Rapid Access From Primary Care to a Multidisciplinary Clinic at Tertiary Care Improves Clinical Outcomes for Patients With Diabetic Foot Ulcers: Results From Diabetic Foot in Primary and Tertiary (DEFINITE) Care's Lower Extremity Amputation Prevention Program (LEAPP) Clinic.

Diabetic Foot in Primary and Tertiary (DEFINITE) Care is an inter-institutional, multidisciplinary team (MDT) program for patients with diabetic foot ulcers (DFU) within a healthcare cluster in Singapore. This is one of our subgroup analyses within DEFINITE Care, assessing clinical outcomes of lower extremity amputation prevention program (LEAPP), a multidisciplinary diabetic foot clinic, and non-LEAPP patients within the program. From June 2020 to June 2022, 2798 patients within the DEFINITE cohort completed a minimum of 12-month follow up. Of these patients, 20.6% were managed by LEAPP, whereas 79.4% were non-LEAPP patients. Patients in the LEAPP cohort were older with co-existing metabolic conditions and complications of diabetes. Using non-LEAPP cohort as the reference group and after adjusting for age, gender, ethnicity, comorbidities, and medications, there was a significantly lower risk of death (odds ratio [OR] 0.60, P = .001) and composite major lower extremity amputation (LEA) or death (OR 0.66, P = .002) among LEAPP patients at 1 year with longer mean days from enrollment to minor LEA, major LEA, and death. The adjusted 1-year healthcare utilization outcomes for LEAPP patients demonstrated an increase in inpatient admissions, primary care polyclinic visits, hospital specialist outpatient clinic (SOC) visits and elective day surgery procedures. Despite the increased in inpatients admissions, cumulative hospital length of stay in LEAPP patients were lower. This subgroup analysis has demonstrated that the MDT approach to caring for patients with DFU in tertiary centers not only improves mortality by 40%, but also delayed the incidence of minor LEA, major LEA, and death.

Functional Electrochemistry: On-Nerve Assessment of Electrode Materials for Electrochemistry and Functional Neurostimulation.

Emerging therapies in bioelectronic medicine highlight the need for deeper understanding of electrode material performance in the context of tissue stimulation. Electrochemical properties are characterized on the benchtop, facilitating standardization across experiments. On-nerve electrochemistry differs from benchtop characterization and the relationship between electrochemical performance and nerve activation thresholds are not commonly established. This relationship is important in understanding differences between electrical stimulation requirements and electrode performance. We report functional electrochemistry as a follow-up to benchtop testing, describing a novel experimental approach for evaluating on-nerve electrochemical performance in the context of nerve activation. An ex-vivo rat sciatic nerve preparation was developed to quantify activation thresholds of fiber subtypes and electrode material charge injection limits for platinum iridium, iridium oxide, titanium nitride and PEDOT. Finally, we address experimental complexities arising in these studies, and demonstrate statistical solutions that support rigorous material performance comparisons for decision making in neural interface development.

Glycated haemoglobin trajectories and one-year risk of potentially avoidable hospitalisations among adult patients with type 2 diabetes from specialist outpatient clinics of a tertiary hospital: A cohort study.

