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Background: Patients with a/mTNBC have limited treatment options and a poor prognosis (objective response rate [ORR] of 37%, median duration of response 6.5 months, median overall survival 15.5 months for 1L chemotherapy [Rugo, et al. Ann Oncol. 2021 LBA16]). Combining checkpoint inhibitors with 1L chemotherapy modestly improves outcomes but only in PD-L1–positive a/mTNBC, emphasizing a critical unmet need for patients with PD-L1–negative disease and for further improving outcomes in PD-L1–positive disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti–PD-L1 antibody, combined with other novel therapies in 1L a/mTNBC, including Dato-DXd, an antibody-drug conjugate consisting of a humanized anti-TROP2 antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Early data from BEGONIA of D in combination with Dato-DXd showed promising responses. Here, we report updated results of Dato-DXd + D. Methods: Patients with unresectable a/mTNBC eligible for 1L treatment were enrolled, regardless of PD-L1 or TROP2 status, and received intravenous Dato-DXd 6 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if ≥ 5% of the tumor area was populated by PD-L1–expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed ORR (RECIST v1.1) and duration of response. Patients included in the efficacy analysis had ≥ 2 on-treatment disease assessments, progressed, died, or withdrew from the study. Results: As of April 8, 2022, 47 patients received Dato-DXd + D (39 ongoing) and 33 of those were included in the efficacy analysis. Median (range) follow-up was 7.5 (0–11) months. Patient age was a median of 51 years, 57% received prior treatment for early stage TNBC, and 60% had visceral metastases at baseline. Confirmed ORR was 26/33 (79%; 95% CI, 61–91); 2/33 patients (6%) had a complete response and 24/33 (73%) had a partial response. Confirmed response was irrespective of PD-L1 expression (PD-L1 high ORR, 4/5 [80%]; PD-L1 low, 16/21 [76%]; PD-L1 missing, 6/7 [86%] patients). Median duration of response was not reached; 100% of patients with a complete or partial response remained in response at 6 month follow-up, and 96% had an ongoing response at data cutoff. Adverse events (AEs) were manageable and consistent with the known safety profiles of each agent, with treatment-related AEs occurring in 41 patients (87%), any Grade 3/4 AEs in 17 patients (36%), and any serious AEs in 7 patients (15%). The most common all-Grade AEs were gastrointestinal (nausea in 26 patients [55%] and stomatitis in 24 patients [51%]). A low rate of diarrhea was reported (6 patients [13%], all Grade 1 or 2); 4 patients had anemia and 1 had neutropenia. There were no cases of interstitial lung disease/pneumonitis or thrombocytopenia. Nine patients (19%) and 11 patients (23%) underwent Dato-DXd dose reduction and delay, respectively; 14 (30%) had D dose delay. Treatment was discontinued due to an AE for 3 patients (6%). There were no deaths due to treatment-related AEs. Conclusions: In this updated analysis with additional patients and longer follow-up, the combination of Dato-DXd + D in 1L a/mTNBC demonstrated a manageable safety profile and compelling high response rates with promising durability. Although subgroups were small, responses occurred irrespective of PD-L1 expression. Further investigation of this treatment combination is warranted. Analysis of translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Piotr Wysocki, Cynthia Ma, Yeon H. Park, Ricardo Fernandes, Simon Lord, Richard D. Baird, Catherine Prady, Kyung Hae Jung, Jamil Asselah, Robert Huisden, Ross Stewart, Petra Vuković, Ana T. Nunes, Zbigniew Nowecki. PD11-09 Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase 1b/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-09.

