Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients.

Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.

How are ECG parameters related to cardiac magnetic resonance images? Electrocardiographic predictors of left ventricular hypertrophy and myocardial fibrosis in hypertrophic cardiomyopathy.

BACKGROUND: Structural myocardial changes in hypertrophic cardiomyopathy (HCM) are associated with different abnormalities on electrocardiographs (ECGs). The diagnostic value of the ECG voltage criteria used to screen for left ventricular hypertrophy (LVH) may depend on the presence and degree of myocardial fibrosis. Fibrosis can cause other changes in ECG parameters, such as pathological Q waves, fragmented QRS (fQRS), or repolarization abnormalities. METHODS: We investigated 146 patients with HCM and 35 healthy individuals who underwent cardiac magnetic resonance imaging (CMR; with late gadolinium enhancement [LGE] in HCM patients) and standard 12-lead ECGs. On the ECG, depolarization and repolarization abnormalities, the Sokolow-Lyon index, the Cornell index, and the Romhilt-Estes score were evaluated. The left ventricular ejection fraction, volumes, and myocardial mass (LVM) were quantified. Myocardial fibrosis was quantified on LGE images. RESULTS: The sensitivity of the Romhilt-Estes score was the highest (75%), and this hypertrophy criterion had the strongest correlation with the LVM index (p < .0001; r = .41). The amount of fibrosis was negatively correlated with the Cornell index (p = .015; r = -.201) and the Sokolow-Lyon index (p = .005; r = -.23), and the Romhilt-Estes score was independent of fibrosis (p = .757; r = 0.026). fQRS and strain pattern predicted more fibrosis, while the Cornell index was a negative predictor of myocardial fibrosis (p < .0001). Among others, the strain pattern was an independent predictor of the LVM (p < .0001). CONCLUSION: The Romhilt-Estes score is the most sensitive ECG criterion for detecting LVH in HCM patients, as myocardial fibrosis does not affect this criterion. The presence of fQRS and strain pattern predicts myocardial fibrosis.

Phase-frequency model of strongly pulse-coupled Belousov-Zhabotinsky oscillators.

We demonstrate that the dynamical behavior of strongly pulse-coupled Belousov-Zhabotinsky oscillators can be reproduced and predicted using a model that treats both the phase and the instantaneous frequency of the oscillators. Model parameters are extracted from the experimental data obtained using a single pulse-perturbed oscillator and are used to simulate the temporal dynamics of a system of two coupled oscillators. Our model exhibits the out-of-phase and anti-phase synchronization and the 1:N and N:M temporal patterns as well as the oscillator suppression that are observed in experiments when the inhibitory coupling is asymmetric. This approach may be adapted to other systems, such as coupled neurons, where the oscillatory dynamics is affected by strong pulses.

The insulin receptor is differentially expressed in somatic and visceral primary sensory neurons.

Recent studies demonstrated the expression of the insulin receptor (InsR) and its functional interaction with the transient receptor potential vanilloid type 1 receptor (TRPV1) in primary sensory neurons (PSNs). The present study was undertaken to reveal the target-specific expression of the InsR and its co-localization with the TRPV1 in rat PSNs. We assessed the localization of the InsR and its co-localization with the TRPV1 in PSNs retrogradely labelled with biotin-conjugated wheat germ agglutinin injected into the dorsal hind paw skin, the gastrocnemius muscle, the pancreas and the urinary bladder wall. The largest proportions of retrogradely labelled InsR-immunoreactive neurons were identified among PSNs serving the pancreas (~ 54%) and the urinary bladder (~ 53%). The proportions of retrogradely labelled InsR-immunoreactive neurons innervating the dorsal hind paw skin and the gastrocnemius muscle amounted to ~ 22 and ~ 21%. TRPV1-immunoreactive neurons amounted to ~ 63, ~ 62, ~ 67 and ~ 65% of retrogradely labelled cutaneous, muscle, pancreatic and urinary bladder PSNs, respectively. Co-localization of the TRPV1 with the InsR was observed in ~ 16, ~ 15, ~ 29 and ~ 30% of retrogradely labelled cutaneous, muscle, pancreatic and urinary bladder PSNs. These quantitative immunohistochemical data demonstrate a preponderance of InsR-immunoreactivity among PSNs, which innervate visceral targets. The present findings suggest that visceral spinal PSNs are more likely to be exposed to the modulatory effects of insulin on sensory functions, including neurotrophic, nociceptive and inflammatory processes.

