STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.

STAC3 disorder, or Native American myopathy, is characterised by congenital myopathy, hypotonia, musculoskeletal and palatal anomalies, and susceptibility to malignant hyperthermia. A STAC3 c.851 G > C (p.Trp284Ser) pathogenic variant, common in the Lumbee Native American tribe, has been identified in other populations worldwide, including patients of African ancestry. We report on the frequency of STAC3 c.851 G > C in a cohort of 127 patients presenting with congenital hypotonia that tested negative for spinal muscular atrophy and/or Prader-Willi syndrome. We present a clinical retrospective, descriptive review on 31 Southern African patients homozygous for STAC3 c.851 G > C. The frequencies of various phenotypic characteristics were calculated. In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3 c.851 G > C. A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated from a healthy cohort. A common haplotype spanning STAC3 was identified in four patients. Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia. The novel finding that STAC3 disorder is a common African myopathy has important clinical implications for the diagnosis, treatment and genetic counselling of individuals, with neonatal and/or childhood hypotonia with or without arthrogryposis multiplex congenita, and their families. The spread of this variant worldwide and the allele frequency higher in the African/African-American ancestry than the Admixed Americans, strongly indicates that the STAC3 c.851 G > C variant has an African origin which may be due to an ancient mutation with migration and population bottlenecks.

Demand forecasting for platelet usage: From univariate time series to multivariable models.

Platelet products are both expensive and have very short shelf lives. As usage rates for platelets are highly variable, the effective management of platelet demand and supply is very important yet challenging. The primary goal of this paper is to present an efficient forecasting model for platelet demand at Canadian Blood Services (CBS). To accomplish this goal, five different demand forecasting methods, ARIMA (Auto Regressive Integrated Moving Average), Prophet, lasso regression (least absolute shrinkage and selection operator), random forest, and LSTM (Long Short-Term Memory) networks are utilized and evaluated via a rolling window method. We use a large clinical dataset for a centralized blood distribution centre for four hospitals in Hamilton, Ontario, spanning from 2010 to 2018 and consisting of daily platelet transfusions along with information such as the product specifications, the recipients' characteristics, and the recipients' laboratory test results. This study is the first to utilize different methods from statistical time series models to data-driven regression and machine learning techniques for platelet transfusion using clinical predictors and with different amounts of data. We find that the multivariable approaches have the highest accuracy in general, however, if sufficient data are available, a simpler time series approach appears to be sufficient. We also comment on the approach to choose predictors for the multivariable models.

Applications of SGLT2 inhibitors beyond glycaemic control.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world.

Can lithium be used in the setting of clozapine commencement in patients with COVID-19 associated neutropenia: A case report.

COVID-19 infection may increase the likelihood of neutropenia in patients already on clozapine. In clozapine treated patients experiencing COVID-19 associated neutropenia, adjunct therapy with lithium can be considered.

The Association of Frailty and Malnutrition With Dietary Intake and Gastrointestinal Symptoms in People With Kidney Failure: 2-Year Prospective Study.

BACKGROUND: Frailty and malnutrition are both associated with worsening morbidity and mortality and become more prevalent in the elderly and as kidney function declines. Anorexia and reduced oral intake are common features of both frailty and malnutrition. However, there are sparse data evaluating the impact of other gastrointestinal (GI) symptoms, such as taste changes, on rates of frailty and malnutrition in people with kidney failure. The aim of this study is to describe the prevalence of frailty and malnutrition and their association with dietary intake and nutrition-related symptoms in people with kidney failure. METHODS: This observational study recruited people with kidney failure who were commencing Conservative Kidney Management or elderly people (aged > 75 years) newly commenced on dialysis from 3 renal units. Participants underwent assessments of frailty, nutritional status, dietary intake, and GI symptom burden when they attended clinic appointments, approximately every 6 months. RESULTS: Of the 85 participants, 57% were assessed as being frail and 33% were assessed as being malnourished. Participants assessed as frail reported more GI symptoms (3 vs. 2, P < .001) that were more severe (1.75 vs. 1.0, P < .001) compared to nonfrail participants. Being malnourished was associated with a 5 times higher chance of being frail (odds ratio 5.8; 95% confidence interval 1.5, 21.8; P = .015) and having more severe symptoms was associated with a 2 times higher chance (odds ratio 2.8; 95% CI 1.1, 7.0; P = .026) of being frail. In addition to experiencing more GI symptoms, that were more severe, participants who were malnourished consumed significantly less energy (1234 kcal vs. 1400 kcal, P = .01) and protein (51 g vs. 74 g, P < .001). CONCLUSIONS: Frailty and malnutrition are common and are associated with a higher GI symptom burden and poorer dietary intake. Future research is needed to determine effective interventions targeting frailty and malnutrition, including nutrition-related symptoms and optimal protein intake.

