Intestinal Blastocystis is linked to healthier diets and more favorable cardiometabolic outcomes in 56,989 individuals from 32 countries.

Diet impacts human health, influencing body adiposity and the risk of developing cardiometabolic diseases. The gut microbiome is a key player in the diet-health axis, but while its bacterial fraction is widely studied, the role of micro-eukaryotes, including Blastocystis, is underexplored. We performed a global-scale analysis on 56,989 metagenomes and showed that human Blastocystis exhibits distinct prevalence patterns linked to geography, lifestyle, and dietary habits. Blastocystis presence defined a specific bacterial signature and was positively associated with more favorable cardiometabolic profiles and negatively with obesity (p < 1e-16) and disorders linked to altered gut ecology (p < 1e-8). In a diet intervention study involving 1,124 individuals, improvements in dietary quality were linked to weight loss and increases in Blastocystis prevalence (p = 0.003) and abundance (p < 1e-7). Our findings suggest a potentially beneficial role for Blastocystis, which may help explain personalized host responses to diet and downstream disease etiopathogenesis.

Molecular mechanism of choline and ethanolamine transport in humans.

Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome2-7. Earlier studies concluded that FLVCR1 may function as a haem exporter8-12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14-16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.

Earth's ambipolar electrostatic field and its role in ion escape to space.

Cold plasma of ionospheric origin has recently been found to be a much larger contributor to the magnetosphere of Earth than expected1-3. Numerous competing mechanisms have been postulated to drive ion escape to space, including heating and acceleration by wave-particle interactions4 and a global electrostatic field between the ionosphere and space (called the ambipolar or polarization field)5,6. Observations of heated O+ ions in the magnetosphere are consistent with resonant wave-particle interactions7. By contrast, observations of cold supersonic H+ flowing out of the polar ionosphere8,9 (called the polar wind) suggest the presence of an electrostatic field. Here we report the existence of a +0.55 ± 0.09 V electric potential drop between 250 km and 768 km from a planetary electrostatic field (E∥⊕ = 1.09 ± 0.17 µV m-1) generated exclusively by the outward pressure of ionospheric electrons. We experimentally demonstrate that the ambipolar field of Earth controls the structure of the polar ionosphere, boosting the scale height by 271%. We infer that this increases the supply of cold O+ ions to the magnetosphere by more than 3,800%, in which other mechanisms such as wave-particle interactions can heat and further accelerate them to escape velocity. The electrostatic field of Earth is strong enough by itself to drive the polar wind9,10 and is probably the origin of the cold H+ ion population1 that dominates much of the magnetosphere2,3.

Microbiome epidemiology and association studies in human health.

Studies of the human microbiome share both technical and conceptual similarities with genome-wide association studies and genetic epidemiology. However, the microbiome has many features that differ from genomes, such as its temporal and spatial variability, highly distinct genetic architecture and person-to-person variation. Moreover, there are various potential mechanisms by which distinct aspects of the human microbiome can relate to health outcomes. Recent advances, including next-generation sequencing and the proliferation of multi-omic data types, have enabled the exploration of the mechanisms that connect microbial communities to human health. Here, we review the ways in which features of the microbiome at various body sites can influence health outcomes, and we describe emerging opportunities and future directions for advanced microbiome epidemiology.

Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence.

S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide evidence for an adaptive response that enables epigenetic persistence to metabolic stress.

Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.

Many oncogenic transcription factors (TFs) are considered to be undruggable because of their reliance on large protein-protein and protein-DNA interfaces. TFs such as hypoxia-inducible factors (HIFs) and X-box-binding protein 1 (XBP1) are induced by hypoxia and other stressors in solid tumors and bind to unfolded protein response element (UPRE) and hypoxia-induced response element (HRE) motifs to control oncogenic gene programs. Here, we report a strategy to create synthetic transcriptional repressors (STRs) that mimic the basic leucine zipper domain of XBP1 and recognize UPRE and HRE motifs. A lead molecule, STR22, binds UPRE and HRE DNA sequences with high fidelity and competes with both TFs in cells. Under hypoxia, STR22 globally suppresses HIF1α binding to HRE-containing promoters and enhancers, inhibits hypoxia-induced gene expression and blocks protumorigenic phenotypes in triple-negative breast cancer (TNBC) cells. In vivo, intratumoral and systemic STR22 treatment inhibited hypoxia-dependent gene expression, primary tumor growth and metastasis of TNBC tumors. These data validate a novel strategy to target the tumor hypoxia response through coordinated inhibition of TF-DNA binding.

The superconducting quasicharge qubit.