Pulse-coupled Belousov-Zhabotinsky oscillators with frequency modulation.

Inhibitory perturbations to the ferroin-catalyzed Belousov-Zhabotinsky (BZ) chemical oscillator operated in a continuously fed stirred tank reactor cause long term changes to the limit cycle: the lengths of the cycles subsequent to the perturbation are longer than that of the unperturbed cycle, and the unperturbed limit cycle is recovered only after several cycles. The frequency of the BZ reaction strongly depends on the acid concentration of the medium. By adding strong acid or base to the perturbing solutions, the magnitude and the direction of the frequency changes concomitant to excitatory or inhibitory perturbations can be controlled independently of the coupling strength. The dynamics of two BZ oscillators coupled through perturbations carrying a coupling agent (activator or inhibitor) and a frequency modulator (strong acid or base) was explored using a numerical model of the system. Here, we report new complex temporal patterns: higher order, partially synchronized modes that develop when inhibitory coupling is combined with positive frequency modulation (FM), and complex bursting patterns when excitatory coupling is combined with negative FM. The role of time delay between the peak and perturbation (the analog of synaptic delays in networks of neurons) has also been studied. The complex patterns found under inhibitory coupling and positive FM vanish when the delay is significant, whereas a sufficiently long time delay is required for the complex temporal dynamics to occur when coupling is excitatory and FM is negative.

Mechanism of the Ferrocyanide-Iodate-Sulfite Oscillatory Chemical Reaction.

Existing models of the ferrocyanide-iodate-sulfite (FIS) reaction seek to replicate the oscillatory pH behavior that occurs in open systems. These models exhibit significant differences in the amplitudes and waveforms of the concentration oscillations of such intermediates as I(-), I3(-), and Fe(CN)6(3-) under identical conditions and do not include several experimentally found intermediates. Here we report measurements of sulfite concentrations during an oscillatory cycle. Knowing the correct concentration of sulfite over the course of a period is important because sulfite is the main component that determines the buffer capacity, the pH extrema, and the amount of oxidizer (iodate) required for the transition to low pH. On the basis of this new result and recent experimental findings on the rate laws and intermediates of component processes taken from the literature, we propose a mass action kinetics model that attempts to faithfully represent the chemistry of the FIS reaction. This new comprehensive mechanism reproduces the pH oscillations and the periodic behavior in [Fe(CN)6(3-)], [I3(-)], [I(-)], and [SO3(2-)]T with characteristics similar to those seen in experiments in both CSTR and semibatch arrangements. The parameter ranges at which stationary and oscillatory behavior is exhibited also show good agreement with those of the experiments.

Diabetes-related dysfunction of the small intestine and the colon: focus on motility.

In contrast to gastric dysfunction, diabetes-related functional impairments of the small and large intestine have been studied less intensively. The gastrointestinal tract accomplishes several functions, such as mixing and propulsion of luminal content, absorption and secretion of ions, water, and nutrients, defense against pathogens, and elimination of waste products. Diverse functions of the gut are regulated by complex interactions among its functional elements, including gut microbiota. The network-forming tissues, the enteric nervous system) and the interstitial cells of Cajal, are definitely impaired in diabetic patients, and their loss of function is closely related to the symptoms in diabetes, but changes of other elements could also play a role in the development of diabetes mellitus-related motility disorders. The development of our understanding over the recent years of the diabetes-induced dysfunctions in the small and large intestine are reviewed in this article.

Pulse-coupled BZ oscillators with unequal coupling strengths.