Huntington disease-like 2: insight into neurodegeneration from an African disease.

Huntington disease (HD)-like 2 (HDL2) is a rare genetic disease caused by an expanded trinucleotide repeat in the JPH3 gene (encoding junctophilin 3) that shows remarkable clinical similarity to HD. To date, HDL2 has been reported only in patients with definite or probable African ancestry. A single haplotype background is shared by patients with HDL2 from different populations, supporting a common African origin for the expansion mutation. Nevertheless, outside South Africa, reports of patients with HDL2 in Africa are scarce, probably owing to limited clinical services across the continent. Systematic comparisons of HDL2 and HD have revealed closely overlapping motor, cognitive and psychiatric features and similar patterns of cerebral and striatal atrophy. The pathogenesis of HDL2 remains unclear but it is proposed to occur through several mechanisms, including loss of protein function and RNA and/or protein toxicity. This Review summarizes our current knowledge of this African-specific HD phenocopy and highlights key areas of overlap between HDL2 and HD. Given the aforementioned similarities in clinical phenotype and pathology, an improved understanding of HDL2 could provide novel insights into HD and other neurodegenerative and/or trinucleotide repeat expansion disorders.

Nutrition in Conservative Kidney Management: From Evidence to Practice.

Conservative kidney management (CKM) is a treatment option for kidney failure, particularly for the elderly and those with co-morbidities. Dietitians can play an important role in the provision of CKM by enhancing patients' quality of life through the management of nutrition impact symptoms (symptoms that result in decreased eating, including anorexia, nausea, dry mouth, and taste changes), as well as symptoms that result from malnutrition, including fatigue, weakness, activity intolerance, slow wound healing, and low mood. There are many gaps in the literature regarding optimal nutritional recommendations for patients on CKM. More research is needed on symptom management and interventions to delay or slow the progression of malnutrition and frailty. This article provides an overview of important nutritional considerations, a synthesis of the current literature, and recommendations for application of evidence into the practice of CKM.

Disparities in Pain Management.

Health disparities in pain management remain a pervasive public health crisis. Racial and ethnic disparities have been identified in all aspects of pain management from acute, chronic, pediatric, obstetric, and advanced pain procedures. Disparities in pain management are not limited to race and ethnicity, and have been identified in multiple other vulnerable populations. This review targets health care disparities in the management of pain, focusing on steps health care providers and organizations can take to promote health care equity. A multifaceted plan of action with a focus on research, advocacy, policy changes, structural changes, and targeted interventions is recommended.

Hematological and Other Cancers in People Using Clozapine: Analysis of Australian Spontaneous Reports Between 1995 and 2020.

BACKGROUND: Recent observational study evidence suggests that clozapine, unlike other antipsychotics, may be associated with a small increased risk of hematological malignancy. This study described characteristics of hematological and other cancers in those taking clozapine reported to the Australian Therapeutic Goods Administration. METHODS: We analyzed public case reports for "clozapine," "Clozaril," or "Clopine" from January 1995 to December 2020 classified as "neoplasm benign, malignant and unspecified" by the Australian Therapeutic Goods Administration. Data on age, sex, dose, clozapine start and cessation dates, Medical Dictionary for Regulatory Activities reaction terms, and date of cancer were extracted. RESULTS: Overall, 384 spontaneous reports of cancers in people taking clozapine were analyzed. The mean age of patients was 53.9 years (SD, 11.4 years), and 224 (58.3%) were male. The most frequent cancers were hematological (n = 104 [27.1%]), lung (n = 50 [13.0%]), breast (n = 37 [9.6%]), and colorectal (n = 28 [7.3%]). The outcome was fatal for 33.9% of cancer reports. Lymphoma comprised 72.1% of all hematological cancers (mean patient age, 52.1 years; SD, 11.6 years). The median daily dose of clozapine at the time of hematological cancer report was 400 mg (interquartile range, 300-543.8 mg), and the median duration of clozapine use before hematological cancer diagnosis was 7.0 years (interquartile range, 2.8-13.2 years). CONCLUSIONS: Lymphoma and other hematological cancers are overrepresented in spontaneous adverse event reports compared with other cancer types. Clinicians should be aware of the possible association with hematological cancers and monitor for and report any hematological cancers identified. Future studies should examine histology of lymphomas in people using clozapine and corresponding blood level of clozapine.

