Effects of a personalized nutrition program on cardiometabolic health: a randomized controlled trial.

Large variability exists in people's responses to foods. However, the efficacy of personalized dietary advice for health remains understudied. We compared a personalized dietary program (PDP) versus general advice (control) on cardiometabolic health using a randomized clinical trial. The PDP used food characteristics, individual postprandial glucose and triglyceride (TG) responses to foods, microbiomes and health history, to produce personalized food scores in an 18-week app-based program. The control group received standard care dietary advice (US Department of Agriculture Guidelines for Americans, 2020-2025) using online resources, check-ins, video lessons and a leaflet. Primary outcomes were serum low-density lipoprotein cholesterol and TG concentrations at baseline and at 18 weeks. Participants (n = 347), aged 41-70 years and generally representative of the average US population, were randomized to the PDP (n = 177) or control (n = 170). Intention-to-treat analysis (n = 347) between groups showed significant reduction in TGs (mean difference = -0.13 mmol l-1; log-transformed 95% confidence interval = -0.07 to -0.01, P = 0.016). Changes in low-density lipoprotein cholesterol were not significant. There were improvements in secondary outcomes, including body weight, waist circumference, HbA1c, diet quality and microbiome (beta-diversity) (P < 0.05), particularly in highly adherent PDP participants. However, blood pressure, insulin, glucose, C-peptide, apolipoprotein A1 and B, and postprandial TGs did not differ between groups. No serious intervention-related adverse events were reported. Following a personalized diet led to some improvements in cardiometabolic health compared to standard dietary advice. ClinicalTrials.gov registration: NCT05273268 .

Association between psoas major muscle mass and CPET performance and long-term survival following major colorectal surgery: A retrospective cohort study.

OBJECTIVES: To evaluate whether computed tomography (CT)-derived psoas major muscle measurements could predict preoperative cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery and to compare predictive performance of psoas muscle measurements using 2D approach and 3D approach. METHODS: A retrospective cohort study compliant with STROCSS standards was conducted. Consecutive patients undergoing major colorectal surgery between January 2011 and January 2017 following CPET as part of their preoperative assessment were included. Regression analyses were modelled to investigate association between the CT-derived psoas major muscle mass variables [total psoas muscle area (TPMA), total psoas muscle volume (TPMV) and psoas muscle index (PMI)] and CPET performance and mortality (1-year and 5-year). Discriminative performances of the variables were evaluated using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: A total of 457 eligible patients were included. The median TPMA and TPMV were 21 â€‹cm2 (IQR: 15-27) and 274 â€‹cm3 (IQR: 201-362), respectively. The median PMI measured via 2D and 3D approaches were 7 â€‹cm2/m2 (IQR: 6-9) and 99 â€‹cm3/m2 (IQR: 76-120), respectively. The risks of 1-year and 5-year mortality were 7.4% and 27.1%, respectively. Regression analyses showed TPMA, TPMV, and PMI can predict preoperative CPET performance and long-term mortality. However, ROC curve analyses showed no significant difference in predictive performance amongst TPMA, TPMV, and PMI. CONCLUSION: Radiologically-measured psoas muscle mass variables may predict preoperative CPET performance and may be helpful with informing more objective selection of patients for preoperative CPET and prehabilitation.

Multiscale Porous Poly (Ether-Ether-Ketone) Structures Manufactured by Powder Bed Fusion Process.

The aim of the study is to create a multiscale highly porous poly (ether-ether-ketone) (PEEK) structure while maintaining mechanical performance; the distribution of pores being generated by the manufacturing process combined with a porogen leaching operation. Salt at 70 wt% concentration was used as a porogen in a dry blend with PEEK powder sintered in the powder bed fusion process. The printed porous PEEK structures were examined and evaluated by scanning electron microscopy, microcomputed tomography, and mechanical testing. The PEEK structures incorporating 70 wt% salt achieved 79-86% porosity, a compressive yield strength of 4.1 MPa, and a yield strain of ∼60%. Due to the salt leaching process, the PEEK porous frameworks were fabricated without the need to drastically reduce the process parameters (defined by the energy density [ED]), hence maintaining the structural integrity and good mechanical performance. The compression results highlighted that the performance is influenced by the printing orientation, level of the PEEK particle coalescence (controlled here by the ED), pore/cell wall thickness, and subsequently, the overall porosity framework. The porous printed PEEK structures could find potential uses in a wide range of applications from tissue engineering, filtration and separation to catalysts, drug release, and gas storage.