The non-dissipative nonlinearity of Josephson junctions1 converts macroscopic superconducting circuits into artificial atoms2, enabling some of the best-controlled qubits today3,4. Three fundamental types of superconducting qubit are known5, each reflecting a distinct behaviour of quantum fluctuations in a Cooper pair condensate: single-charge tunnelling (charge qubit6,7), single-flux tunnelling (flux qubit8) and phase oscillations (phase qubit9 or transmon10). Yet, the dual nature of charge and flux suggests that circuit atoms must come in pairs. Here we introduce the missing superconducting qubit, 'blochnium', which exploits a coherent insulating response of a single Josephson junction that emerges from the extension of phase fluctuations beyond 2π (refs. 11-14). Evidence for such an effect has been found in out-of-equilibrium direct-current transport through junctions connected to high-impedance leads15-19, although a full consensus on the existence of extended phase fluctuations is so far absent20-22. We shunt a weak junction with an extremely high inductance-the key technological innovation in our experiment-and measure the radiofrequency excitation spectrum as a function of external magnetic flux through the resulting loop. The insulating character of the junction is manifested by the vanishing flux sensitivity of the qubit transition between the ground state and the first excited state, which recovers rapidly for transitions to higher-energy states. The spectrum agrees with a duality mapping of blochnium onto a transmon, which replaces the external flux by the offset charge and introduces a new collective quasicharge variable instead of the superconducting phase23,24. Our findings may motivate the exploration of macroscopic quantum dynamics in ultrahigh-impedance circuits, with potential applications in quantum computing and metrology.

Structure-function study of a Ca2+-independent metacaspase involved in lateral root emergence.

Metacaspases are part of an evolutionarily broad family of multifunctional cysteine proteases, involved in disease and normal development. As the structure-function relationship of metacaspases remains poorly understood, we solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) belonging to a particular subgroup not requiring calcium ions for activation. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors and found several hits with a minimal thioxodihydropyrimidine-dione structure, of which some are specific AtMCA-IIf inhibitors. We provide mechanistic insight into the basis of inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) effectively hampered lateral root emergence in vivo, probably through inhibition of metacaspases specifically expressed in the endodermal cells overlying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in other species, such as important human pathogens, including those causing neglected diseases.

An Empirical Dietary Pattern Associated with the Gut Microbial Features in Relation to Colorectal Cancer Risk.

BACKGROUND & AIMS: Epidemiologic evidence for dietary influence on colorectal cancer (CRC) risk through the gut microbiome remains limited. METHODS: Leveraging 307 men and 212 women with stool metagenomes and dietary data, we characterized and validated a sex-specific dietary pattern associated with the CRC-related gut microbial signature (CRC Microbial Dietary Score [CMDS]). We evaluated the associations of CMDS with CRC risk according to Fusobacterium nucleatum, pks+Escherichia coli, and enterotoxigenic Bacteroides fragilis status in tumor tissue using Cox proportional hazards regression in the Health Professionals Follow-Up Study (1986-2018), Nurses' Health Study (1984-2020), and Nurses' Health Study II (1991-2019). RESULTS: The CMDS was characterized by high industrially processed food and low unprocessed fiber-rich food intakes. In 259,200 participants, we documented 3854 incident CRC cases over 6,467,378 person-years of follow-up. CMDS was associated with a higher risk of CRC (Ptrend < .001), with a multivariable hazard ratio (HRQ5 vs Q1) of 1.25 (95% CI, 1.13-1.39). The association remained after adjusting for previously established dietary patterns, for example, the Western and prudent diets. Notably, the association was stronger for tumoral F nucleatum-positive (HRQ5 vs Q1, 2.51; 95% CI, 1.68-3.75; Ptrend < .001; Pheterogeneity = .03, positivity vs negativity), pks+E coli-positive (HRQ5 vs Q1, 1.68; 95% CI, 0.84-3.38; Ptrend = .005; Pheterogeneity = .01, positivity vs negativity), and enterotoxigenic Bacteroides fragilis-positive CRC (HRQ5 vs Q1, 2.06; 95% CI, 1.10-3.88; Ptrend = .016; Pheterogeneity = .06, positivity vs negativity), compared with their negative counterparts. CONCLUSIONS: CMDS was associated with increased CRC risk, especially for tumors with detectable F nucleatum, pks+E coli, and enterotoxigenic Bacteroides fragilis in tissue. Our findings support a potential role of the gut microbiome underlying the dietary effects on CRC.

Nonmonotone invasion landscape by noise-aware control of metastasis activator levels.