Endocrine therapy forms the backbone treatment for patients with estrogen receptor (ER) positive tumors in both the adjuvant and metastatic setting. Aromatase inhibitors (AI) are the most common endocrine treatment option. Mutation of ESR1, the gene encoding ERα, is a common mechanism of resistance to AIs which leads to ligand independent activity of ERα. Camizestrant (AZD9833) is a next generation SERD and pure ER antagonist that is in Phase 3 trials (SERENA-4: NCT04711252; SERENA-6: NCT04964934). Here we report the preclinical and clinical activity of camizestrant in patients with ESR1 wild-type (ESR1wt) and mutant (ESR1m) tumors. The binding affinities of camizestrant, fulvestrant, and estradiol to wt ERα and ERα variants with mutations in the ligand binding domain were assessed. All three compounds exhibited reduced binding to mutant forms of ERα compared with wt ERα; the Y537S mutation had the greatest impact on binding. This was reflected in requirement for greater concentrations of camizestrant and fulvestrant to degrade and antagonize mutated ERα and to impact cellular proliferation in MCF-7 cells that expressed Y537S ESR1m compared to ESR1wt MCF-7 cells. Furthermore, while a 3 mg/kg dose of camizestrant achieved a maximal anti-tumor effect in a ESR1wt patient derived xenograft model, a 10 mg/kg was required for maximal effect in a D538G ESR1m model. Considering this difference between ESR1m and ESR1wt, pharmacokinetic/pharmacodynamic modelling of preclinical data predicted that a camizestrant dose of 75 mg would be maximally efficacious in patients with ESR1m tumors. Indeed, analysis of ESR1m circulating tumor DNA levels in patients from the SERENA-1 (NCT03616587) Phase 1 trial showed a clear effect of 14 days treatment with 75 mg camizestrant resulting in a >2-fold reduction in ESR1m variant allele frequency in 12/13 (92%) cases with complete clearance of ESR1m ctDNA in 7/13 (54%) cases. Interestingly, the clinical activity of camizestrant was higher in heavily pretreated patients with metastatic breast cancer with ESR1m tumors compared to those with no detectable mutation (ESR1m not detected). At a camizestrant dose of 75 mg, median progression-free survival was 8.3 months (maturity 12/15) in patients with ESR1m tumors compared to 5.6 months (8/9) in those with ESR1m not detected (data cut-off 6 October 2021). Camizestrant-induced ERα degradation was seen in both groups (mean reduction in H-score 42% in ESR1m tumors (n= 12 evaluable pairs) and 46% in tumors with ESR1m not detected (n=7)). Whole transcriptome analysis revealed a trend towards higher ERα activity at baseline in ESR1m tumors compared to ESR1m not detected; ERα activity reduced on treatment in both groups. Consistent with the clinical activity data, camizestrant induced more profound reductions in cell proliferation in ESR1m tumors compared to ESR1m not detected tumors (as seen by greater reductions in Ki67-positive tumor cells). These data demonstrate the activity of camizestrant in patients with ESR1m tumors. Clinical activity along with degradation and antagonism of the ERα is also seen in patients with tumors in which ESR1 mutations are not detected. In this heavily pre-treated Phase 1 patient population from SERENA-1, ESR1m may be a predictive biomarker to enrich for patients with maintained endocrine sensitivity. The SERENA-6 trial is investigating the efficacy and safety of camizestrant plus a CDK4/6 inhibitor in patients with metastatic breast cancer and detectable ESR1m. We acknowledge Helen Heffron, PhD, from InterComm International who provided medical writing support funded by AstraZeneca. Citation Format: Christopher Morrow, Larissa Carnevalli, Richard D. Baird, Tim Brier, Carmela Ciardullo, Natalie Cureton, Mandy Lawson, Robert McEwen, Myria Nikolaou, Anne Armstrong, Begoña Bermejo, Emiliano Calvo, Eva Ciruelos, Javier Garcia-Corbacho, Erika Hamilton, Jason Incorvati, Peter Kabos, Mafalda Oliveira, Manish R Patel, Manuel Ruiz-Borregó, Nicholas Turner, Chris Twelves, Christos Vaklavas, Danielle Carroll, Steven Ching, Nevena Cvetesic, Michelle DuPont, Lisa Gibbons, Alastair Mathewson, Rhiannon Maudsley, Pablo Morentin Gutierrez, Avinash Reddy, Jaime Rodriguez-Canales, Susana Ros, Dhivya Sudhan, Andy Sykes, David Whitson, Teresa Klinowska, Justin Lindemann. The next generation oral selective estrogen receptor degrader (SERD) camizestrant (AZD9833) is active against wild type and mutant estrogen receptor α [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-13.

Funder: Infectious Diseases Institute, Makerere University, Funder: John Hopkins University, INTRODUCTION: The evaluation of the patterns of liver injury, derived from liver chemistry panels, often may narrow on probable causes of the liver insult especially when coupled with clinical history, examination, and other diagnostic tests. METHODS: Among people living with and without HIV and attending care, we used the R ratio to evaluate for liver injury patterns. Liver injury patterns were defined as cholestatic (R < 2), mixed (R = 2-5), and hepatocellular (R > 5). RESULTS: Overall, the proportions of participants with cholestatic liver injury, mixed liver injury, and hepatocellular liver injury were 55%, 34%, and 4%, respectively, with similar distribution when stratified by HIV status. Alcohol use among participants without HIV was associated with all patterns of liver injury (cholestatic liver injury (OR = 4.9 CI (1.0-24.2); p = 0.054), mixed liver injury (OR = 5.3 CI (1.1-27.3); p = 0.043), and hepatocellular liver injury (OR = 13.2 CI (1.0-167.3); p = 0.046)). Increasing age was associated with cholestatic liver injury among participants with HIV (OR = 2.3 CI (1.0-5.3); p = 0.038). Despite a high hepatitis B prevalence among participants with HIV, there was no association with liver injury. CONCLUSIONS: Liver injury is prevalent among both people living with and without HIV in care, and cholestatic liver injury is the most common pattern. Alcohol is associated with all patterns of liver injury and increasing age associated with cholestatic liver injury among people living without HIV and people living with HIV, respectively.

Background Water fluoridation was introduced in the UK against a background of high dental decay within the population. Levels of decay have dramatically reduced over the last 40 years following widespread use of fluoride toothpaste. Objective The aim of the CATFISH (Cumbrian Assessment of Teeth a Fluoride Intervention Study for Health) study was to address the question of whether or not the addition of fluoride to community drinking water, in a contemporary population, lead to a reduction in the number of children with caries and, if so, is this reduction cost-effective? Design A longitudinal prospective cohort design was used in two distinct recruited populations: (1) a birth cohort to assess systemic and topical effects of water fluoridation and (2) an older school cohort to assess the topical effects of drinking fluoridated water. Setting The study was conducted in Cumbria, UK. Broadly, the intervention group (i.e. individuals receiving fluoridated drinking water) were from the west of Cumbria and the control group were from the east of Cumbria. Participants Children who were lifetime residents of Cumbria were recruited. For the birth cohort, children were recruited at birth (2014–15), and followed until age 5 years. For the older school cohort, children were recruited at age 5 years (2013–14) and followed until the age of 11 years. Intervention The provision of a ‘reintroduced fluoridated water scheme’. Main outcome measures The primary outcome measure was the presence or absence of decay into dentine in the primary teeth (birth cohort) and permanent teeth (older school cohort). The cost per quality-adjusted life-year was also assessed. Results In the birth cohort (n = 1444), 17.4% of children in the intervention group had decay into dentine, compared with 21.4% of children in the control group. The evidence, after adjusting for deprivation, age and sex, with an adjusted odds ratio of 0.74 (95% confidence interval 0.56 to 0.98), suggested that water fluoridation was likely to have a modest beneficial effect. There was insufficient evidence of difference in the presence of decay in children in the older school cohort (n = 1192), with 19.1% of children in the intervention group having decay into dentine, compared with 21.9% of children in the control group (adjusted odds ratio 0.80, 95% confidence interval 0.58 to 1.09). The intervention was found to be likely to be cost-effective for both the birth cohort and the older school cohort at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. There was no significant difference in the performance of water fluoridation on caries experience across deprivation quintiles. Conclusions The prevalence of caries and the impact of water fluoridation was much smaller than previous studies have reported. The intervention was effective in the birth cohort group; however, the importance of the modest absolute reduction in caries (into dentine) needs to be considered against the use of other dental caries preventative measures. Longer-term follow-up will be required to fully understand the balance of benefits and potential risks (e.g. fluorosis) of water fluoridation in contemporary low-caries populations. Limitations The low response rates to the questionnaires reduced their value for generalisations. The observed numbers of children with decay and the postulated differences between the groups were far smaller than anticipated and, consequently, the power of the study was affected (i.e. increasing the uncertainty indicated in the confidence intervals). Study registration This study is registered as Integrated Research Application System 131824 and 149278. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 11. See the NIHR Journals Library website for further project information.