Prototype Design for Grading Structures in Powder Bed Fusion Processes.

While targeted alignment in certain additive manufacturing (AM) methods such as material extrusion (MEX) and stereolithography (SLA) has been well documented in the research community, a method for targeted alignment of added fillers or fibrous materials in powder bed fusion (PBF) AM devices has yet to be successfully achieved. Similarly, incorporation of multimaterials does not work easily with any of the AM technologies. This study creates a prototype design that could be integrated into a PBF system to allow for multimaterial layer deposition and alignment of powders and powder blends. The rheological properties of polyamide powder and a range of polyamide composite blends (incorporating milled carbon fibre, graphite flakes, polytetrafluoroethylene, and glass microspheres) in different concentrations were studied, and together with the particle size distribution and particle morphology analysis were applied for the design of a prototype hopper for incorporation in the PBF system to create targeted multimaterial deposition. Different concept designs, multichambered and multi-hopper with hopper angles calculated specifically for the composite blend powders selected, were proposed. Initial deposition trials outside a PBF process were tested, and the deposited layers were measured.

Glycaemic variability, assessed with continuous glucose monitors, is associated with diet, lifestyle and health in people without diabetes.

Background: Continuous glucose monitors (CGMs) provide high-frequency information regarding daily glucose variation and are recognised as effective for improving glycaemic control in individuals living with diabetes. Despite increased use in individuals with non-diabetic blood glucose concentrations (euglycemia), their utility as a health tool in this population remains unclear. Objectives: To characterise variation in time in range (TIR) and glycaemic variability in large populations without diabetes or impaired glucose tolerance; describe associations between CGM-derived glycaemic metrics and metabolic and cardiometabolic health traits; identify key diet and lifestyle factors associated with TIR and glycaemic variability. Design: Glycaemic variability (coefficient of variation) and time spent in both the ADA secondary target range (TIRADA; 3.9-7.8 mmol/L) and a more stringent range (TIR3.9-5.6; 3.9-5.6 mmol/L) were calculated during free-living in PREDICT 1, PREDICT 2, and PREDICT 3 euglycaemic community-based volunteer cohorts. Associations between CGM derived glycaemic metrics, markers of cardiometabolic health, diet (food frequency questionnaire and logged diet records), diet-habits, and lifestyle were explored. Results: Data from N=4135 participants (Mean SD; Age: 47 12 y; Sex: 83% Female, BMI: 27 6 kg/m2). Median glycaemic variability was 14.8% (IQR 12.6-17.6%), median TIRADA was 95.8% (IQR 89.6-98.6%) and TIR3.9-5.6 was 75.0% (IQR 64.6-82.8%). Greater TIR3.9-5.6 was associated with lower HbA1c, ASCVD 10y risk and HOMA-IR (all p < 0.05). Lower glycaemic variability was associated with lower % energy derived from carbohydrate (rs: 0.17, p < 0.01), ultra-processed foods (NOVA 4, % EI; rs: 0.12, p = 0.01) and a longer overnight fasting duration (rs: -0.10, p = 0.01). Conclusions: A stringent TIR target provides sensitivity to detect changes in HOMA-IR, ASCVD 10 y risk and HbA1c that were not detected using ADA secondary targets. Associations among TIR, glycaemic variability, dietary intake (e.g. carbohydrate and protein) and habits (e.g. nocturnal fasting duration) highlight potential strategic targets to improve glycaemic metrics derived from continuous glucose monitors.

Extension of the Segatella copri complex to 13 species with distinct large extrachromosomal elements and associations with host conditions.