Coupled chemical oscillators are usually studied with symmetric coupling, either between identical oscillators or between oscillators whose frequencies differ. Asymmetric connectivity is important in neuroscience, where synaptic strength inequality in neural networks commonly occurs. While the properties of the individual oscillators in some coupled chemical systems may be readily changed, enforcing inequality between the connection strengths in a reciprocal coupling is more challenging. We recently demonstrated a novel way of coupling chemical oscillators, which allows for manipulation of individual connection strengths. Here we study two identical, pulse-coupled Belousov-Zhabotinsky (BZ) oscillators with unequal connection strengths. When the pulse perturbations contain KBr (inhibitor), this system exhibits simple out-of-phase and complex oscillations, oscillatory-suppressed states as well as temporally periodic patterns (N : M) in which the two oscillators exhibit different numbers of peaks per cycle. The N : M patterns emerge due to the long-term effect of the inhibitory pulse-perturbations, a feature that has not been considered in earlier works. Time delay was previously shown to have a profound effect on the system's behaviour when pulse coupling was inhibitory and the coupling strengths were equal. When the coupling is asymmetric, however, delay produces no qualitative change in behaviour, though the 1 : 2 temporal pattern becomes more robust. Asymmetry in instantaneous excitatory coupling via AgNO3 injection produces a previously unseen temporal pattern (1 : N patterns starting with a double peak) with time delay and high [AgNO3]. Numerical simulations of the behaviour agree well with theoretical predictions in asymmetrical pulse-coupled systems.

[Cardiovascular side effects of non-steroidal anti-inflammatory drugs in the light of recent recommendations. Diclofenac is not more dangerous]. / A nem szteroid gyulladásgátló készítmények cardiovascularis mellékhatásai a legújabb ajánlások fényében. Nem veszélyesebb a diclofenac.

Among their beneficial effects, non-steroidal anti-inflammatory drugs may also exert several side effects which depend on the dosage and the type of these medications. The most frequent gastrointestinal side effects usually develop shortly after the beginning of their administration, but others such as cardiovascular interactions (which are present much less frequently than gastrointestinal side effects) can also occur after the beginning of drug administration without a latency period. For a long-term treatment, non-steroidal anti-inflammatory drugs are most frequently used in the elderly population where patients typically have high cardiovascular risk and take other medicines, e.g. low dose acetylsalicylic acid that can interact with non-steroidal anti-inflammatory drugs; in this aspect diclofenac may cause less side effects. In this review, the authors briefly review cardiovascular side effects of non-steroidal anti-inflammatory drugs, the processes which potentially influence them, therapeutic consequences and their interaction with acetylsalicylic acid.

Diabetic gastroparesis: functional/morphologic background, diagnosis, and treatment options.

The regulation of gastrointestinal motility mainly involves the smooth muscle, neural (extrinsic and intrinsic), and hormonal elements, the glial cells, and the interstitial cells of Cajal. An orchestrated function of all these components is required for the appropriate propulsive movement of the food in the gastrointestinal tract. Gastroparesis, a pathological slowing-down of gastric emptying, is a result of the damage to the tissue elements involved in the regulation of motility. Gastroparesis is one of the well-known complications of long-standing diabetes mellitus. Although it is rarely a life-threatening complication, it has a deteriorating effect on the quality of life, leads to unpredictable oscillation of the blood glucose level, and increases the time required for the absorption of food and medicines. This review describes the clinical characteristics of diabetic gastroparesis and summarizes the organic and functional motility abnormalities caused by this complication. Finally, the currently available and potential future therapeutic approaches are summarized.

Periodic changes in the distribution of species observed in the Ni(2+)-histidine equilibrium coupled to the BrO3(-)-SO3(2-) pH oscillator.

The dynamical behavior of the system comprising of the pH-dependent complex formation between histidine and Ni(II) ions coupled to the BrO3(-)-SO3(2-) pH oscillator was studied. The pH oscillator was demonstrated to be capable of forcing the pH-sensitive nickel ion-histidine equilibrium to alternate periodically between the unreacted and the fully complexed states. The periodic interconversions gave rise to an oscillatory distribution of the species that participate in the equilibrium and resulted in oscillations in the free [Ni(2+)], [NiHis(+)], and [Ni(His)2]. The preconditions of the successful coupling of metal ion-amino acid complexes to a primary pH oscillator are briefly discussed. Model calculations were performed to simulate the dynamics observed in the BrO3(-)-SO3(2-) - Ni(2+)-His CSTR system.

