1. Fulltext Global characteristics and outcomes of autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: A study of the worldwide network for blood and marrow transplantation (WBMT)
    Garderet L, Gras L, Koster L, Baaij L, Hamad N, Dsouza A, et al.
    Am J Hematol, 2024 Nov;99(11):2084-2095.
    PMID: 39158218 DOI: 10.1002/ajh.27451
    Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS.
  2. Characteristics of and risk factors for COVID-19 breakthrough infections in idiopathic inflammatory myopathies: results from the COVAD study
    Hoff LS, Ravichandran N, Sen P, Day J, Joshi M, Nune A, et al.
    Rheumatology (Oxford), 2025 Feb 01;64(2):597-606.
    PMID: 38430474 DOI: 10.1093/rheumatology/keae128
    OBJECTIVES: The objective of this study was to explore the prevalence, characteristics and risk factors of COVID-19 breakthrough infections (BIs) in idiopathic inflammatory myopathies (IIMs) using data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study.

    METHODS: A validated patient self-reporting e-survey was circulated by the COVAD study group to collect data on COVID-19 infection and vaccination in 2022. BIs were defined as COVID-19 occurring ≥14 days after two vaccine doses. We compared BI characteristics and severity among patients with IIMs, patients with other autoimmune rheumatic and non-rheumatic diseases (AIRD, nrAID), and healthy controls (HCs). Multivariable Cox regression models were used to assess the risk factors for BI, severe BI ,and hospitalizations among patients with IIMs.

    RESULTS: Among the 9449 included responses, BIs occurred in 1447 respondents (15.3%). The median age was 44 years [interquartile range (IQR) 21], 77.4% were female, and 182 BIs (12.9%) occurred among the 1406 patients with IIMs. Multivariable Cox regression among the data for patients with IIMs showed increasing age to be a protective factor for BIs [hazard ratio (HR) = 0.98, 95% CI = 0.97-0.99], and HCQ and SSZ use were risk factors (HR = 1.81, 95% CI = 1.24-2.64, and HR = 3.79, 95% CI = 1.69-8.42, respectively). Glucocorticoid use was a risk factor for a severe BI (HR = 3.61, 95% CI = 1.09-11.8). Non-white ethnicity (HR = 2.61, 95% CI = 1.03-6.59) was a risk factor for hospitalization. Compared with other groups, patients with IIMs required more supplemental oxygen therapy (IIMs = 6.0% vs AIRDs = 1.8%, nrAIDs = 2.2% and HCs = 0.9%), intensive care unit admission (IIMs = 2.2% vs AIRDs = 0.6%, nrAIDs and HCs = 0%), advanced treatment with antiviral or monoclonal antibodies (IIMs = 34.1% vs AIRDs = 25.8%, nrAIDs = 14.6% and HCs = 12.8%) and had more hospitalization (IIMs = 7.7% vs AIRDs = 4.6%, nrAIDs = 1.1% and HCs = 1.5%).

    CONCLUSION: Patients with IIMs are susceptible to severe COVID-19 BIs. Age and immunosuppressive treatments were related to the risk of BIs.