Clonal hematopoiesis (CH) is an age-related condition driven by stem- and progenitor cells harboring recurrent mutations linked to myeloid neoplasms. Currently, potential effects on hematopoiesis, stem cell function and regenerative potential under stress conditions are unknown. We performed targeted DNA sequencing of 457 hematopoietic stem cell grafts collected for autologous stem cell transplantation (ASCT) in myeloma patients and correlated our findings with high-dimensional longitudinal clinical and laboratory data (26,510 data points for blood cell counts/serum values in 25 days around transplantation). We detected CH-related mutations in 152 patients (33.3%). Since many patients (n = 54) harbored multiple CH mutations in one or more genes, we applied a non-negative matrix factorization (NMF) clustering algorithm to identify genes that are commonly co-mutated in an unbiased approach. Patients with CH were assigned to one of three clusters (C1-C3) and compared to patients without CH (C0) in a gene specific manner. To study the dynamics of blood cell regeneration following ASCT, we developed a time-dependent linear mixed effect model to validate differences in blood cell count trajectories amongst different clusters. The results demonstrated that C2, composed of patients with DNMT3A and PPM1D single and comutated CH, correlated with reduced stem cell yields and delayed platelet count recovery following ASCT. Also, the benefit of maintenance therapy was particularly strong in C2 patients. Taken together, these data indicate an impaired regenerative potential of hematopoietic stem cell grafts harboring CH with DNMT3A and PPM1D mutations.

BACKGROUND: Vancomycin-resistant Enterococcus faecium (VRE) is a leading cause of nosocomial infection, driven by its ability to spread between patients and persist in the hospital environment. Here, we investigated the impact of a long-established cardiothoracic hospital moving to new premises with close to 100% single-occupancy rooms on the rates of environmental contamination and infection or colonisation by VRE. METHOD: Prospective environmental surveillance for VRE was conducted at five time-points between April and November 2019, once in the original building, and four times in the new building. Flocked swabs (n=100/time-point) were used to sample bedspaces, bathrooms, computers and sluices in the critical care unit and the cardiothoracic ward. Environmental VRE was supplemented by clinical VRE isolates from the same time period, and underwent whole genome sequencing. Incidence rate ratios (IRR) of VRE infection/colonisation was determined for the one-year period before and after the hospital move, and compared to a nearby hospital. FINDINGS: In the original location, the first environmental screen found 29% VRE positivity. The following four screens in the new location showed a significant reduction in positivity (1-6%, p

Large-scale recordings of neural activity over days and weeks have revealed that neural representations of familiar tasks, precepts and actions continually evolve without obvious changes in behaviour. We hypothesise that this steady drift in neural activity and accompanying physiological changes is due in part to the continuous application of a learning rule at the cellular and population level. Explicit predictions of this drift can be found in neural network models that use iterative learning to optimise weights. Drift therefore provides a measurable signal that can reveal systems-level properties of biological plasticity mechanisms, such as their precision and effective learning rates.

The human embryo undergoes morphogenetic transformations following implantation into the uterus, yet our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo. Stem cell-derived models of the embryo are important tools to interrogate developmental events and tissue-tissue crosstalk during these stages1. Here, we establish a model of the human post-implantation embryo, a human embryoid, comprised of embryonic and extraembryonic tissues. We combine two types of extraembryonic-like cells generated by transcription factor overexpression with wildtype embryonic stem cells and promote their self-organization into structures that mimic several aspects of the post-implantation human embryo. These self-organized aggregates contain a pluripotent epiblast-like domain surrounded by extraembryonic-like tissues. Our functional studies demonstrate that the epiblast-like domain robustly differentiates to amnion, extraembryonic mesenchyme, and primordial germ cell-like cells in response to BMP cues. In addition, we identify an inhibitory role for SOX17 in the specification of anterior hypoblast-like cells2. Modulation of the subpopulations in the hypoblast-like compartment demonstrated that extraembryonic-like cells impact epiblast-like domain differentiation, highlighting functional tissue-tissue crosstalk. In conclusion, we present a modular, tractable, integrated3 model of the human embryo that will allow us to probe key questions of human post-implantation development, a critical window when significant numbers of pregnancies fail.