No clear evidence of neuropathy among patients with high risk for the development of prediabetes/diabetes-a pilot study.

Introduction: Autonomic and sensory neuropathy have been observed in both prediabetes and manifest diabetes mellitus. However, there is a lack of available data regarding whether patients at a moderate or high risk of developing diabetes, yet without a current diagnosis of prediabetes or diabetes, exhibit an increased prevalence of neuropathy. Methods: FINDRISC (Finnish Diabetes Risk Score) was used to classify individuals at risk (≥12 points, n = 44; control <12 points, n = 28). HbA1c levels >5.6% served as exclusion criteria, and patients with known medical conditions predisposing to neuropathy were also excluded. Cardiac autonomic function (Ewing tests) and peripheral sensory neuropathy (Neurometer and Q-sense) were assessed by standardized protocols, and their potential association with increased FINDRISC points was analyzed using a regression model. Results: Mean age was 46.7 ± 14.3 years in the control and 55.7 ± 14.1 years in the increased risk group. Male/female ratio did not differ. Individuals with increased risk of diabetes were more obese (BMI: 29.9 ± 12.5 kg/m2 vs. 25.9 ± 8.9 kg/m2). Additionally, hypertension was more frequent among them (68.2% vs. 17.9%), and their lipid parameters were also less favorable. Parasympathetic neuropathy was present in both groups (56.8% vs. 32.1%, respectively). Sympathetic neuropathy was not found. Sensory nerve dysfunction was of low prevalence in the high-risk group and did not occur in healthy controls. In multiple logistic regression analysis, HbA1c exhibited an independent association with parasympathetic neuropathy (OR: 5.9; 95% CI: 1.08-32.68; p < 0.041). Discussion: An increased risk of developing prediabetes/diabetes does not appear to have a strong correlation with an increased likelihood of developing autonomic or sensory neuropathy. However, the etiology behind the occurrence of parasympathetic autonomic neuropathy in healthy individuals remains unknown.

Direct therapeutic effect of sulfadoxine-pyrimethamine on nutritional deficiency-induced enteric dysfunction in a human Intestine Chip.

BACKGROUND: Sulfadoxine-pyrimethamine (SP) antimalarial therapy has been suggested to potentially increase the birth weight of infants in pregnant women in sub-Saharan Africa, independently of malarial infection. Here, we utilized female intestinal organoid-derived cells cultured within microfluidic Organ Chips to investigate whether SP could directly impact intestinal function and thereby improve the absorption of essential fats and nutrients crucial for fetal growth. METHODS: Using a human organ-on-a-chip model, we replicated the adult female intestine with patient organoid-derived duodenal epithelial cells interfaced with human intestinal endothelial cells. Nutrient-deficient (ND) medium was perfused to simulate malnutrition, resulting in the appearance of enteric dysfunction indicators such as villus blunting, reduced mucus production, impaired nutrient absorption, and increased inflammatory cytokine secretion. SP was administered to these chips in the presence or absence of human peripheral blood mononuclear cells (PBMCs). FINDINGS: Our findings revealed that SP treatment effectively reversed multiple intestinal absorptive abnormalities observed in malnourished female Intestine Chips, as validated by transcriptomic and proteomic analyses. SP also reduced the production of inflammatory cytokines and suppressed the recruitment of PBMCs in ND chips. INTERPRETATION: Our results indicate that SP could potentially increase birth weights by preventing enteric dysfunction and suppressing intestinal inflammation. This underscores the potential of SP as a targeted intervention to improve maternal absorption, subsequently contributing to healthier fetal growth. While SP treatment shows promise in addressing malabsorption issues that can influence infant birth weight, we did not model pregnancy in our chips, and thus its usefulness for treatment of malnourished pregnant women requires further investigation through clinical trials. FUNDING: The Bill and Melinda Gates Foundation, and the Wyss Institute for Biologically Inspired Engineering at Harvard University, and the HDDC Organoid Core of the P30 DK034854.