The Segatella copri (formerly Prevotella copri) complex (ScC) comprises taxa that are key members of the human gut microbiome. It was previously described to contain four distinct phylogenetic clades. Combining targeted isolation with large-scale metagenomic analysis, we defined 13 distinct Segatella copri-related species, expanding the ScC complex beyond four clades. Complete genome reconstruction of thirteen strains from seven species unveiled the presence of genetically diverse large circular extrachromosomal elements. These elements are consistently present in most ScC species, contributing to intra- and inter-species diversities. The nine species-level clades present in humans display striking differences in prevalence and intra-species genetic makeup across human populations. Based on a meta-analysis, we found reproducible associations between members of ScC and the male sex and positive correlations with lower visceral fat and favorable markers of cardiometabolic health. Our work uncovers genomic diversity within ScC, facilitating a better characterization of the human microbiome.

Powder Bed Fusion Versus Material Extrusion: A Comparative Case Study on Polyether-Ether-Ketone Cranial Implants.

As the choice of additive manufacturing (AM) technologies is becoming wider with reliable processes and a wider range of materials, the selection of the right technology to fabricate a certain product is becoming increasingly difficult from a technical and cost perspective. In this study polyether-ether-ketone cranial implants were manufactured by two AM techniques: powder bed fusion (PBF) and fused filament fabrication (FFF) and their dimensional accuracy, compression performance, and drop tower impact behavior were evaluated and compared. The results showed that both types of specimens differed from the original computer-aided design; although the origin of the deviation was different, the PBF samples were slightly inaccurate owing to the printing process where the accuracy of the FFF samples was influenced by postprocessing and removal of the scaffolds. The cranial implants fabricated using the FFF method absorbed more energy during the compression and impact tests in comparison with the PBF process. The failure mechanisms revealed that FFF samples have a higher ability to deform and a more consistent failure mechanisms, with the damage localized around the puncture head region. The brittle nature of the PBF samples, a feature observed with other polymers as well, led to complete failure of the cranial implants into several pieces.

Herring roe oil in treatment of psoriasis - influence on immune cells and cytokine network.

Background: Psoriasis is a chronic immune-mediated skin disease with systemic inflammation and comorbidities. Although the disease severity may vary over time, many patients suffer from mild to moderate disease. Often local treatment will be sufficient to control the symptoms, but they may have several side effects. ω-3 polyunsaturated fatty acids have shown promising results in clinical trials with mild-to-moderate psoriasis. Methods: We explored the impact of phospholipid bound docosahexaenoic acid and eicosapentaenoic acid in a 3:1 ratio on immune cells and cytokine networks in peripheral blood of patients with psoriasis. We investigated the inter-relation of plasma cytokine levels and disease severity in 58 patients, and explored the status of circulating immune cell activity in 18 patients with non-severe psoriasis before and during herring roe oil supplementation. Plasma concentration of 22 cytokines was measured by Luminex technology and circulating immune cells were analyzed by multicolor flow cytometry. Results: CCL2 levels decreased over time, and IFN-γR1 increased, possibly related to the action of ω-3 polyunsaturated fatty acids. We observed a shift from naïve to effector CD4+ T cells and decreases of CD38 expression on CD4+ and CD8+ T cells, CD56bright NK cells and CD14+CD16- classical monocytes. Conclusions: These findings support the beneficial effect of herring roe oil supplementation.

Exploring the relationship between social jetlag with gut microbial composition, diet and cardiometabolic health, in the ZOE PREDICT 1 cohort.