The Prostate Cancer Radiological Estimation of Change in sequential Evaluation (PRECISE) recommendations were published in 2016 to standardize the reporting of MRI examinations performed to assess for disease progression in patients on active surveillance (AS) for prostate cancer. Although a limited number of studies have reported outcomes from use of PRECISE in clinical practice, the available studies have demonstrated PRECISE to have high pooled NPV but low pooled PPV for predicting progression. Our experience in using PRECISE in clinical practice at two teaching hospitals has highlighted issues with its application and areas requiring clarification. This Clinical Perspective critically appraises PRECISE based on this experience, focusing on the system's key advantages and disadvantages and exploring potential changes to improve the system's utility. These include consideration of image quality when applying PRECISE scoring, incorporation of quantitative thresholds for disease progression, adoption of a PRECISE 3F subcategory for progression not qualifying as substantial, and comparisons with both the baseline and most recent prior examinations. Items requiring clarification include derivation of a patient-level score in patients with multiple lesions, intended application of PRECISE score 5 (i.e., if requiring development of non organ-confined disease), and categorization of new lesions in patients with prior MRI-invisible disease.

OBJECTIVES: There's paucity of longitudinal studies assessing the role of adolescent growth on adult body composition in developing countries. The aims of this study were to assess the association between adolescent change in height, weight and BMI and early adult height, weight, body fat and lean mass. METHODS: Magnitude, timing and intensity of height, weight and BMI growth were modelled for participants from the Birth to Thirty (Bt30) cohort (7-23 years). Early adult height, weight, BMI and DXA-derived body composition were obtained 1881 black participants (21-24 years). Linear regression analyses were used to assess associations. RESULTS: Adolescents with an earlier onset of puberty were heavier in childhood and had an earlier timing and faster weight gain velocity in late adolescence. The intensity of adolescent weight gain was positively associated with adult BMI and fat mass index (FMI) in females. Early timing of adolescent BMI gain was associated with increased weight and BMI in adult females and FMI in adult males. Achieving peak weight velocity around age at peak height velocity was associated with lower BMI and fat mass in both sexes. CONCLUSION: This study confirms the adverse consequences of excessive weight gain prior to puberty, which is associated with an earlier and faster resurgence in weight gain velocity in early adulthood. Factors that contribute to an asynchronous timing of ages of peak weight and peak height velocities may accentuate the risk of adult obesity.

Mammalian genomes harbour a large number of transposable elements (TEs) and their remnants. Many epigenetic repression mechanisms are known to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here we demonstrated that the male-specific lethal (MSL) complex mediated acetylation of histone H4 lysine 16 (H4K16ac) activates transcription of long interspersed nuclear elements (LINE1, L1) and long terminal repeats (LTRs). Furthermore, we show that the H4K16ac marked L1 and LTR subfamilies function as enhancers and are enriched with chromatin features associated with active enhancers and looping factors. L1 and LTRs enriched with histone acetylations are bound by chromatin looping factors and these regions loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac marked L1s and LTRs regulate the expression of genes in cis. Overall, TEs enriched with H4K16ac contribute to the cis-regulatory landscape of a significant portion of the mammalian genome by maintaining an active chromatin landscape at TEs.One Sentence SummaryH4K16ac activates LINE1 and ERV/LTR transcription and rewires the cis-regulatory landscape of a significant portion of the mammalian genome by increasing the transcriptional activity at TEs.

Psychotic symptoms occur in a majority of schizophrenia patients and in ~50% of all Parkinson's disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little is known, however, about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as in schizophrenia and PD. The present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals in at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD, PDN and Con-PD, as well as PDN and PDP, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC ~0.80) of FEP and Con-Psy, and fair performance (AUC ~0.72) when differentiating PDP from Con-PD. Importantly, the best performance was found in partly the same networks, including the thalamus. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.

Background. Only some individuals using drugs recreationally eventually develop a substance use disorder, characterised in part by the rigid engagement in drug foraging behaviour (drug seeking), often maintained in the face of adverse consequences (e.g., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. Methods. Using a prospective longitudinal study involving 40 male rats we combined a multidimensional characterisation of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging (MRI) to identify in drug-naïve subjects the structural and functional brain correlates of the later emergence of compulsive drug seeking. We developed a novel behavioral procedure to investigate in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus, the individual tendency to persist in drug seeking behavior in the face of punishment in a drug free state. Results. We report that in drug-naïve rats the future tendency to develop compulsive cocaine seeking is characterised by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula and nucleus accumbens. Conclusions. These findings show that the vulnerability to develop compulsive cocaine seeking behavior stems from pre-existing structural or functional changes in two distinct cortico-striatal systems that underlie deficits in impulse control and goal-directed behavior.

Given well‐established links between socio‐economic adversity and mental health, it is unsurprising that young people's mental health is deteriorating amidst economic crises. The World Health Organisation (WHO) recognises mental health as “crucial to personal, community, and socio‐economic development” and outlines goals to reshape environments such as schools to protect mental health. Schools offer an ideal setting to promote wellbeing and prevent mental ill‐health during a key developmental window. We describe how social inequalities present a challenge to designing school‐based interventions for prevention and promotion for mental health and wellbeing, and suggest priorities to aid and evaluate their effectiveness.

Current serum tumour markers α-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase show limited value for testicular cancer relapse detection. A recent study highlights that false-positive elevations in follow-up monitoring are common and, conversely, many patients do not have elevations despite proven relapse. These findings highlight the potential for circulating microRNAs to be used as improved biomarkers for relapse detection.