A major pharmacological assumption is that lowering disease-promoting protein levels is generally beneficial. For example, inhibiting metastasis activator BACH1 is proposed to decrease cancer metastases. Testing such assumptions requires approaches to measure disease phenotypes while precisely adjusting disease-promoting protein levels. Here we developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic safe harbor locus. Unexpectedly, engineered MDA-MB-231 metastatic human breast cancer cells become more, then less and then more invasive as we tune BACH1 levels up, irrespective of the native BACH1. BACH1 expression shifts in invading cells, and expression of BACH1's transcriptional targets confirm BACH1's nonmonotone phenotypic and regulatory effects. Thus, chemical inhibition of BACH1 could have unwanted effects on invasion. Additionally, BACH1's expression variability aids invasion at high BACH1 expression. Overall, precisely engineered, noise-aware protein-level control is necessary and important to unravel disease effects of genes to improve clinical drug efficacy.

Clonal tracking in cancer and metastasis.

The eradication of many cancers has proven challenging due to the presence of functionally and genetically heterogeneous clones maintained by rare cancer stem cells (CSCs), which contribute to disease progression, treatment refractoriness, and late relapse. The characterization of functional CSC activity has necessitated the development of modern clonal tracking strategies. This review describes viral-based and CRISPR-Cas9-based cellular barcoding, lineage tracing, and imaging-based approaches. DNA-based cellular barcoding technology is emerging as a powerful and robust strategy that has been widely applied to in vitro and in vivo model systems, including patient-derived xenograft models. This review also highlights the potential of these methods for use in the clinical and drug discovery contexts and discusses the important insights gained from such approaches.

Automated antibody dispensing to improve high-parameter flow cytometry throughput and analysis.

Over the past decade, the flow cytometry field has witnessed significant advancements in the number of fluorochromes that can be detected. This enables researchers to analyze more than 40 markers simultaneously on thousands of cells per second. However, with this increased complexity and multiplicity of markers, the manual dispensing of antibodies for flow cytometry experiments has become laborious, time-consuming, and prone to errors. An automated antibody dispensing system could provide a potential solution by enhancing the efficiency, and by improving data quality by faithfully dispensing the fluorochrome-conjugated antibodies and by enabling the easy addition of extra controls. In this study, a comprehensive comparison of different liquid handlers for dispensing fluorochrome-labeled antibodies was conducted for the preparation of flow cytometry stainings. The evaluation focused on key criteria including dispensing time, dead volume, and reliability of dispensing. After benchmarking, the I.DOT, a non-contact liquid handler, was selected and optimized in more detail. In the end, the I.DOT was able to prepare a 25-marker panel in 20 min, including the full stain, all FMOs and all single stain controls for cells and beads. Having all these controls improved the validation of the panel, visualization, and analysis of the data. Thus, automated antibody dispensing by dispensers such as the I.DOT reduces time and errors, enhances data quality, and can be easily integrated in an automated workflow to prepare samples for flow cytometry.

Online digital compensation of pump dithering induced phase and amplitude distortions in transmission links with cascaded fibre-optical parametric amplifiers.

We present an advanced online digital signal processing (DSP) method for correcting the phase and amplitude distortions caused by the phase modulation of the pump source and its interaction with the dispersive fibre channel in transmission systems using cascaded fibre-optical parametric amplifiers. The proposed algorithm is numerically demonstrated to achieve significant (up to 3.7 dB for a four-tone pump-phase modulation scheme) Q2-factor performance improvement over conventional DSP in 16 quadrature-amplitude modulation signal transmission.

Arabidopsis casein kinase 2 triggers stem cell exhaustion under Al toxicity and phosphate deficiency through activating the DNA damage response pathway.

Aluminum (Al) toxicity and inorganic phosphate (Pi) limitation are widespread chronic abiotic and mutually enhancing stresses that profoundly affect crop yield. Both stresses strongly inhibit root growth, resulting from a progressive exhaustion of the stem cell niche. Here, we report on a casein kinase 2 (CK2) inhibitor identified by its capability to maintain a functional root stem cell niche in Arabidopsis thaliana under Al toxic conditions. CK2 operates through phosphorylation of the cell cycle checkpoint activator SUPPRESSOR OF GAMMA RADIATION1 (SOG1), priming its activity under DNA-damaging conditions. In addition to yielding Al tolerance, CK2 and SOG1 inactivation prevents meristem exhaustion under Pi starvation, revealing the existence of a low Pi-induced cell cycle checkpoint that depends on the DNA damage activator ATAXIA-TELANGIECTASIA MUTATED (ATM). Overall, our data reveal an important physiological role for the plant DNA damage response pathway under agriculturally limiting growth conditions, opening new avenues to cope with Pi limitation.