AIM: To evaluate the association between trajectories of glycated haemoglobin (HbA1c) and potentially avoidable hospitalisations (PAH). METHODS: We performed a cohort study in a tertiary hospital in Singapore among adult type 2 diabetes patients with ≥ 3 HbA1c tests over two years. Then, we followed up for one year after the last HbA1c reading to determine the PAH outcome. Glycaemic control was analysed by (1) HbA1c trajectories through group-based trajectory modelling, and (2) mean HbA1c. PAH was defined using the Agency of Healthcare Research and Quality criteria, categorising as overall, diabetes, acute, and chronic-composites. RESULTS: A total of 14,923 patients (mean age: 62.9 ± 12.8 years; 55.2% men) were included. Four HbA1c trajectories were observed; low-stable (n = 9854, 66.0%), moderate-stable (n = 3125, 20.9%), high-decrease (n = 1017, 6.8%) and high-persistent (n = 927, 6.2%). Compared to the low-stable trajectory, one-year risk ratio (RR) and 95% confidence interval (CI), respectively for moderate-stable, high-decrease and high-persistent trajectories were as follows: (1) overall PAH: 1.15 (1.00-1.31), 1.53 (1.31-1.80), 1.96 (1.58-2.43); (2) diabetes PAH: 1.30 (1.04-1.64), 1.98 (1.55-2.53), 2.24 (1.59-3.15); (3) acute PAH: 1.14 (0.90-1.44), 1.29 (0.95-1.77), 1.75 (1.17-2.62); and (4) chronic PAH: 1.21 (1.02-1.43), 1.62 (1.34-1.97), 2.14 (1.67-2.75). Mean HbA1c was significantly associated with overall and chronic-composites of PAH whilst evidence of a non-linear relationship with diabetes-composite of PAH was noted. CONCLUSION: Patients with high-decrease trajectory had a risk lower than those with persistently-high HbA1c, highlighting that a greater risk of hospitalisation conferred by poor glycaemic control is potentially reversible. Determining HbA1c trajectories could help to identify the high-risk individuals for targeted and intensive management to improve care and reduce hospitalisations.

Acute effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity and cardiorespiratory responses in dogs.

NEW FINDINGS: What is the central question of this study? What are the effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity in vivo and how do carotid body chemoreceptor stimulation-mediated cardiorespiratory responses in beagle dogs compare during euglycaemia and insulin-induced hypoglycaemia? What is the main finding and its importance? Intracarotid insulin administration leads to sustained increase in carotid body chemoreceptor activity and respiratory response with significant cardiovascular effects. Insulin-induced hypoglycaemia exacerbated NaCN-mediated carotid body chemoreceptor activity and respiratory response with enhanced cardiovascular reflex response. These findings suggest that insulin-induced hypoglycaemia augments the carotid body chemoreceptors to initiate the adaptive counter-regulatory responses to restore the normoglycaemic condition. ABSTRACT: The carotid body chemoreceptors (CBC) play an important role in the adaptive counter-regulatory response to hypoglycaemia by evoking the CBC-mediated sympathetic neuronal system to restore normoglycaemia. Ex vivo studies have shown varied responses of insulin-induced hypoglycaemia on CBC function, and several in vivo studies have indirectly established the role of CBCs in restoring normoglycaemia in both animals and humans. However, a direct effect of insulin and/or insulin-induced hypoglycaemia on CBC activity is not established in animal models. Therefore, the aim of this study was to evaluate in vivo effects of insulin and insulin-induced hypoglycaemia on CBC activity and cardiorespiration in a preclinical large animal model. The carotid sinus nerve (CSN) activity and cardiorespiratory responses to sodium cyanide (NaCN; 25 µg/kg) were compared before (euglycaemic) and after (hypoglycaemic) intracarotid administration of insulin (12.5-100 µU/dogs) in beagle dogs. Insulin administration increased CSN activity and minute ventilation ( V ̇ $\dot V$ E ) with significant (P < 0.0001) effects on heart rate and blood pressure. Insulin-mediated effects on CSN and cardiorespiration were sustained and the change in V ̇ $\dot V$ E was driven by tidal volume only. Insulin significantly (P < 0.0001) lowered blood glucose level. NaCN-mediated CSN activity and V ̇ $\dot V$ E were significantly (P < 0.0001) augmented during insulin-induced hypoglycaemia. The augmented V ̇ $\dot V$ E was primarily driven by respiratory frequency and partially by tidal volume. The cardiovascular reflex response mediated through CBC stimulation was significantly (P < 0.0001) exacerbated during insulin-induced hypoglycaemia. Collectively, these results demonstrate direct effects of insulin and insulin-induced hypoglycaemia on CBC chemosensitivity to potentiate CBC-mediated neuroregulatory pathways to initiate adaptive neuroendocrine and cardiorespiratory counter-regulatory responses to restore normoglycaemia.

Diabetic foot in primary and tertiary (DEFINITE) Care: A health services innovation in coordination of diabetic foot ulcer (DFU) Care within a healthcare cluster - 18-month results from an observational population health cohort study.