PURPOSE: In this study, we explore the relationship between social jetlag (SJL), a parameter of circadian misalignment, and gut microbial composition, diet and cardiometabolic health in the ZOE PREDICT 1 cohort (NCT03479866). METHODS: We assessed demographic, diet, cardiometabolic, stool metagenomics and postprandial metabolic measures (n = 1002). We used self-reported habitual sleep (n = 934) to calculate SJL (difference in mid-sleep time point of ≥ 1.5 h on week versus weekend days). We tested group differences (SJL vs no-SJL) in cardiometabolic markers and diet (ANCOVA) adjusting for sex, age, BMI, ethnicity, and socio-economic status. We performed comparisons of gut microbial composition using machine learning and association analyses on the species level genome bins present in at least 20% of the samples. RESULTS: The SJL group (16%, n = 145) had a greater proportion of males (39% vs 25%), shorter sleepers (average sleep < 7 h; 5% vs 3%), and were younger (38.4 ± 11.3y vs 46.8 ± 11.7y) compared to the no-SJL group. SJL was associated with a higher relative abundance of 9 gut bacteria and lower abundance of 8 gut bacteria (q < 0.2 and absolute Cohen's effect size > 0.2), in part mediated by diet. SJL was associated with unfavourable diet quality (less healthful Plant-based Diet Index), higher intakes of potatoes and sugar-sweetened beverages, and lower intakes of fruits, and nuts, and slightly higher markers of inflammation (GlycA and IL-6) compared with no-SJL (P < 0.05 adjusted for covariates); rendered non-significant after multiple testing adjustments. CONCLUSIONS: Novel associations between SJL and a more disadvantageous gut microbiome in a cohort of predominantly adequate sleepers highlight the potential implications of SJL for health.

Genetic and gut microbiome determinants of SCFA circulating and fecal levels, postprandial responses and links to chronic and acute inflammation.

Short-chain fatty acids (SCFA) are involved in immune system and inflammatory responses. We comprehensively assessed the host genetic and gut microbial contribution to a panel of eight serum and stool SCFAs in two cohorts (TwinsUK, n = 2507; ZOE PREDICT-1, n = 328), examined their postprandial changes and explored their links with chronic and acute inflammatory responses in healthy individuals and trauma patients. We report low concordance between circulating and fecal SCFAs, significant postprandial changes in most circulating SCFAs, and a heritable genetic component (average h2: serum = 14%(SD = 14%); stool = 12%(SD = 6%)). Furthermore, we find that gut microbiome can accurately predict their fecal levels (AUC>0.71) while presenting weaker associations with serum. Finally, we report different correlation patterns with inflammatory markers depending on the type of inflammatory response (chronic or acute trauma). Our results illustrate the breadth of the physiological relevance of SCFAs on human inflammatory and metabolic responses highlighting the need for a deeper understanding of this important class of molecules.

Management of Acute Cholecystitis in High-Risk Patients: Percutaneous Gallbladder Drainage as a Definitive Treatment vs. Emergency Cholecystectomy-Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review aims to investigate whether percutaneous transhepatic gallbladder biliary drainage (PTGBD) is superior to emergency cholecystectomy (EC) as a definitive treatment in high-risk patients with acute cholecystitis (AC). MATERIAL AND METHODS: A systematic literature search was performed until December 2022 using the Scopus, Medline/PubMed and Web of Science databases. RESULTS: Seventeen studies have been included with a total of 783,672 patients (32,634 treated with PTGBD vs. 4663 who underwent laparoscopic cholecystectomy, 343 who had open cholecystectomy and 746,032 who had some form of cholecystectomy, but without laparoscopic or open approach being specified). An analysis of the results shows that PTGBD, despite being less invasive, is not associated with lower morbidity with respect to EC (RR 0.77 95% CI [0.44 to 1.34]; I2 = 99%; p = 0.36). A lower postoperative mortality was reported in patients who underwent EC (2.37%) with respect to the PTGBD group (13.78%) (RR 4.21; 95% CI [2.69 to 6.58]; p < 0.00001); furthermore, the risk of hospital readmission for biliary complications (RR 2.19 95% CI [1.72 to 2.79]; I2 = 48%; p < 0.00001) and hospital stay (MD 4.29 95% CI [2.40 to 6.19]; p < 0.00001) were lower in the EC group. CONCLUSIONS: In our systematic review, the majority of studies have very low-quality evidence and more RCTs are needed; furthermore, PTGBD is inferior in the treatment of AC in high-risk patients. The definition of high-risk patients is important in interpreting the results, but the methods of assessment and definitions differ between studies. The results of our systematic review and meta-analysis failed to demonstrate any advantage of using PTGBD over ER as a definitive treatment of AC in critically ill patients, which suggests that EC should be considered as the treatment of choice even in very high-risk patients. Most likely, the inferiority of PTGBD versus early LC for high-risk patients is related to an association of various patient-side factor conditions and the severity of acute cholecystitis.