Reading the room: Autistic traits, gaze behaviour, and the ability to infer social relationships.

Individuals high in autistic traits can have difficulty understanding verbal and non-verbal cues, and may display atypical gaze behaviour during social interactions. The aim of this study was to examine differences among neurotypical individuals with high and low levels of autistic traits with regard to their gaze behaviour and their ability to assess peers' social status accurately. Fifty-four university students who completed the 10-item Autism Quotient (AQ-10) were eye-tracked as they watched six 20-second video clips of people ("targets") involved in a group decision-making task. Simulating natural, everyday social interactions, the video clips included moments of debate, humour, interruptions, and cross talk. Results showed that high-scorers on the AQ-10 (i.e., those with more autistic traits) did not differ from the low-scorers in either gaze behaviour or assessing the targets' relative social status. The results based on this neurotypical group of participants suggest that the ability of individuals high in autistic traits to read social cues may be preserved in certain tasks crucial to navigating day-to-day social relationships. These findings are discussed in terms of their implications for theory of mind, weak central coherence, and social motivation theories of autism.

Are Digital Health Technologies and Models of Nutrition Care the Future of Chronic Kidney Disease Management?

People living with chronic kidney disease (CKD) require long-term support at varying levels of individualization, intensity, and frequency. Mobile and digital models of nutrition care can facilitate long-term behavior change, address nutrition issues proactively, reduce travel burden, and reach people without access to health care more easily. However, while traditional health delivery continues to be digitally disrupted, there are many barriers to address before mobile and digitally supported models of nutrition care can become business as usual in nephrology and nutrition care practice. This paper overviews the current evidence base concerning the past and present mobile and digital health programs to improve nutrition in CKD and highlights the novel future trends in this field. The way nutrition and dietetic care can be feasible, safe, and potentially effective when delivered using various digital and virtual technologies, including consultations, assessments, establishment of diagnoses, formulation of plans, and monitoring/reviewing clinical progress is discussed. Of the available evidence to date, these modalities appear to improve dietary sodium intake and diet quality, self-efficacy, interdialytic weight gain, and body weight. Many barriers exist to sustaining the continued and widespread adoption of digital and mobile health-supported nutrition care in CKD. These include patient-, clinician-, and health system-specific and are discussed in detail. Mobile and digital-supported models of nutrition care present an exciting opportunity to assist kidney dietitians deliver patient-centred nutrition care in CKD.

Comprehensive investigation of a structural variant in a bi-specific, N-and C-terminal Fc-fusion molecule, and its monitoring with LC-MS based method.

There is an increasing interest in the generation of Fc-fusion molecules to exploit the effector functions of Fc and the fusion partner, towards improving the therapeutic potential. The Fc-fusion molecules have unique structural and functional attributes that impart various advantages. However, the manufacturing of Fc-fusion molecules possesses certain challenges in the biopharmaceutical development. The fusion of unnaturally occurring two or more domains in a construct can pose problems for proper folding and are prone to aggregation and degradation. Reshuffling of disulfide bridges represents a posttranslational event that affects folding. This can play a critical role in the correct structure of a molecule and leads to structural heterogeneity in biotherapeutics; it may also impact the in vivo biological activities, safety, and efficacy of the biopharmaceutical. Our work presents an investigation case of a doublet band, as observed only in nonreducing sodium dodecyl sulfate - polyacrylamide gel electrophoresis (SDS-PAGE) for a bi-specific, N- and C-terminal Fc-fusion molecule. Other characterization and orthogonal methods from the analytical panel did not indicate the presence of two distinct species, including the orthogonal CE-SDS (Caliper Lab Chip GXII). Therefore, it was necessary to determine if the phenomenon was an analytical artifact or a real variant of our Fc-fusion molecule. With the comprehensive mass spectrometry-based characterization, we were able to determine that the doublet band was related to the reshuffling of one disulfide bridge in one of the fused domains. Our work illustrates the application of nonreducing peptide mapping by mass spectrometry to characterize and identify disulfide variants in a complex N- and C-terminal Fc-fusion molecule, and further adoption to monitor the disulfide structural variants in the intermediate process samples to drive the manufacturing of a consistent product with the desired quality attributes.