Throughout adult life, there is a physiological decline in almost all body systems and with a greater proportion of population living to old age, dental practitioners will need to provide operative intervention in more medically complex patients. Dental implants are a common modality for the replacement of missing teeth; however, implant failure and associated disease present complex challenges to clinicians. Therefore, the aim of this narrative review is to discuss the cardiovascular, respiratory, haematological, endocrine, and musculoskeletal systems with respect to diseases affecting patients of an older age which can impact dental implant treatment.

Cardiovascular disease and its concurrent risk factors are prevalent after liver transplant (LT). Most of these risk factors are modifiable by diet. We aimed to synthesise the literature reporting the nutritional intake of liver transplant recipients (LTR) and the potential determinants of intake. We performed a systematic review and meta-analyses of studies published up until July 2021 reporting the nutritional intake of LTR. The pooled daily mean intakes were recorded as 1998 (95% CI 1889, 2108) kcal, 17 (17, 18)% energy from protein, 49 (48, 51)% energy from carbohydrates, 34 (33, 35)% energy from total fat, 10 (7, 13)% energy from saturated fat, and 20 (18, 21) g of fibre. The average fruit and vegetable intake ranged from 105 to 418 g/day. The length of time post-LT and the age and sex of the cohorts, as well as the continent and year of publication of each study, were sources of heterogeneity. Nine studies investigated the potential determinants of intake, time post-LT, gender and immunosuppression medication, with inconclusive results. Energy and protein requirements were not met in the first month post-transplant. After this point, energy intake was significantly higher and remained stable over time, with a high fat intake and low intake of fibre, fruits and vegetables. This suggests that LTR consume a high-energy, low-quality diet in the long term and do not adhere to the dietary guidelines for cardiovascular disease prevention.

BACKGROUND: The paradigm of early phase dose-finding trials has evolved in recent years. Innovative dose-finding designs and protocols which combine phases I and II are becoming more popular in health research. However, the quality of these trial protocols is unknown due to a lack of specific reporting guidelines. Here, we evaluated the reporting quality of dose-finding trial protocols. METHODS: We conducted a cross-sectional study of oncology and non-oncology early phase dose-finding trial protocols posted on ClinicalTrials.gov in 2017-2023. A checklist of items comprising: 1) the original 33-items from the SPIRIT 2013 Statement and 2) additional items unique to dose-finding trials were used to assess reporting quality. The primary endpoint was the overall proportion of adequately reported items. This study was registered with PROSPERO (no: CRD42022314572). FINDING: A total of 106 trial protocols were included in the study with the rule-based 3 + 3 being the most used trial design (39.6%). Eleven model-based and model-assisted designs were identified in oncology trials only (11/58, 19.0%). The overall proportion of adequately reported items was 65.1% (95%CI: 63.9-66.3%). However, the reporting quality of each individual item varied substantially (range 9.4%-100%). Oncology study protocols showed lower reporting quality than non-oncology. In the multivariable analysis, trials with larger sample sizes and industry funding were associated with higher proportions of adequately reported items (all p-values

In this issue of Blood1, Bamezai et al reveal an unexpected, moonlighting* function of the germ cell associated RNA binding protein, PIWIL4 in AML. The authors show a tumor-specific requirement for PIWIL4 in R-loop homeostasis. Loss of PIWIL4 in AML cells led to uncontrolled R-loop formation, transcriptional stalling, DNA damage and an enhanced sensitivity to ATR inhibition, findings that may inform future therapeutic approaches.

INTRODUCTION: The impact of infection on infant nutritional status, body size, and growth is well documented. However, research into the impact of infection on infant body composition is limited. Greater understanding is, therefore, needed on the effects of infection in early life. METHODS: Associations between a composite morbidity index consisting of the sum of the cumulative tallies for a range of symptoms representing infection and morbidity in the infants and nutritional status (height-for-age (HAZ), and weight-for-height (WHZ)), and body composition (fat-free mass (FFM), fat mass (FM), fat-free mass index (FFMI), and fat mass index (FMI)) at 6 months of age were investigated using hierarchical regression analysis. RESULTS: The sample comprised data between birth and 6 months postnatally, of 156 infants who were a priori born healthy in Soweto, South Africa. Morbidity, over the cumulative period of birth to 6 months, was associated with lower FMI (β = -1.77) and lower FM (β = -0.61), and conversely with higher FFM (β = 0.94), in infants at 6 months. No associations were found between the morbidity index and FFMI, HAZ, and WHZ. Increased birthweight was associated with a higher FFM (β = 0.66), HAZ (β = 1.14), and WHZ (β = 0.87). Finally, safely managed sanitation facilities, representative of reduced environmental exposure to fecal-oral transmission pathways were associated with a higher HAZ (β = 1.21). DISCUSSION: Reduction in FMI and FM and exposure to inflammatory cytokines associated with mounting an immune response could alter phenotypic trajectories during to this period of plasticity. From a public health perspective, these results imply that it is important to intensify efforts to prevent infection in infants in the first 6 months postnatally, and that these efforts should concentrate on access to safely managed sanitation facilities.