Inferior mesenteric artery ligation level in rectal cancer surgery: still no answer-a systematic review and meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis is to summarize the current scientific evidence regarding the impact of the level of inferior mesenteric artery (IMA) ligation on post-operative and oncological outcomes in rectal cancer surgery. METHODS: We conducted a systematic review of the literature up to 06 September 2022. Included were RCTs that compared patients who underwent high (HL) vs. anterior (LL) IMA ligation for resection of rectal cancer. The literature search was performed on Medline/PubMed, Scopus, and the Web of Science without any language restrictions. The primary endpoint was overall anastomotic leakage (AL). Secondary endpoints were oncological outcomes, intraoperative complications, urogenital functional outcomes, and length of hospital stay. RESULTS: Eleven RCTs (1331 patients) were included. The overall rate of AL was lower in the LL group, but the difference was not statistically significant (RR 1.43, 95% CI 0.95 to 2.96). The overall number of harvested lymph nodes was higher in the LL group, but the difference was not statistically significant (MD 0.93, 95% CI - 2.21 to 0.34). The number of lymph nodes harvested was assessed in 256 patients, and all had a laparoscopic procedure. The number of lymph nodes was higher when LL was associated with lymphadenectomy of the vascular root than when IMA was ligated at its origin, but there the difference was not statistically significant (MD - 0.37, 95% CI - 1.00 to 0.26). Overall survival at 5 years was slightly better in the LL group, but the difference was not statistically significant (RR 0.98, 95% CI 0.93 to 1.05). Disease-free survival at 5 years was higher in the LL group, but the difference was not statistically significant (RR 0.97, 95% CI 0.89 to 1.04). CONCLUSIONS: There is no evidence to support HL or LL according to results in terms of AL or oncologic outcome. Moreover, there is not enough evidence to determine the impact of the level of IMA ligation on functional outcomes. The level of IMA ligation should be chosen case by case based on expected functional and oncological outcomes.

Myths and methodologies: Cardiopulmonary exercise testing for surgical risk stratification in patients with an abdominal aortic aneurysm; balancing risk over benefit.

The extent to which patients with an abdominal aortic aneurysm (AAA) should exercise remains unclear, given theoretical concerns over the perceived risk of blood pressure-induced rupture, which is often catastrophic. This is especially pertinent during cardiopulmonary exercise testing, when patients are required to perform incremental exercise to symptom-limited exhaustion for the determination of cardiorespiratory fitness. This multimodal metric is being used increasingly as a complementary diagnostic tool to inform risk stratification and subsequent management of patients undergoing AAA surgery. In this review, we bring together a multidisciplinary group of physiologists, exercise scientists, anaesthetists, radiologists and surgeons to challenge the enduring 'myth' that AAA patients should be fearful of and avoid rigorous exercise. On the contrary, by appraising fundamental vascular mechanobiological forces associated with exercise, in conjunction with 'methodological' recommendations for risk mitigation specific to this patient population, we highlight that the benefits conferred by cardiopulmonary exercise testing and exercise training across the continuum of intensity far outweigh the short-term risks posed by potential AAA rupture.

Assessing cardiorespiratory fitness relative to sex improves surgical risk stratification.