Revisiting Intradialytic Parenteral Nutrition: How Can We Apply the Evidence in Clinical Practice?

Intradialytic parenteral nutrition (IDPN) remains a controversial nutrition support practice in hemodialysis. Multiple reviews and evidence-based clinical practice guidelines have been published in the past 20 years. Despite essentially looking at the same evidence, conclusions and recommendations vary significantly, leading to widespread uncertainty among clinicians on the value of and indications for IDPN. This paper aims to bring a clinical perspective to the current state of evidence and clinical practice, recognizing the strengths and weaknesses of current evidence and the clinical questions that remain unanswered, as well as providing guidance for using IDPN in clinical practice. IDPN should be considered a strategy to complement spontaneous oral intake in clinically stable patients receiving maintenance hemodialysis or who have or are at risk of malnutrition and who have substantial but not adequate protein and/or energy intake. There is a clear need for robust randomized controlled trials evaluating the impact of IDPN in appropriately selected patients. Additionally, future trials should include patient-centered outcome measures such as appetite, spontaneous oral intake, quality of life, and reliable measures of nutritional status.

Interventions for improving health literacy in people with chronic kidney disease.

BACKGROUND: Low health literacy affects 25% of people with chronic kidney disease (CKD) and is associated with increased morbidity and death. Improving health literacy is a recognised priority, but effective interventions are not clear. OBJECTIVES: This review looked the benefits and harms of interventions for improving health literacy in people with CKD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. We also searched MEDLINE (OVID) and EMBASE (OVID) for non-randomised studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies that assessed interventions aimed at improving health literacy in people with CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and performed risk of bias analysis. We classified studies as either interventions aimed at improving aspects of health literacy or interventions targeting a population of people with poor health literacy. The interventions were further sub-classified in terms of the type of intervention (educational, self-management training, or educational with self-management training). Results were expressed as mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) for continuous outcomes and risk ratios (RR) with 95% CI for dichotomous outcomes. MAIN RESULTS: We identified 120 studies (21,149 participants) which aimed to improve health literacy. There were 107 RCTs and 13 non-randomised studies. No studies targeted low literacy populations. For the RCTs, selection bias was low or unclear in 94% of studies, performance bias was high in 86% of studies, detection bias was high in 86% of studies reporting subjective outcomes and low in 93% of studies reporting objective outcomes. Attrition and other biases were low or unclear in 86% and 78% of studies, respectively. Compared to usual care, low certainty evidence showed educational interventions may increase kidney-related knowledge (14 RCTs, 2632 participants: SMD 0.99, 95% CI 0.69 to 1.32; I² = 94%). Data for self-care, self-efficacy, quality of life (QoL), death, estimated glomerular filtration rate (eGFR) and hospitalisations could not be pooled or was not reported. Compared to usual care, low-certainty evidence showed self-management interventions may improve self-efficacy (5 RCTs, 417 participants: SMD 0.58, 95% CI 0.13 to 1.03; I² = 74%) and QoL physical component score (3 RCTs, 131 participants: MD 4.02, 95% CI 1.09 to 6.94; I² = 0%). There was moderate-certainty evidence that self-management interventions probably did not slow the decline in eGFR after one year (3 RCTs, 855 participants: MD 1.53 mL/min/1.73 m², 95% CI -1.41 to 4.46; I² = 33%). Data for knowledge, self-care behaviour, death and hospitalisations could not be pooled or was not reported. Compared to usual care, low-certainty evidence showed educational with self-management interventions may increase knowledge (15 RCTs, 2185 participants: SMD 0.65, 95% CI 0.36 to 0.93; I² = 90%), improve self-care behaviour scores (4 RCTs, 913 participants: SMD 0.91, 95% CI 0.00 to 1.82; I² =97%), self-efficacy (8 RCTs, 687 participants: SMD 0.50, 95% CI 0.10 to 0.89; I² = 82%), improve QoL physical component score (3 RCTs, 2771 participants: MD 2.56, 95% CI 1.73 to 3.38; I² = 0%) and may make little or no difference to slowing the decline of eGFR (4 RCTs, 618 participants: MD 4.28 mL/min/1.73 m², 95% CI -0.03 to 8.85; I² = 43%). Moderate-certainty evidence shows educational with self-management interventions probably decreases the risk of death (any cause) (4 RCTs, 2801 participants: RR 0.73, 95% CI 0.53 to 1.02; I² = 0%). Data for hospitalisation could not be pooled. AUTHORS' CONCLUSIONS: Interventions to improve aspects of health literacy are a very broad category, including educational interventions, self-management interventions and educational with self-management interventions. Overall, this type of health literacy intervention is probably beneficial in this cohort however, due to methodological limitations and high heterogeneity in interventions and outcomes, the evidence is of low certainty.