Diabetic Foot in Primary and Tertiary (DEFINITE) Care is an inter-institutional and multi-disciplinary team (MDT) health systems innovation programme at a healthcare cluster in Singapore. We aim to achieve coordinated MDT care across primary and tertiary care for patients with diabetic foot ulcers (DFU), within our public healthcare cluster - an integrated network of seven primary care polyclinics and two acute care tertiary hospitals (1700-bed and 800-bed) with a total catchment population of 2.2 million residents. Results from prospective DEFINITE Care is referenced against a retrospective 2013-2017 cohort, which was previously published. Cardiovascular profile of the study population is compared against the same population's profile in the preceding 12 months. Between June 2020 and December 2021, there were 3475 unique patients with DFU with mean age at 65.9 years, 61.2% male, mean baseline HbA1c at 8.3% with mean diabetes duration at 13.3 years, mean diabetes complication severity index (DCSI) at 5.6 and mean Charlson Comorbidity Index (CCI) at 6.8. In the 12-months preceding enrolment to DEFINITE Care, 35.5% had surgical foot debridement, 21.2% had minor lower extremity amputation (LEA), 7.5% had major LEA whilst 16.8% had revascularisation procedures. At 18-months after the implementation of DEFINITE Care programme, the absolute minor and major amputation rates were 8.7% (n = 302) and 5.1% (n = 176), respectively, equating to a minor and major LEA per 100000 population at 13.7 and 8.0, respectively. This represents an 80% reduction in minor amputation rates (P < .001) and a 35% reduction in major amputation rates (P = .005) when referenced against a retrospective 2013-2017 cohort, which had minor and major LEA per 100000 population at 68.9 and 12.4, respectively. As compared to the preceding 12 months, there was also a significant improvement in cardiovascular profile (glycemic and lipid control) within the DEFINITE population, with improved mean HbAc1 (7.9% from 8.4%, P < .001), low-density lipoprotein (LDL) levels (2.1 mmol/L from 2.2, P < .001), total cholesterol (3.9 mmol/L from 4.1, P < .001) and triglycerides levels (1.6 mmol/L from 1.8, P = .002). Multivariate analysis revealed a history of minor amputation in the preceding 12 months to be an independent predictor for major and minor amputation within the study period of 18 months (Hazard Ratio 3.4 and 1.8, respectively, P < .001). In conclusion, within DEFINITE care, 18-month data showed a significant reduction of minor and major LEA rates, with improved medical optimisation and cardiovascular profile within the study population.

Splenic arterial neurovascular bundle stimulation in esophagectomy: A feasibility and safety prospective cohort study.

Introduction: The autonomic nervous system is a key regulator of inflammation. Electrical stimulation of the vagus nerve has been shown to have some preclinical efficacy. However, only a few clinical studies have been reported to treat inflammatory diseases. The present study evaluates, for the first time, neuromodulation of the splenic arterial neurovascular bundle (SpA NVB) in patients undergoing minimally invasive esophagectomy (MIE), in which the SpA NVB is exposed as part of the procedure. Methods: This single-center, single-arm study enrolled 13 patients undergoing MIE. During the abdominal phase of the MIE, a novel cuff was placed around the SpA NVB, and stimulation was applied. The primary endpoint was the feasibility and safety of cuff application and removal. A secondary endpoint included the impact of stimulation on SpA blood flow changes during the stimulation, and an exploratory point was C-reactive protein (CRP) levels on postoperative day (POD) 2 and 3. Results: All patients successfully underwent placement, stimulation, and removal of the cuff on the SpA NVB with no adverse events related to the investigational procedure. Stimulation was associated with an overall reduction in splenic arterial blood flow but not with changes in blood pressure or heart rate. When compared to historic Propensity Score Matched (PSM) controls, CRP levels on POD2 (124 vs. 197 mg/ml, p = 0.032) and POD3 (151 vs. 221 mg/ml, p = 0.033) were lower in patients receiving stimulation. Conclusion: This first-in-human study demonstrated for the first time that applying a cuff around the SpA NVB and subsequent stimulation is safe, feasible, and may have an effect on the postoperative inflammatory response following MIE. These findings suggest that SpA NVB stimulation may offer a new method for immunomodulatory therapy in acute or chronic inflammatory conditions.