  3. Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation
    Kim DS, Yoon YI, Kim BK, Choudhury A, Kulkarni A, Park JY, et al.
    Hepatol Int, 2024 Apr;18(2):299-383.
    PMID: 38416312 DOI: 10.1007/s12072-023-10629-3
    Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.
  4. APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure
    Maiwall R, Singh SP, Angeli P, Moreau R, Krag A, Singh V, et al.
    Hepatol Int, 2024 Jun;18(3):833-869.
    PMID: 38578541 DOI: 10.1007/s12072-024-10650-0
    Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.
  5. Fulltext Pathogen genomic surveillance status among lower resource settings in Asia
    Getchell M, Wulandari S, de Alwis R, Agoramurthy S, Khoo YK, Mak TM, et al.
    Nat Microbiol, 2024 Oct;9(10):2738-2747.
    PMID: 39317773 DOI: 10.1038/s41564-024-01809-4
    Asia remains vulnerable to new and emerging infectious diseases. Understanding how to improve next generation sequencing (NGS) use in pathogen surveillance is an urgent priority for regional health security. Here we developed a pathogen genomic surveillance assessment framework to assess capacity in low-resource settings in South and Southeast Asia. Data collected between June 2022 and March 2023 from 42 institutions in 13 countries showed pathogen genomics capacity exists, but use is limited and under-resourced. All countries had NGS capacity and seven countries had strategic plans integrating pathogen genomics into wider surveillance efforts. Several pathogens were prioritized for human surveillance, but NGS application to environmental and human-animal interface surveillance was limited. Barriers to NGS implementation include reliance on external funding, supply chain challenges, trained personnel shortages and limited quality assurance mechanisms. Coordinated efforts are required to support national planning, address capacity gaps, enhance quality assurance and facilitate data sharing for decision making.
  6. Fulltext Author Correction: Pathogen genomic surveillance status among lower resource settings in Asia
    Getchell M, Wulandari S, de Alwis R, Agoramurthy S, Khoo YK, Mak TM, et al.
    Nat Microbiol, 2025 Jan;10(1):258.
    PMID: 39414934 DOI: 10.1038/s41564-024-01848-x
  7. Fulltext Management of adult sepsis in resource-limited settings: global expert consensus statements using a Delphi method
    Thwaites L, Nasa P, Abbenbroek B, Dat VQ, Finfer S, Kwizera A, et al.
    Intensive Care Med, 2025 Jan;51(1):21-38.
    PMID: 39714613 DOI: 10.1007/s00134-024-07735-7
    PURPOSE: To generate consensus and provide expert clinical practice statements for the management of adult sepsis in resource-limited settings.

    METHODS: An international multidisciplinary Steering Committee with expertise in sepsis management and including a Delphi methodologist was convened by the Asia Pacific Sepsis Alliance (APSA). The committee selected an international panel of clinicians and researchers with expertise in sepsis management. A Delphi process based on an iterative approach was used to obtain the final consensus statements.

    RESULTS: A stable consensus was achieved for 30 (94%) of the statements by 41 experts after four survey rounds. These include consensus on managing patients with sepsis outside a designated critical care area, triggers for escalating clinical management and criteria for safe transfer to another facility. The experts agreed on the following: in the absence of serum lactate, clinical parameters such as altered mental status, capillary refill time and urine output may be used to guide resuscitation; special considerations regarding the volume of fluid used for resuscitation, especially in tropical infections, including the use of simple tests to assess fluid responsiveness when facilities for advanced hemodynamic monitoring are limited; use of Ringer's lactate or Hartmann's solution as balanced salt solutions; epinephrine when norepinephrine or vasopressin are unavailable; and the administration of vasopressors via a peripheral vein if central venous access is unavailable or not feasible. Similarly, where facilities for investigation are unavailable, there was consensus for empirical antimicrobial administration without delay when sepsis was strongly suspected, as was the empirical use of antiparasitic agents in patients with suspicion of parasitic infections.

    CONCLUSION: Using a Delphi method, international experts reached consensus to generate expert clinical practice statements providing guidance to clinicians worldwide on the management of sepsis in resource-limited settings. These statements complement existing guidelines where evidence is lacking and add relevant aspects of sepsis management that are not addressed by current international guidelines. Future studies are needed to assess the effects of these practice statements and address remaining uncertainties.