Digital health technologies to support medication adherence in chronic kidney disease.

Non-adherence to medications is a critical challenge in the management of people with chronic kidney disease (CKD). This review explores the complexities of adherence in this population, the unique barriers and enablers of good adherence behaviours, and the role of emerging digital health technologies in bridging the gap between evidence-based treatment plans and the real-world standard of care. We present the current evidence supporting the use of digital health interventions among CKD populations, identifying the key research questions that remain unanswered, and providing practical strategies for clinicians to support medication adherence in a digital age.

A probable cis-acting genetic modifier of Huntington disease frequent in individuals with African ancestry.

Huntington disease (HD)is a dominantly inherited neurodegenerative disorder caused by the expansion of a polyglutamine encoding CAG repeat in the huntingtin gene. Recently, it has been established that disease severity in HD is best predicted by the number of pure CAG repeats rather than total glutamines encoded. Along with uncovering DNA repair gene variants as trans-acting modifiers of HD severity, these data reveal somatic expansion of the CAG repeat as a key driver of HD onset. Using high-throughput DNA sequencing, we have determined the precise sequence and somatic expansion profiles of the HTT repeat tract of 68 HD-affected and 158 HD-unaffected African ancestry individuals. A high level of HTT repeat sequence diversity was observed, with three likely African-specific alleles identified. In the most common disease allele (30 out of 68), the typical proline-encoding CCGCCA sequence was absent. This CCGCCA-loss disease allele was associated with an earlier age of diagnosis of approximately 7.1 years and occurred exclusively on haplotype B2. Although somatic expansion was associated with an earlier age of diagnosis in the study overall, the CCGCCA-loss disease allele displayed reduced somatic expansion relative to the typical HTT expansions in blood DNA. We propose that the CCGCCA loss occurring on haplotype B2 is an African cis-acting modifier that appears to alter disease diagnosis of HD through a mechanism that is not driven by somatic expansion. The assessment of a group of individuals from an understudied population has highlighted population-specific differences that emphasize the importance of studying genetically diverse populations in the context of disease.

Reflexive Practice as an Approach to Improve Healthcare Delivery for Indigenous Peoples: A Systematic Critical Synthesis and Exploration of the Cultural Safety Education Literature.

Cultural safety is increasingly being taught in tertiary programmes of study for health professionals. Reflexivity is a key skill required to engage in culturally safe practice, however, there is currently limited literature examining how reflexivity is taught or assessed within cultural safety curricula. A systematic review of the literature up until November 2021 was conducted, examining educational interventions which aimed to produce culturally safe learners. Studies were limited to those with a focus on Indigenous health and delivered in Australia, Aotearoa New Zealand, Canada, and the United States. A total of 46 documents describing 43 different educational interventions were identified. We found that definitions and conceptualisations of reflexivity varied considerably, resulting in a lack of conceptual clarity. Reflexive catalysts were the primary pedagogical approaches used, where objects, people, or Indigenous pedagogies provided a counterpoint to learners' knowledges and experiences. Information regarding assessment methods was limited but indicates that the focus of existing programmes has been on changes in learner knowledge and attitudes rather than the ability to engage in reflexivity. The results demonstrate a need for greater conceptual clarity regarding reflexivity as it relates to cultural safety, and to develop methods of assessment that focus on process rather than outcomes.

Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland.

BACKGROUND: Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics. METHODS: We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions. FINDINGS: For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis. INTERPRETATION: Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine. FUNDING: The Finnish Ministry of Social Affairs and Health and Academy of Finland.