BACKGROUND: To what extent sex-related differences in cardiorespiratory fitness (CRF) impact postoperative patient mortality and corresponding implications for surgical risk stratification remains to be established. METHODS: To examine this, we recruited 640 patients (366 males vs. 274 females) who underwent cardiopulmonary exercise testing prior to elective colorectal surgery. Patients were defined high risk if peak oxygen uptake was <14.3 mL kg-1  min-1 and ventilatory equivalent for carbon dioxide at 'anaerobic threshold' >34. Between-sex CRF and mortality was assessed, and sex-specific CRF thresholds predictive of mortality was calculated. RESULTS: Seventeen percent of deaths were attributed to sub-threshold CRF, which was higher than established risk factors for cardiovascular disease (CVD). The group (independent of sex) exhibited a 5-fold higher mortality (high vs. low risk patients hazard ratio = 4.80, 95% confidence interval 2.73-8.45, p < 0.001). Females exhibited 39% lower CRF (p < 0.001) with more classified high risk than males (36 vs. 23%, p = 0.001), yet mortality was not different (p = 0.544). Upon reformulation of sex-specific CRF thresholds, lower cut-offs for mortality were observed in females, and consequently, fewer (20%) were stratified with sub-threshold CRF compared to the original 36% (p < 0.001). CONCLUSIONS: Low CRF accounted for more deaths than traditional CVD risk factors, and when CRF was considered relative to sex, the disproportionate number of females stratified unfit was corrected. These findings support clinical consideration of 'sex-specific' CRF thresholds to better inform postoperative mortality and improve surgical risk stratification.

Extending and improving metagenomic taxonomic profiling with uncharacterized species using MetaPhlAn 4.

Metagenomic assembly enables new organism discovery from microbial communities, but it can only capture few abundant organisms from most metagenomes. Here we present MetaPhlAn 4, which integrates information from metagenome assemblies and microbial isolate genomes for more comprehensive metagenomic taxonomic profiling. From a curated collection of 1.01 M prokaryotic reference and metagenome-assembled genomes, we define unique marker genes for 26,970 species-level genome bins, 4,992 of them taxonomically unidentified at the species level. MetaPhlAn 4 explains ~20% more reads in most international human gut microbiomes and >40% in less-characterized environments such as the rumen microbiome and proves more accurate than available alternatives on synthetic evaluations while also reliably quantifying organisms with no cultured isolates. Application of the method to >24,500 metagenomes highlights previously undetected species to be strong biomarkers for host conditions and lifestyles in human and mouse microbiomes and shows that even previously uncharacterized species can be genetically profiled at the resolution of single microbial strains.

Does Prophylactic Negative-Pressure Wound Therapy Prevent Surgical Site Infection After Laparotomy? A Systematic Review and Meta-analysis of Randomized Controlled trials.

BACKGROUND: Prophylactic negative-pressure wound therapy (pNPWT) may prevent surgical site infection (SSI) after laparotomy, but existing meta-analyses pooling only high-quality evidence have failed to confirm this effect. Recently, several randomized controlled trials (RCTs) have been published. We performed an updated systematic review and meta-analysis to determine if pNPWT reduces the incidence of SSI after laparotomy. METHODS: MEDLINE, Embase, CENTRAL and Web of Science were searched on the 25.08.2021 for RCTs reporting on the incidence of SSI in patients who underwent laparotomy with and without pNPWT. The systematic review was compliant with the AMSTAR2 recommendation and registered into PROSPERO. Risk ratios (RR) for SSI in patients with pNPWT, and risk difference (RD) between control and pNPWT patients, were obtained using random effects models. Heterogeneity was quantified using the I2 value, and investigated using subgroup analyses, funnel plots and bubble plots. Risk of bias of included RCTs was assessed using the RoB2 tool. RESULTS: Eleven RCTs were included, representing 973 patients who received pNPWT and 970 patients who received standard wound dressing. Pooled RR and RD between patients with and without pNPWT were of, respectively, 0.665 (95% CI 0.49-0.91, I2: 38.7%, p = 0.0098) and -0.07 (95% CI -0.12 to -0.03, I2: 53.6%, p = 0.0018), therefore demonstrating that pNPWT decreases the incidence of SSI after laparotomy. Investigation of source of heterogeneity identified a potential small-study effect. CONCLUSION: The protective effect of pNPWT against SSI after laparotomy is confirmed by high-quality pooled evidence.

Factors Influencing Continued Wearable Device Use in Older Adult Populations: Quantitative Study.