Clinical and economic outcomes of a multidisciplinary team approach in a lower extremity amputation prevention programme for diabetic foot ulcer care in an Asian population: A case-control study.

Present guidelines recommend a multidisciplinary team (MDT) approach to diabetic foot ulcer (DFU) care, but relevant data from Asia are lacking. We aim to evaluate the clinical and economic outcomes of an MDT approach in a lower extremity amputation prevention programme (LEAPP) for DFU care in an Asian population. We performed a case-control study of 84 patients with DFU between January 2017 and October 2017 (retrospective control) vs 117 patients with DFU between December 2017 and July 2018 (prospective LEAPP cohort). Comparing the clinical outcomes between the retrospective cohort and the LEAPP cohort, there was a significant decrease in mean time from referral to index clinic visit (38.6 vs 9.5 days, P < .001), increase in outpatient podiatry follow-up (33% vs 76%, P < .001), decrease in 1-year minor amputation rate (14% vs 3%, P = .007), and decrease in 1-year major amputation rate (9% vs 3%, P = .05). Simulation of cost avoidance demonstrated an annualised cost avoidance of USD $1.86m (SGD $2.5m) for patients within the LEAPP cohort. In conclusion, similar to the data from Western societies, an MDT approach in an Asian population, via a LEAPP for patients with DFU, demonstrated a significant reduction in minor and major amputation rates, with annualised cost avoidance of USD $1.86m.

Autologous protein solution: a promising solution for osteoarthritis?

Osteoarthritis (OA) is a global health issue with myriad pathophysiological factors and is one of the most common causes of chronic disability in adults due to pain and altered joint function.The end stage of OA develops from a destructive inflammatory cycle, driven by the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and tumour necrosis factor alpha (TNFα).Owing to the less predictable results of total knee arthroplasty (TKA) in younger patients presenting with knee OA, there has been a surge in research evaluating less invasive biological treatment options, one of which is autologous protein solution (APS).APS is an autologous blood derivative obtained by using a proprietary device, made of APS separator, which isolates white blood cells (WBCs) and platelets in a small volume of plasma, and APS concentrator, which further concentrates platelets, WBCs and plasma proteins, resulting in a concentrated solution with high levels of growth factors including the anti-inflammatory mediators against IL-1ß and TNFα.A single intraarticular injection of APS appears to be a promising solution for treatment of early-stage OA from current evidence, the majority of which comes from preclinical studies.More clinical studies are needed before APS can be widely accepted as a treatment modality for OA. Cite this article: EFORT Open Rev 2021;6:716-726. DOI: 10.1302/2058-5241.6.200040.

Metabolic effects of brown fat in transitioning from hyperthyroidism to euthyroidism.

OBJECTIVE: Brown adipose tissue (BAT) controls metabolic rate through thermogenesis. As its regulatory factors during the transition from hyperthyroidism to euthyroidism are not well established, our study investigated the relationships between supraclavicular brown adipose tissue (sBAT) activity and physiological/metabolic changes with changes in thyroid status. DESIGN: Participants with newly diagnosed Graves' disease were recruited. A thionamide antithyroid drug (ATD) such as carbimazole (CMZ) or thiamazole (TMZ) was prescribed in every case. All underwent energy expenditure (EE) measurement and supraclavicular infrared thermography (IRT) within a chamber calorimeter, as well as 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scanning, with clinical and biochemical parameters measured during hyperthyroidism and repeated in early euthyroidism. PET sBAT mean/maximum standardized uptake value (SUV mean/max), MR supraclavicular fat fraction (sFF) and mean temperature (Tscv) quantified sBAT activity. RESULTS: Twenty-one (16 female/5 male) participants aged 39.5 ± 2.5 years completed the study. The average duration to attain euthyroidism was 28.6 ± 2.3 weeks. Eight participants were BAT-positive while 13 were BAT-negative. sFF increased with euthyroidism (72.3 ± 1.4% to 76.8 ± 1.4%; P < 0.01), but no changes were observed in PET SUV mean and Tscv. Significant changes in serum-free triiodothyronine (FT3) levels were related to BAT status (interaction P value = 0.04). FT3 concentration at hyperthyroid state was positively associated with sBAT PET SUV mean (r = 0.58, P = 0.01) and resting metabolic rate (RMR) (P < 0.01). CONCLUSION: Hyperthyroidism does not consistently lead to a detectable increase in BAT activity. FT3 reduction during the transition to euthyroidism correlated with BAT activity.