Derivation and External Validation of the Ottawa Bloodstream Infection Model for Acutely Ill Adults.

BACKGROUND: Knowing the probability that patients have a bloodstream infection (BSI) could influence the ordering of blood cultures and interpretation of their preliminary results. Many previous BSI probability models have limited applicability and accuracy. This study used currently recommended modeling techniques and a large sample to derive and validate the Ottawa BSI Model. METHODS: At a tertiary care teaching hospital, we retrieved a random sample of 4180 adults having blood cultures in our emergency department or during the initial 48 h of the encounter. Variable selection was based on clinical experience and a systematic review of previous model performance. Model performance was measured in a temporal external validation group of 4680 patients. RESULTS: A total of 327 derivation patients had a BSI (8.0%). BSI risk increased with increased number of culture sets (2 sets: adjusted odds ratio [aOR] 1.52 [1.10-2.11]; 3 sets: 1.99 [0.86-4.58]); with indwelling catheter (aOR 2.07 [1.34-3.20); with increasing temperature, heart rate, and neutrophil-lymphocyte ratio; and with decreasing systolic blood pressure, platelet count, urea-creatinine ratio, and estimated glomerular filtration rate. In the temporal external validation group, model discrimination was good (c-statistic 0.71 [0.69-0.74]) and calibration was very good (integrated calibration index .016 [.010-.024]). Exclusion of validation patients with acute SARS-CoV-2 infection improved discrimination slightly (c-statistic 0.73 [0.69-0.76]). CONCLUSIONS: The Ottawa BSI Model uses commonly available data to return an expected BSI probability for acutely ill patients. However, it cannot exclude BSI and its complexity requires computational assistance to use.

Mfsd7b facilitates choline transport and missense mutations affect choline transport function.

MFSD7b belongs to the Major Facilitator Superfamily of transporters that transport small molecules. Two isoforms of MFSD7b have been identified and they are reported to be heme exporters that play a crucial role in maintaining the cytosolic and mitochondrial heme levels, respectively. Mutations of MFSD7b (also known as FLVCR1) have been linked to retinitis pigmentosa, posterior column ataxia, and hereditary sensory and autonomic neuropathy. Although MFSD7b functions have been linked to heme detoxification by exporting excess heme from erythroid cells, it is ubiquitously expressed with a high level in the kidney, gastrointestinal tract, lungs, liver, and brain. Here, we showed that MFSD7b functions as a facilitative choline transporter. Expression of MFSD7b slightly but significantly increased choline import, while its knockdown reduced choline influx in mammalian cells. The influx of choline transported by MFSD7b is dependent on the expression of choline metabolizing enzymes such as choline kinase (CHKA) and intracellular choline levels, but it is independent of gradient of cations. Additionally, we showed that choline transport function of Mfsd7b is conserved from fly to man. Employing our transport assays, we showed that missense mutations of MFSD7b caused reduced choline transport functions. Our results show that MFSD7b functions as a facilitative choline transporter in mammalian cells.

Effects of pericardiocentesis on renal function and cardiac hemodynamics.

BACKGROUND: Previous case studies have reported reversal of acute renal failure after pericardiocentesis in pericardial effusion. This study examines the effects of pericardiocentesis on preprocedural low cardiac output and acute renal dysfunction in patients with pericardial effusion. METHODS: This is a retrospective study of 95 patients undergoing pericardiocentesis between 2015 and 2020. Pre- and post-procedure transthoracic echocardiograms (TTE) were reviewed for evidence of cardiac tamponade, resolution of pericardial effusion, and for estimation of right atrial (RA) pressure and cardiac output. Laboratory values were compared at presentation and post-procedure. Patients on active renal replacement therapy were excluded. RESULTS: Ninety-five patients were included for analysis (mean age 62.2 ± 17.8 years, 58% male). There was a significant increase in glomerular filtration rate pre- and post-procedure. Fifty-six patients (58.9%) had an improvement in glomerular filtration rate after pericardiocentesis (termed "responders"), and these patients had a lower pre-procedure glomerular filtration rate than "non-responders." There was a significant improvement in estimated cardiac output and right atrial pressure for patients in both groups. Patients who had an improvement in renal function had significantly lower pre-procedural diastolic blood pressure and mean arterial pressure. CONCLUSIONS: Pericardial drainage may improve effusion-mediated acute renal dysfunction by reducing right atrial pressure and thus systemic venous congestion, and by increasing forward stroke volume and perfusion pressure.