OBJECTIVES: Traditional jumping-dance rituals performed by Maasai men involve prolonged physical exertion that may contribute significantly to overall physical activity level. We aimed to objectively quantify the metabolic intensity of jumping-dance activity and assess associations with habitual physical activity and cardiorespiratory fitness (CRF). METHODS: Twenty Maasai men (18-37 years) from rural Tanzania volunteered to participate in the study. Habitual physical activity was monitored using combined heart rate (HR) and movement sensing over 3 days, and jumping-dance engagement was self-reported. A 1-h jumping-dance session resembling a traditional ritual was organized, during which participants' vertical acceleration and HR were monitored. An incremental, submaximal 8-min step test was performed to calibrate HR to physical activity energy expenditure (PAEE) and assess CRF. RESULTS: Mean (range) habitual PAEE was 60 (37-116) kJ day-1 kg-1 , and CRF was 43 (32-54) mL O2 min-1 kg-1 . The jumping-dance activity was performed at an absolute HR of 122 (83-169) beats·min-1 , and PAEE of 283 (84-484) J min-1 kg-1 or 42 (18-75)% when expressed relative to CRF. The total PAEE for the session was 17 (range 5-29) kJ kg-1 , ~28% of the daily total. Self-reported engagement in habitual jumping-dance frequency was 3.8 (1-7) sessions/week, with a total duration of 2.1 (0.5-6.0) h/session. CONCLUSIONS: Intensity during traditional jumping-dance activity was moderate, but on average sevenfold higher than habitual physical activity. These rituals are common, and can make a substantial contribution to overall physical activity in Maasai men, and thus be promoted as a culture-specific activity to increase energy expenditure and maintain good health in this population.

The MedLey trial was funded by a National Health and Medical Research Council Grant (#APP1050949 to KJM). The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197 to NJW). Biomarker measurements for carotenoids were funded jointly by the InterAct project, the EPIC-CVD project, and the MRC Cambridge Initiative (RG71466 and SJAH/004 to NJW, NGF, JD, AB). EPIC-CVD has been supported by the UK Medical Research Council (MR/L003120/1 to ASB and JD), the British Heart Foundation (RG/13/13/30194 and RG/18/13/33946 to ASB and JD), the European Commission Framework Programme 7 (HEALTH -F2-2012-279233 to ASB and JD), the European Research Council (268834 to ASB and JD), and the National Institute for Health Research (NIHR; Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust, BRC-1215-20014 to ASB and JD). This work was also supported by Health Data Research UK (to ASB and JD), which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), and Wellcome. The coordination of EPIC is financially supported by the International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Ge'ne'rale de l'Education Nationale, Institut National de la Sante' et de la Recherche Me'dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Iblea Ricerca Epidemiologica (A.I.R.E. - ONLUS) Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di San Paolo, National Research Council and Sicilian Regional Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands~Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluci'a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology -ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to NJW; C8221/A29017), Medical Research Council (1000143 to NJW; MR/M012190/1) (United Kingdom). JGS was supported by the MRC PhD studentship. NJW, NGF, and FI acknowledge funding from the Medical Research Council Epidemiology Unit (MC_UU_00006/1, MC_UU_00006/3); and NJW, NGF and AK from the NIHR Cambridge Biomedical Research Centre (IS-BRC-1215-20014; NIHR203312). NGF and JD are NIHR Senior Investigators. JD holds a British Heart Foundation Professorship. MBS acknowledges funding from the Federal Ministry of Education and Research and the State of Brandenburg (DZD grant 82DZD03D03). JSZ has received funding from Westlake University (No YSYY0209) and European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 701708. PWF has received funding from Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation, European Research Council. ER has received funding from Imperial College Biomedical Research Centre. The funders of the studies had no role in the study design, data collection, data analysis, data interpretation, or report preparation. Trial Australian., Background Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. Methods and findings We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. Conclusions These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully., EU FP6 programme LSHM_CT_2006_037197, European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), World Health Organization, Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Catalan Institute of Oncology - ICO (Spain), Spanish Government 701708, Marie Curie Actions 701708, European Union's Horizon 2020, Marie Sklodowska-Curie 701708

Metabolomic approaches, such as in clinical applications of living individuals, have shown potential use for solving questions regarding the past when applied to archaeological material. Here, we study for the first time the potential of this Omic approach as applied to metabolites extracted from archaeological human dentin. Dentin obtained from micro sampling the dental pulp of teeth of victims and non-victims of Yersinia pestis (plague) from a 6th century Cambridgeshire site are used to evaluate the potential use of such unique material for untargeted metabolomic studies on disease state through liquid chromatography hyphenated to high-resolution mass spectrometry (LC-HRMS). Results show that small molecules of both likely endogenous and exogenous sources are preserved for a range of polar and less polar/apolar metabolites in archaeological dentin; however, untargeted metabolomic profiles show no clear differentiation between healthy and infected individuals in the small sample analysed (n = 20). This study discusses the potential of dentin as a source of small molecules for metabolomic assays and highlights: (1) the need for follow up research to optimise sampling protocols, (2) the requirements of studies with larger sample numbers and (3) the necessity of more databases to amplify the positive results achievable with this Omic technique in the archaeological sciences.

Sclerostin inhibition is a new therapeutic approach for increasing bone mineral density (BMD) but its cardiovascular safety is unclear. We conducted a genome-wide association study (GWAS) meta-analysis of circulating sclerostin in 33,961 Europeans followed by Mendelian randomization (MR) to estimate the causal effects of sclerostin on 15 atherosclerosis-related diseases and risk factors. GWAS meta-analysis identified 18 variants independently associated with sclerostin, which including a novel cis signal in the SOST region and three trans signals in B4GALNT3, RIN3 and SERPINA1 regions that were associated with opposite effects on circulating sclerostin and eBMD. MR combining these four SNPs suggested lower sclerostin increased hypertension risk (odds ratio [OR]=1.09, 95%CI=1.04 to 1.15), whereas bi-directional analyses revealed little evidence for an effect of genetic liability to hypertension on sclerostin levels. MR restricted to cis (SOST) SNPs additionally suggested sclerostin inhibition increased risk of type 2 diabetes (T2DM) (OR=1.26; 95%CI=1.08 to 1.48) and myocardial infarction (MI) (OR=1.31, 95% CI=1.183 to 1.45). Furthermore, these analyses suggested sclerostin inhibition increased coronary artery calcification (CAC) (β=0.74, 95%CI=0.33 to 1.15), levels of apoB (β=0.07; 95%CI=0.04 to 0.10; this result was driven by rs4793023) and triglycerides (β=0.18; 95%CI=0.13 to 0.24), and reduced HDL-C (β=-0.14; 95%CI=-0.17 to -0.10). This study provides genetic evidence to support a causal effect of sclerostin inhibition on increased hypertension risk. Cis-only analyses suggested that sclerostin inhibition additionally increases the risk of T2DM, MI, CAC, and an atherogenic lipid profile. Together, our findings reinforce the requirement for strategies to mitigate against adverse effects of sclerostin inhibitors like romosozumab on atherosclerosis and its related risk factors.