Postoperative delirium following total joint arthroplasties in a multi-ethnic population - A prospective observational study.

BACKGROUND: Postoperative delirium (POD) is a cause of poorer patient outcomes following total joint arthroplasties (TJA). However, it often goes undiagnosed. Although various risk factors have been documented, study heterogeneity leads to poor understanding within a South East Asian population. This study aims to evaluate POD within this demographic and elucidate its risk factors. METHODS: This was a single-centre prospective observational study comprising 462 patients. Inclusion criteria was patients 65-90 years old undergoing elective TJA. Exclusion criteria was patients unable to personally provide consent for TJA. Preoperative, intraoperative, and postoperative data was recorded to analyse treatment pathway factors. Patients were assessed for POD twice daily for 3 days after TJA using the Confusion Assessment Method (CAM). RESULTS: Mean age of the study cohort was 72 ± 5 years; 70.1% were female; and mean MMSE score preoperatively was 27.3 ± 3.3. 419 patients underwent total knee arthroplasty (TKA) and 43 patients underwent total hip arthroplasty (THA). 164 patients received general anaesthesia, and 298 patients received regional anaesthesia. Overall, 0% (0/462) of patients tested positive for POD at any postoperative timepoint. While various CAM components were met, no patients were positive for the complete requisite criteria for POD diagnosis. CONCLUSION: We report zero incidence of POD in 462 patients who underwent elective TJA in our institution. We believe that our streamlined care process including pre-operative assessment, patient-specific anaesthesia regime as well as a strictly administered inpatient clinical care pathway with opioid-reducing strategy and early mobilization are protective factors against POD.

Psychometric properties of the thyroid-specific quality of life questionnaire ThyPRO in Singaporean patients with Graves' disease.

BACKGROUND: Graves' disease is the most common cause of hyperthyroidism. It results in accelerated tissue metabolism with multi-organ involvement ranging from cardiovascular to neuropsychological function. This results in a negative impact on the quality of life (QOL) of the individual patient. We aim to evaluate the psychometric properties of ThyPRO, a Thyroid-related Patient Reported Outcome questionnaire, and validate its use in our multi-ethnic Asian patients with Graves' hyperthyroidism. METHODS: Forty-seven consecutive Graves' hyperthyroidism patients answered the ThyPRO questionnaire at baseline and at 4 months after treatment initiation. Data were recorded for thyroid related symptoms and signs, thyroid function tests and thyroid volume. We analyzed the internal consistency using Cronbach's alpha, construct validity by evaluating relationship between clinical variables and ThyPRO scales, ceiling and floor effects, and responsiveness of ThyPRO to treatment based on Cohen's effect size. RESULTS: Correlations between individual scale scores and free thyroxine concentrations were moderate and statistically significant: 0.21-0.64 (p <  0.05). There was high internal consistency between the items in this instrument, Cronbach's alpha > 0.7 for all scales. ThyPRO was responsive to the changes in QOL after treatment (Effect Size: 0.20-0.77) in 9 of the 14 scales including the hyperthyroid symptoms and psychosocial scales (Tiredness, Cognitive complaints, Anxiety, Emotional susceptibility, Impact on Social, Daily and Sex life). CONCLUSION: This study provides evidence that ThyPRO has satisfactory measurement properties in hyperthyroid Graves' disease patients in Singapore population with the potential to complement clinical care.

Human-relevant near-organ neuromodulation of the immune system via the splenic nerve.

Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve-induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

Diabetes Care During COVID-19 Pandemic in Singapore Using a Telehealth Strategy.