Effectiveness of a Smartphone-Based Stress Management Program for Depression in Hospital Nurses During COVID-19 in Vietnam and Thailand: 2-Arm Parallel-Group Randomized Controlled Trial.

BACKGROUND: During the COVID-19 pandemic, health care professionals experienced high levels of depression. However, extant research has not highlighted effective internet-based psychological interventions to improve the mental health in this population during the pandemic. It remains unclear whether self-guided, internet-based cognitive behavioral therapy (iCBT) programs are effective in improving the mental health of health care workers during the COVID-19 pandemic. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a smartphone-based iCBT stress management program for reducing the depression experienced by nurses in Vietnam and Thailand. METHODS: From March to April 2022, a 2-arm, parallel-group randomized controlled trial was implemented. One arm offered a 7-week self-guided iCBT program, and the other offered treatment as usual as a control arm. Full-time nurses were recruited from 6 hospitals: 2 hospitals in Vietnam and 4 hospitals in Thailand. The primary outcome of this program was the severity of depression measured by the Depression Anxiety Stress Scale-21 items. Follow-up surveys were conducted to measure the change in depression severity at 3 months (July-August 2022) and at 6 months (October-November 2022) after baseline. Mixed modeling for repeated measures was used to test the effects of the intervention compared with the control for the follow-up. RESULTS: A total of 1203 nurses were included in this study: 602 in the intervention group and 601 in the control group. The follow-up rate at 3 and 6 months ranged from 85.7% (515/601) to 87.5% (527/602). The completion rate for the program was 68.1% (410/602). The group difference in depression was significant at the 3-month follow-up (coefficient=-0.92, 95% CI -1.66 to -0.18; P=.02) and nonsignificant at the 6-month follow-up (coefficient=-0.33, 95% CI -1.11 to 0.45; P=.41). The estimated effect sizes were -0.15 and -0.06 at the 3- and 6-month follow-ups, respectively. CONCLUSIONS: Our study shows that the smartphone-based iCBT program was effective in reducing depression at the 3-month follow-up among hospital nurses in Vietnam and Thailand during the COVID-19 pandemic. However, the effect size was small, and therefore, these results may not be clinically meaningful. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000044145; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000050128. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.20944/preprints202303.0450.v1.

Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised. METHODS: We conducted a prospective cohort study using data collected from the Nurses' Health Study (2004-2018) and the Health Professionals Follow-up Study (2004-2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias). RESULTS: Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13-1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10-2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97-1.11; cancer: HR, 1.07; 95% CI, 0.89-1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81-1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95-1.50; digestive diseases: HR, 1.38; 95% CI, 0.88-2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality. CONCLUSIONS: After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.

Recruiting and retaining community-based participants in a COVID-19 longitudinal cohort and social networks study: lessons from Victoria, Australia.

BACKGROUND: Longitudinal studies are critical to informing evolving responses to COVID-19 but can be hampered by attrition bias, which undermines their reliability for guiding policy and practice. We describe recruitment and retention in the Optimise Study, a longitudinal cohort and social networks study that aimed to inform public health and policy responses to COVID-19. METHODS: Optimise recruited adults residing in Victoria, Australia September 01 2020-September 30 2021. High-frequency follow-up data collection included nominating social networks for study participation and completing a follow-up survey and four follow-up diaries each month, plus additional surveys if they tested positive for COVID-19 or were a close contact. This study compared number recruited to a-priori targets as of September 302,021, retention as of December 31 2021, comparing participants retained and not retained, and follow-up survey and diary completion October 2020-December 2021. Retained participants completed a follow-up survey or diary in each of the final three-months of their follow-up time. Attrition was defined by the number of participants not retained, divided by the number who completed a baseline survey by September 302,021. Survey completion was calculated as the proportion of follow-up surveys or diaries sent to participants that were completed between October 2020-December 2021. RESULTS: At September 302,021, 663 participants were recruited and at December 312,021, 563 were retained giving an overall attrition of 15% (n = 100/663). Among the 563 retained, survey completion was 90% (n = 19,354/21,524) for follow-up diaries and 89% (n = 4936/5560) for monthly follow-up surveys. Compared to participants not retained, those retained were older (t-test, p <  0.001), and more likely to be female (χ2, p = 0.001), and tertiary educated (χ2, p = 0.018). CONCLUSION: High levels of study retention and survey completion demonstrate a willingness to participate in a complex, longitudinal cohort study with high participant burden during a global pandemic. We believe comprehensive follow-up strategies, frequent dissemination of study findings to participants, and unique data collection systems have contributed to high levels of study retention.