  8. Fulltext Genetic Diversity and Expanded Phenotypes in Dystonia: Insights from Large-Scale Exome Sequencing
    Thomsen M, Ott F, Loens S, Kilic-Berkmen G, Tan AH, Lim SY, et al.
    medRxiv, 2024 Dec 05.
    PMID: 39677454 DOI: 10.1101/2024.12.02.24316741
    Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (∼25%) and the identification of several disease-linked genes, the etiology in most patients remains elusive. Moreover, understanding the correlations between clinical manifestation and genetic variants has become increasingly complex. To comprehensively unravel dystonia's genetic spectrum, we performed exome sequencing on 1,924 dystonia patients [40.3% male, 92.9% White, 93.2% isolated dystonia, median age at onset (AAO) 33 years], including 1,895 index patients, who were previously genetically unsolved. The sample was mainly based on two dystonia registries (DysTract and the Dystonia Coalition). Further, 72 additional patients of Asian ethnicity, mainly from Malaysia, were also included. We prioritized patients with negative genetic prescreening, early AAO, positive family history, and multisite involvement of dystonia. Rare variants in genes previously linked to dystonia ( n =405) were examined. Variants were confirmed via Sanger sequencing, and segregation analysis was performed when possible. We identified 137 distinct likely pathogenic or pathogenic variants (according to ACMG criteria) across 51 genes in 163/1,924 patients [42.9% male, 85.9% White, 68.7% isolated dystonia, median AAO 19 years]. This included 153/1,895 index patients, resulting in a diagnostic yield of 8.1%. Notably, 77/137 (56.2%) of these variants were novel, with recurrent variants in EIF2AK2 , VPS16 , KCNMA1 , and SLC2A1 , and novel variant types such as two splice site variants in KMT2B , supported by functional evidence. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16 , THAP1 , GCH1 , SGCE , GNAL , and KMT2B. Presumably pathogenic variants in less well-established dystonia genes were also found, including KCNMA1 , KIF1A , and ZMYND11. At least six variants (in ADCY5 , GNB1 , IR2BPL, KCNN2 , KMT2B , and VPS16 ) occurred de novo, supporting pathogenicity. ROC curve analysis indicated that AAO and the presence of generalized dystonia were the strongest predictors of a genetic diagnosis, with diagnostic yields of 28.6% in patients with generalized dystonia and 20.4% in those with AAO < 30 years. This study provides a comprehensive examination of the genetic landscape of dystonia, revealing valuable insights into the frequency of dystonia-linked genes and their associated phenotypes. It underscores the utility of exome sequencing in establishing diagnoses within this heterogeneous condition. Despite prescreening, presumably pathogenic variants were identified in almost 10% of patients. Our findings reaffirm several dystonia candidate genes and expand the phenotypic spectrum of some of these genes to include prominent, sometimes isolated dystonia.
  9. The Lancet HIV Commission on ageing and HIV: a global perspective
    Justice AC, Althoff KN, Clarfield AM, Ramirez BC, Ford N, Hartley MA, et al.
    Lancet HIV, 2026 Aug;13(8):e569-e610.
    PMID: 42508440 DOI: 10.1016/S2352-3018(26)00058-5
  10. Fulltext Latitudinal patterns in stabilizing density dependence of forest communities
    Hülsmann L, Chisholm RA, Comita L, Visser MD, de Souza Leite M, Aguilar S, et al.
    Nature, 2024 Mar;627(8004):564-571.
    PMID: 38418889 DOI: 10.1038/s41586-024-07118-4
    Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10-12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.
  11. Cutaneous T-cell lymphoma in Asian patients: a multinational, multicenter, prospective registry study in Asia
    Lee YP, Yoon SE, Song Y, Kim SJ, Yoon DH, Chen TY, et al.
    Int J Hematol, 2021 Sep;114(3):355-362.
    PMID: 34302593 DOI: 10.1007/s12185-021-03179-7
    Cutaneous T-cell lymphomas (CTCLs) are a group of T-cell lymphomas with low incidence. Due to their indolent characteristics, treatment strategies have not yet been established for advanced CTCLs. In this study, relative incidence of CTCLs in Asia was estimated and the therapeutic outcomes presented based on various treatments currently used in clinics for advanced CTCLs. As part of a prospective registry study of peripheral T-cell lymphoma (PTCL) conducted across Asia, including Korea, China, Taiwan, Singapore, Malaysia, and Indonesia, subgroup analysis was performed for patients with CTCLs. Among 486 patients with PTCL, 37 with CTCL (7.6%) were identified between April 2016 and February 2019. Primary cutaneous ALK-negative anaplastic large cell lymphoma (ALCL, 35.1%) was the most common subtype. With a median follow-up period of 32.1 months, median progression-free survival (PFS) was 53.5 months (95% CI 0.0-122.5), and overall survival was not reached. 14 patients (48.2%) underwent subsequent treatment after the first relapse, but the response rate was 20% with a PFS of 2.2 months (95% CI 0.3-4.0). Six patients received autologous stem cell transplantation (auto-SCT). However, auto-SCT did not result in better outcomes. Additional studies are needed on standard care treatment of advanced or refractory and relapsed CTCLs.
  12. Comprehensive analysis of peripheral T-cell and natural killer/T-cell lymphoma in Asian patients: A multinational, multicenter, prospective registry study in Asia
    Yoon SE, Song Y, Kim SJ, Yoon DH, Chen TY, Koh Y, et al.
    Lancet Reg Health West Pac, 2021 May;10:100126.
    PMID: 34327343 DOI: 10.1016/j.lanwpc.2021.100126
    Background: Peripheral T-cell lymphomas (PTCLs) are uncommon and their frequency is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative frequency and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative frequency of PTCLs and assess treatments and their outcomes in Asian patients.