Singapore currently has one of highest number of confirmed COVID-19 cases in Southeast Asia. To curb the further spread of COVID-19, Singapore government announced a temporary nationwide lockdown (circuit breaker). In view of restrictions of patients' mobility and the enforcement of safe distancing measures, usual in-person visits were discouraged. Here we describe how diabetes care delivery was ad hoc redesigned applying a telehealth strategy. We describe a retrospective assessment of subjects with diabetes, with and without COVID-19 infection, during the circuit breaker period of 7th April to 1st June 2020 managed through Tan Tock Seng Hospital's telehealth platform. The virtual health applications consisted of telephone consultations, video telehealth visits via smartphones, and remote patient monitoring. The TTSH team intensively managed 298 diabetes patients using a telehealth strategy. The group comprised of (1) 84 inpatient COVID-19 patients with diabetes who received virtual diabetes education and blood glucose management during their hospitalisation and follow-up via phone calls after discharge and (2) 214 (n=192 non-COVID; n=22 COVID-positive) outpatient subjects with suboptimal glycaemic control who received intensive diabetes care through telehealth approaches. Remote continuous glucose monitoring was applied in 80 patients to facilitate treatment adjustment and hypoglycaemia prevention. The COVID-19 pandemic situation mooted an immediate disruptive transformation of healthcare processes. Virtual health applications were found to be safe, effective and efficient to replace current in-person visits.

Model-based geometrical optimisation and in vivo validation of a spatially selective multielectrode cuff array for vagus nerve neuromodulation.

BACKGROUND: Neuromodulation by electrical stimulation of the human cervical vagus nerve may be limited by adverse side effects due to stimulation of off-target organs. It may be possible to overcome this by spatially selective stimulation of peripheral nerves. Preliminary studies have shown this is possible using a cylindrical multielectrode human-sized nerve cuff in vagus nerve selective neuromodulation. NEW METHOD: The model-based optimisation method for multi-electrode geometric design is presented. The method was applied for vagus nerve cuff array and suggested two rings of 14 electrodes, 3 mm apart, with 0.4 mm electrode width and separation and length 0.5-3 mm, with stimulation through a pair in the same radial position on the two rings. The electrodes were fabricated using PDMS-embedded stainless steel foil and PEDOT: pTS coating. RESULTS: In the cervical vagus nerve in anaesthetised sheep, it was possible to selectively reduce the respiratory breath rate (RBR) by 85 ± 5% without affecting heart rate, or selectively reduce heart rate (HR) by 20 ± 7% without affecting respiratory rate. The cardiac- and pulmonary-specific sites on the nerve cross-sectional perimeter were localised with a radial separation of 105 ± 5 degrees (P < 0.01, N = 24 in 12 sheep). CONCLUSIONS: Results suggest organotopic or function-specific organisation of neural fibres in the cervical vagus nerve. The optimised electrode array demonstrated selective electrical neuromodulation without adverse side effects. It may be possible to translate this to improved treatment by electrical autonomic neuromodulation for currently intractable conditions.

Statin use is associated with lower disease severity in COVID-19 infection.

We aim to study the association of hyperlipidemia and statin use with COVID-19 severity. We analysed a retrospective cohort of 717 patients admitted to a tertiary centre in Singapore for COVID-19 infection. Clinical outcomes of interest were oxygen saturation ≤ 94% requiring supplemental oxygen, intensive-care unit (ICU) admission, invasive mechanical-ventilation and death. Patients on long term dyslipidaemia medications (statins, fibrates or ezetimibe) were considered to have dyslipidaemia. Logistic regression models were used to study the association between dyslipidaemia and clinical outcomes adjusted for age, gender and ethnicity. Statin treatment effect was determined, in a nested case-control design, through logistic treatment models with 1:3 propensity matching for age, gender and ethnicity. All statistical tests were two-sided, and statistical significance was taken as p < 0.05. One hundred fifty-six (21.8%) patients had dyslipidaemia and 97% of these were on statins. Logistic treatment models showed a lower chance of ICU admission for statin users when compared to non-statin users (ATET: Coeff (risk difference): - 0.12 (- 0.23, - 0.01); p = 0.028). There were no other significant differences in other outcomes. Statin use was independently associated with lower ICU admission. This supports current practice to continue prescription of statins in COVID-19 patients.