A liquid-based surface-enhanced Raman spectroscopy assay termed PSALM is developed for the selective sensing of neurotransmitters (NTs) with a limit of detection below the physiological range of NT concentrations in urine. This assay is formed by quick and simple nanoparticle (NP) "mix-and-measure" protocols, in which FeIII bridges NTs and gold NPs inside the sensing hotspots. Detection limits of NTs from PreNP PSALM are significantly lower than those of PostNP PSALM, when urine is pretreated by affinity separation. Optimized PSALM enables the long-term monitoring of NT variation in urine in conventional settings for the first time, allowing the development of NTs as predictive or correlative biomarkers for clinical diagnosis.

Appointment keeping and self-report within 7-day or and 30-days recall periods are non-objective measures of antiretroviral treatment (ART) adherence. We assessed incidence of virological failure (VF), predictive performance and associations of these adherence measures with VF among adults on long-term ART. Data for persons initiated on ART between April 2004 and April 2005, enrolled in a long-term ART cohort at 10-years on ART (baseline) and followed until December 2021 was analyzed. VF was defined as two consecutives viral loads ≥1000 copies/ml at least within 3-months after enhanced adherence counselling. We estimated VF incidence using Kaplan-Meier and Cox-proportional hazards regression for associations between each adherence measure (analyzed as time-dependent annual values) and VF. The predictive performance of appointment keeping and self-reporting for identifying VF was assessed using receiver operating characteristic curves and reported as area under the curve (AUC). We included 900 of 1,000 participants without VF at baseline: median age was 47 years (Interquartile range: 41-51), 60% were women and 88% were virally suppressed. ART adherence was ≥95% for all three adherence measures. Twenty-one VF cases were observed with an incidence rate of 4.37 per 1000 person-years and incidence risk of 2.4% (95% CI: 1.6%-3.7%) over the 5-years of follow-up. Only 30-day self-report measure was associated with lower risk of VF, adjusted hazard ratio (aHR)=0.14, 95% CI:0.05–0.37). Baseline CD4 count ≥200cells/ml was associated with lower VF for all adherence measures. The 30-day self-report measure demonstrated the highest predictive performance for VF (AUC=0.751) compared to appointment keeping (AUC=0.674), and 7-day self-report (AUC=0.687). The incidence of virological failure in this study cohort was low. Whilst 30-day self-report was predictive, appointment keeping and 7-day self-reported adherence measures had low predictive performance in identifying VF. Viral load monitoring remains the gold standard for adherence monitoring and confirming HIV treatment response.

Funder: MQ: Transforming Mental Health; Grant(s): MQDS17/40, Around a quarter of people who experience a first episode of psychosis (FEP) will develop treatment-resistant schizophrenia (TRS), but there are currently no established clinically useful methods to predict this from baseline. We aimed to explore the predictive potential for clozapine use as a proxy for TRS of routinely collected, objective biomedical predictors at FEP onset, and to externally validate the model in a separate clinical sample of people with FEP. We developed and externally validated a forced-entry logistic regression risk prediction Model fOr cloZApine tReaTment, or MOZART, to predict up to 8-year risk of clozapine use from FEP using routinely recorded information including age, sex, ethnicity, triglycerides, alkaline phosphatase levels, and lymphocyte counts. We also produced a least-absolute shrinkage and selection operator (LASSO) based model, additionally including neutrophil count, smoking status, body mass index, and random glucose levels. The models were developed using data from two UK psychosis early intervention services (EIS) and externally validated in another UK EIS. Model performance was assessed via discrimination and calibration. We developed the models in 785 patients, and validated externally in 1,110 patients. Both models predicted clozapine use well at internal validation (MOZART: C 0.70; 95%CI 0.63,0.76; LASSO: 0.69; 95%CI 0.63,0.77). At external validation, discrimination performance reduced (MOZART: 0.63; 0.58,0.69; LASSO: 0.64; 0.58,0.69) but recovered after re-estimation of the lymphocyte predictor (C: 0.67; 0.62,0.73). Calibration plots showed good agreement between observed and predicted risk in the forced-entry model. We also present a decision-curve analysis and an online data visualisation tool. The use of routinely collected clinical information including blood-based biomarkers taken at FEP onset can help to predict the individual risk of clozapine use, and should be considered equally alongside other potentially useful information such as symptom scores in large-scale efforts to predict psychiatric outcomes.