    Methods: We performed a multinational, multicenter, prospective registry of adult patients with PTCLs that was named as the International Cooperative non-Hodgkin T-cell lymphoma prospective registry study where thirty-two institutes from six Asian countries and territories (Korea, China, Taiwan, Singapore, Malaysia, and Indonesia) participated.

    Findings: A total of 486 patients were registered between April 2016 and February 2019, and more than a half of patients (57%) had stage III or IV. Extranodal natural killer (NK)/T- cell lymphoma was the most common subtype (n = 139,28.6%), followed by angioimmunoblastic T-cell lymphoma (AITL, n = 120,24.7%), PTCL-not otherwise specified (PTCL-NOS, n = 101,20.8%), ALK-positive anaplastic large cell lymphoma (ALCL, n = 34,6.9%), and ALK-negative ALCL (n = 30,6.2%). The median progression-free survival (PFS) and overall survival (OS) were 21.1 months (95% CI,10.6-31.6) and 83.6 months (95% CI, 56.7-110.5), respectively. Upfront use of combined treatment with chemotherapy and radiotherapy showed better PFS than chemotherapy alone in localized ENKTL whereas consolidation with upfront autologous stem cell transplantation (SCT) provided longer PFS in advance stage ENKTL. In patients with PTCLs other than ENKTL, anthracycline-containing chemotherapies were widely used, but the outcome of those regimens was not satisfactory, and upfront autologous SCT was not significantly associated with survival benefit, either. The treatment outcome of salvage chemotherapy was disappointing, and none of the salvage strategies showed superiority to one another.

    Interpretation: This multinational, multicenter study identified the relative frequency of each subtype of PTCLs across Asian countries, and the survival outcomes according to the therapeutic strategies currently used.

    Funding: Samsung Biomedical Research Institute.

  13. Fulltext Effects of Varicocele Repair on Sperm DNA Fragmentation and Seminal Malondialdehyde Levels in Infertile Men with Clinical Varicocele: A Systematic Review and Meta-Analysis
    Cannarella R, Shah R, Saleh R, Boitrelle F, Hamoda TAA, Singh R, et al.
    World J Mens Health, 2024 Apr;42(2):321-337.
    PMID: 38164034 DOI: 10.5534/wjmh.230235
    PURPOSE: Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could reduce these parameters. This systematic review and meta-analysis (SRMA) aims to investigate the impact of VR on SDF and seminal malondialdehyde (MDA).

    MATERIALS AND METHODS: A literature search was performed in Scopus, PubMed, Ovid, Embase, and Cochrane databases. This SRMA included randomized controlled trials and observational studies reporting the pre- and postoperative levels of SDF and seminal OS in infertile men with clinical varicocele that underwent VR. Subgroup analyses included techniques of VR and SDF testing. The effect size was expressed as standardized mean difference (SMD).