Quantification of clinically applicable stimulation parameters for precision near-organ neuromodulation of human splenic nerves.

Neuromodulation is a new therapeutic pathway to treat inflammatory conditions by modulating the electrical signalling pattern of the autonomic connections to the spleen. However, targeting this sub-division of the nervous system presents specific challenges in translating nerve stimulation parameters. Firstly, autonomic nerves are typically embedded non-uniformly among visceral and connective tissues with complex interfacing requirements. Secondly, these nerves contain axons with populations of varying phenotypes leading to complexities for axon engagement and activation. Thirdly, clinical translational of methodologies attained using preclinical animal models are limited due to heterogeneity of the intra- and inter-species comparative anatomy and physiology. Here we demonstrate how this can be accomplished by the use of in silico modelling of target anatomy, and validation of these estimations through ex vivo human tissue electrophysiology studies. Neuroelectrical models are developed to address the challenges in translation of parameters, which provides strong input criteria for device design and dose selection prior to a first-in-human trial.

Printable microscale interfaces for long-term peripheral nerve mapping and precision control.

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying peripheral interfacing technologies. Here, we present a microscale implantable device - the nanoclip - for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high signal-to-noise ratio recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation within the confines of the small device can achieve multi-dimensional control of a small nerve. These results highlight the potential of new microscale design and fabrication techniques for realizing viable devices for long-term peripheral interfacing.

Impact of Vitamin E supplementation on vascular function in haptoglobin genotype stratified diabetes patients (EVAS Trial): a randomised controlled trial.

AIMS: Vitamin E (Vit-E) may preferentially improve cardiovascular risk in haptoglobin 2-2 (Hp2-2) genotype diabetes individuals. We studied the impact of Vit-E supplementation on vascular function in diabetes individuals stratified by haptoglobin genotype in Singapore. METHODS: In this 24-week, double blind, placebo-controlled RCT, we recruited 187 subjects (101 Hp2-2, 86 non-Hp2-2). INTERVENTION: alpha-tocopherol-400 IU. PRIMARY OUTCOME: Change in EndoPAT-derived reactive-hyperaemia index (RHI) and augmentation index (AIx); Secondary Outcomes: Pulse-Wave velocity (Sphygmocor-PWV), carotid intima media thickness (CIMT), inflammation (hsCRP), derivatives of reactive-oxygen metabolites (dROMs), biological antioxidant-potential (BAPs), HbA1c, LDL-C, HDL-C and oxidised LDL-C (ox-LDL). RESULTS: Overall, with Vit-E supplementation no significant change in RHI, PWV, CIMT, hsCRP, dROMS, BAPs, HDL-C and HbA1c was observed (p > 0.05); an increase in LDL-C with concomitant decrease in ox-LDL, and incidentally increase in eGFR was observed (p < 0.05). No interaction effect with haptoglobin genotype was seen for all outcomes (p > 0.05). Subgroup analysis: In the non-Hp-2-2 group, Vit-E supplementation led to a higher EndoPAT-derived AIx, accompanied by higher LDL and ox-LDL concentrations (p < 0.05); Hp2-2 group: Vit-E supplementation led to higher eGFR when compared to the non-Hp2-2 group (exploratory) (p < 0.05). We observed an interaction effect for baseline haptoglobin concentration (threshold > 119 mg/dl) with intervention in terms of increased EndoPAT-derived AIx in the Hp > 119 mg/dl group whereas no change in the group with Hp ≤ 119 mg/dl. CONCLUSION: Vit-E supplementation did not show any preferential benefit or deleterious effect on vascular function in Hp2-2 diabetes subjects in Singapore. A possible deleterious effect of an increase in arterial stiffness in individuals with Hp > 119 mg/dl was observed. Future studies should consider personalisation based on baseline Hp concentrations in patients with T2DM rather than just Hp2-2 genotype to evaluate impact on the detailed lipid pathways, cardiac and renal physiology. The impact of ethnic differences needs to be explored in greater details.