BACKGROUND: The increased use of wearable sensor technology has highlighted the potential for remote telehealth services such as rehabilitation. Telehealth services incorporating wearable sensors are most likely to appeal to the older adult population in remote and rural areas, who may struggle with long commutes to clinics. However, the usability of such systems often discourages patients from adopting these services. OBJECTIVE: This study aimed to understand the usability factors that most influence whether an older adult will decide to continue using a wearable device. METHODS: Older adults across 4 different regions (Northern Ireland, Ireland, Sweden, and Finland) wore an activity tracker for 7 days under a free-living environment protocol. In total, 4 surveys were administered, and biometrics were measured by the researchers before the trial began. At the end of the trial period, the researchers administered 2 further surveys to gain insights into the perceived usability of the wearable device. These were the standardized System Usability Scale (SUS) and a custom usability questionnaire designed by the research team. Statistical analyses were performed to identify the key factors that affect participants' intention to continue using the wearable device in the future. Machine learning classifiers were used to provide an early prediction of the intention to continue using the wearable device. RESULTS: The study was conducted with older adult volunteers (N=65; mean age 70.52, SD 5.65 years) wearing a Xiaomi Mi Band 3 activity tracker for 7 days in a free-living environment. The results from the SUS survey showed no notable difference in perceived system usability regardless of region, sex, or age, eliminating the notion that usability perception differs based on geographical location, sex, or deviation in participants' age. There was also no statistically significant difference in SUS score between participants who had previously owned a wearable device and those who wore 1 or 2 devices during the trial. The bespoke usability questionnaire determined that the 2 most important factors that influenced an intention to continue device use in an older adult cohort were device comfort (τ=0.34) and whether the device was fit for purpose (τ=0.34). A computational model providing an early identifier of intention to continue device use was developed using these 2 features. Random forest classifiers were shown to provide the highest predictive performance (80% accuracy). After including the top 8 ranked questions from the bespoke questionnaire as features of our model, the accuracy increased to 88%. CONCLUSIONS: This study concludes that comfort and accuracy are the 2 main influencing factors in sustaining wearable device use. This study suggests that the reported factors influencing usability are transferable to other wearable sensor systems. Future work will aim to test this hypothesis using the same methodology on a cohort using other wearable technologies.

Time Is a Critical Factor When Evaluating Oligonucleotide Therapeutics in hERG Assays.

In accord with International Conference on Harmonization S7B guidelines, an in vitro human ether-a-go-go-related gene (hERG) assay is one component of an integrated risk assessment for delayed ventricular repolarization. Function of hERG could be affected by direct (acute) mechanisms, or by indirect (chronic) mechanisms. Some approved oligonucleotide therapeutics had submitted hERG data to regulatory agents, which were all collected with the same protocol used for small-molecule testing (incubation time <20 min; acute), however, oligonucleotides have unique mechanisms and time courses of action (indirect). To reframe the hERG testing strategy for silencing RNA (siRNA), an investigation was performed to assess the time course for siRNA-mediated inhibition of hERG function and gene expression. Commercially available siRNAs of hERG were evaluated in a stable hERG-expressed cell line by whole-cell voltage clamp using automated electrophysiology and polymerase chain reaction. In the acute hERG study, no effects were observed after treatment with 100 nM siRNA for 20 min. The chronic effects of 100 nM siRNAs on hERG function were evaluated and recorded over 8-48 h following transfection. At 8 h there was no significant effect, whereas 77% reduction was observed at 48 h. Measurement of hERG mRNA levels demonstrated a 79% and 93% decrease of hERG mRNA at 8 and 48 h, respectively, consistent with inhibition of hERG transcription. The results indicate that an anti-hERG siRNA requires a long exposure time (48 h) in the hERG assay to produce a maximal reduction in hERG current; short exposures (20 min-8 h) had no effect. These findings imply that off-target profiling of novel oligonucleotides could benefit from using hERG protocol with long incubation times to de-risk potential off-target (indirect) effects on the hERG channel. This hERG assay modification may be important to consider if the findings are used to support an integrated nonclinical-clinical risk assessment for QTc (the duration of the QT interval adjusted for heart rate) prolongation.