The size and anatomical complexity make giant intracranial aneurysms challenging surgical lesions. There is limited literature available for those arising from distal branches. The cases that have been reported in the literature have all presented with symptoms from a rupture leading to an intracranial haemorrhage. In this case report, the authors present a case of a giant aneurysm arising from a cortical branch of the middle cerebral artery presenting as an extra-axial tumour. A 76-year-old gentleman presented with a 2-day history of subjective left arm numbness. Imaging revealed a large conical right-sided parietal lesion. Intraoperatively, it was found that the lesion was being supplied by a single vascular pedicle. Histology was consistent with an aneurysm. In this case, that patient did not have any evidence of a rupture unlike all reported cases of cortical giant aneurysms. This case highlights the myriad location and presentation of giant intracranial aneurysms.

BACKGROUND: This cross-sectional study examined the relationship between socioeconomic status (SES), dietary knowledge and patterns, and physical activity level with body mass index of urban South African young women. METHODS: Data were collected on 160 black South African women (aged 18–24 years) and included household SES, food frequency and nutritional knowledge questionnaires, self-reported physical activity and anthropometry. To assess household SES index, 1–7 assets were categorised as a lower household SES and those with 8–13 assets as a higher household SES. Structural equation modelling analysis was used to determine the direct, indirect and total effects on adiposity of household SES, age, education, nutrition knowledge score, dietary patterns and physical activity. RESULTS: The prevalence of overweight and obesity was similar among women from high SES households compared with their low SES peers (48.4 vs. 44.8%). More than half (53%) of the women had poor dietary knowledge. Women from low SES households spent more time in moderate to vigorous intensity exercise (MVPA) compared with their high SES counterparts. Two distinct dietary patterns (Western and mixed) were identified. SEM results show that a unit increase in adherence to the ‘Mixed’ dietary pattern compared with ‘Western’ was associated with a 0.81 lower BMI kg/m2 (95% CI −1.54; −0.08), while ≥ 150 minutes’ MVPA per week was associated with a 1.94 lower BMI kg/m2 (95% CI −3.48; −0.41). CONCLUSION: The associations of SES, diet and physical activity on BMI must be taken into account when developing and designing interventions that target improvement in young women’s health.

Abstract. Emotion recognition ability of emotions expressed by other people (ERA-O) can be important for job performance, leadership, bargaining, and career success. Traditional personnel assessment tools of this ability, however, are contaminated by linguistic skills. In a time of global work migration, more and more people speak a language at work that is not their mother tongue. Consequently, we developed and validated the Face-Based Emotion Matching Test (FEMT), a nonlinguistic objective test of ERA-O in gainfully employed adults. We demonstrate the FEMT’s validity with psychological constructs (cognitive and emotional intelligence, Big Five personality traits) and its criterion validity and interethnic fit.

Attachment is an infant's inherent drive to seek comfort from their caregiver, particularly at times of perceived threat. A child can show a number of attachment patterns, with a secure attachment pattern linked to improved long term outcomes, such as healthy social and emotional development. A range of parenting interventions have been developed aiming to increase secure attachment. To understand what interventions are being used and the evidence base behind these a national survey of UK services was conducted to find about how attachment problems are assessed and treated. We identified the ten most commonly used interventions in UK practice. We then conducted two systematic reviews. One searched for all randomised controlled trial (RCT) evidence for any attachment parenting intervention. The second review searched for all available research focused on the ten interventions identified from the survey. For the first review, a meta-analysis showed parenting interventions are effective at increasing secure attachment in children. The second review found that the most commonly used interventions in UK services have a limited evidence base whereas the interventions with the most evidence are not as widely used. It is important to improve the integration of research and practice to develop the best care.

Gut microflora dysbiosis affects the majority of individuals after COVID-19, contributing to both gastro-intestinal (GI) and non-GI symptoms. Natural phytochemicals have reported anti-viral properties and favourable effects on inflammatory and oxidative pathways, both important for tissue damage post-viral pneumonia. This study involved 147 participants with symptomatic COVID-19, randomised to receive a placebo (P) or a phytochemical-rich concentrated food capsule (PC) in addition to a pre/probiotic lactobacillus capsule. Participants taking the PC had an almost two-fold reduction in mean fatigue scores compared to P [p = 0.02], a three-fold reduction in cough score and more than a double improvement in overall well-being scores [p = 0.02]. Two (1.5%) participants reported mild, increased bloating which they felt was attributable to the capsules, although GI symptoms improved in 25 of 31 participants (82%) who reported them at baseline. Sedentary, older, previously hospitalised men with GI symptoms had a statistically significantly improvement among those given the probiotic. Although some participants with early disease would have improved spontaneously, such a rapid improvement observed in the majority of participants, who had been suffering for an average of 108 days, was clinically relevant and welcomed, especially among those more likely to have pre-existing gut dysbiosis. We are now evaluating whether this blend could also enhance antibody titres post-COVID-19 vaccination.

As smartphone and wearable device ownership increase, interest in their utility to monitor physical activity has risen concurrently. Numerous examples of the application of wearables in clinical and epidemiological research settings already exist. However, whether these devices are all suitable for physical activity surveillance is open for debate. In this commentary, we respond to a commentary by Mair et al. (2021) and discuss four key issues specifically relevant to surveillance that we believe need to be tackled before consumer wearables can be considered for this measurement purpose: representative sampling, representative wear time, validity and reliability, and compatibility between devices. A recurring theme is how to deal with systematic biases by demographic groups. We suggest some potential solutions to the issues of concern such as providing individuals with standardized devices, considering summary metrics of physical activity less prone to wear time biases, and the development of a framework to harmonize estimates between device types and their inbuilt algorithms. We encourage collaborative efforts from researchers and consumer wearable manufacturers in this area. In the meantime, we caution against the use of consumer wearable device data for inference of population-level activity without the consideration of these issues.