    RESULTS: Out of 1,632 abstracts assessed for eligibility, 29 studies with 1,491 infertile men were included. The analysis showed a significant reduction in SDF after VR, compared to preoperative values (SMD -1.125, 95% confidence interval [CI] -1.410, -0.840; p<0.0001) with high inter-study heterogeneity (I²=90.965%). Reduction in SDF was evident with microsurgical technique and non-microsurgical inguinal approaches (SMD -1.014, 95% CI -1.263, -0.765; p<0.0001, and SMD -1.495, 95% CI -2.116, -0.873; p<0.0001), respectively. Reduction in SDF was significant irrespective of testing was done by sperm chromatin dispersion (SMD -2.197, 95% CI -3.187, -1.207; p<0.0001), sperm chromatin structure assay (SMD -0.857, 95% CI -1.156, -0.559; p<0.0001) or TUNEL (SMD -1.599, 95% CI -2.478, -0.719; p<0.0001). A significant decrease in seminal MDA levels was observed following VR (SMD -2.450, 95% CI -3.903 to -0.997, p=0.001) with high inter-study heterogeneity (I²=93.7%).

    CONCLUSIONS: Using pre- and post-intervention data, this SRMA indicates a significant reduction in SDF and seminal MDA levels in infertile men with clinical varicocele treated with VR. These findings may have important implications for the future management of this selected group of infertile patients.

  14. Fulltext Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries
    Jaenisch T, Tam DT, Kieu NT, Van Ngoc T, Nam NT, Van Kinh N, et al.
    BMC Infect Dis, 2016 Mar 11;16:120.
    PMID: 26968374 DOI: 10.1186/s12879-016-1440-3
    The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course.
  15. Asia-Pacific association for study of liver guidelines on management of ascites in liver disease
    Singh V, De A, Mehtani R, Angeli P, Maiwall R, Satapathy S, et al.
    Hepatol Int, 2023 Aug;17(4):792-826.
    PMID: 37237088 DOI: 10.1007/s12072-023-10536-7
  16. Rate of tree carbon accumulation increases continuously with tree size
    Stephenson NL, Das AJ, Condit R, Russo SE, Baker PJ, Beckman NG, et al.
    Nature, 2014 Mar 6;507(7490):90-3.
    PMID: 24429523 DOI: 10.1038/nature12914
    Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations. Our ability to understand and predict changes in the forest carbon cycle--particularly net primary productivity and carbon storage--increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands. Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree, in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level and stand-level productivity can be explained, respectively, by increases in a tree's total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation and plant senescence.
  17. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort
    Vollstedt EJ, Schaake S, Lohmann K, Padmanabhan S, Brice A, Lesage S, et al.
    Mov Disord, 2023 Feb;38(2):286-303.
    PMID: 36692014 DOI: 10.1002/mds.29288
    BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited.

    OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.

    METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed.

    RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.

    CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  18. Fulltext Williams-Beuren syndrome in diverse populations
    Kruszka P, Porras AR, de Souza DH, Moresco A, Huckstadt V, Gill AD, et al.
    Am J Med Genet A, 2018 05;176(5):1128-1136.
    PMID: 29681090 DOI: 10.1002/ajmg.a.38672
    Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value 
  19. Fulltext Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study
    Adams CD, Richmond R, Ferreira DLS, Spiller W, Tan V, Zheng J, et al.
    Cancer Epidemiol Biomarkers Prev, 2019 Jan;28(1):208-216.
    PMID: 30352818 DOI: 10.1158/1055-9965.EPI-18-0079
    BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).

    METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

    RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.

    CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.

    IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

  20. Fulltext Equivalency of the diagnostic accuracy of the PHQ-8 and PHQ-9: a systematic review and individual participant data meta-analysis
    Wu Y, Levis B, Riehm KE, Saadat N, Levis AW, Azar M, et al.
    Psychol Med, 2020 06;50(8):1368-1380.
    PMID: 31298180 DOI: 10.1017/S0033291719001314
    BACKGROUND: Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.

    METHODS: We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.

    RESULTS: 16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (-0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).

    CONCLUSIONS: PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.

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