The handgrip test - A historical test for diabetic autonomic neuropathy or a marker of something else?

Cardiovascular autonomic neuropathy (CAN) is a frequent complication of diabetes mellitus and is associated with increased morbidity and mortality in patients with diabetes. Hence, early and correct diagnosis of CAN is crucial. Standard cardiovascular reflex rests (CARTs) have been the gold standard of CAN assessment. Originally, CARTs consisted of five reflex tests, but measuring diastolic blood pressure response to sustained handgrip exercise has no longer been suggested as an established clinical test. Increasing body of evidence suggests that isometric handgrip test should no longer be used for the evaluation of sympathetic dysfunction during cardiovascular autonomic neuropathy assessment in diabetic patients. The associations of isometric handgrip test results with parameters of hypertension and markers of hypertension-related target-organ damage in diabetic and non-diabetic individuals point toward its potential role as a screening tool to identify patients with high cardiovascular risk. The current review summarizes historical view of standard cardiovascular reflex tests and latest data on isometric handgrip test.

Prevalence and determinants of diagnosed and undiagnosed diabetes in Hungary based on the nationally representative cross-sectional H-UNCOVER study.

AIMS: To estimate prevalence of diagnosed (dDM) and undiagnosed diabetes (uDM) in Hungary and investigate determinants of uDM. METHODS: Data was obtained from the nationally representative H-UNCOVER study. As laboratory measurements were available for 11/19 Hungarian counties, n = 5,974/17,787 people were eligible. After exclusions, 5,673 (representing 4,976,097 people) were included. dDM was defined by self-reporting, while uDM as negative self-reporting and elevated fasting glucose (≥7 mmol/l) and/or HbA1c (≥48 mmol/mol). Logistic regression for complex samples was used to calculate comparisons between dDM and uDM adjusted for age and BMI. RESULTS: Diabetes prevalence was 12.0 %/11.9 % (women/men, 95 %CI:10.7-13.4 %/10.7-13.2 %), while 2.2 %/2.8 % (1.7-2.8 %/2.2-3.6 %) of women/men were uDM. While the proportion of uDM vs. dDM was similar for women ≥ 40, men in their forties had the highest odds for uDM. Neither unemployment (women/men OR:0.58 [0.14-2.45]/0.50 [0.13-1.92]), nor education level (tertiary vs. primary; women/men OR: 1.16 [0.53-2.56]/ 0.53 [0.24-1.18]) were associated with uDM. The risk of uDM was lower in both sexes with chronic morbidities. CONCLUSIONS: We report higher prevalence of diabetes and undiagnosed diabetes than previous Hungarian estimates. The finding that socioeconomic factors are not associated to uDM suggests that universal health care could provide equitable access to diabetes diagnosis.

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic.

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Mucus production, host-microbiome interactions, hormone sensitivity, and innate immune responses modeled in human cervix chips.

Modulation of the cervix by steroid hormones and commensal microbiome play a central role in the health of the female reproductive tract. Here we describe organ-on-a-chip (Organ Chip) models that recreate the human cervical epithelial-stromal interface with a functional epithelial barrier and production of mucus with biochemical and hormone-responsive properties similar to living cervix. When Cervix Chips are populated with optimal healthy versus dysbiotic microbial communities (dominated by Lactobacillus crispatus and Gardnerella vaginalis, respectively), significant differences in tissue innate immune responses, barrier function, cell viability, proteome, and mucus composition are observed that are similar to those seen in vivo. Thus, human Cervix Organ Chips represent physiologically relevant in vitro models to study cervix physiology and host-microbiome interactions, and hence may be used as a preclinical testbed for development of therapeutic interventions to enhance women's health.

Comparison of Efficacy and Safety of Commercially Available Fixed-Ratio Combinations of Insulin Degludec/Liraglutide and Insulin Glargine/Lixisenatide: A Network Meta-analysis.

OBJECTIVES: Our aim in this study was to compare the efficacy and safety of commercially available fixed-ratio combinations (FRCs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and basal insulins by a network meta-analysis of randomized controlled trials (RCTs) of people with type 2 diabetes. METHODS: We present a systematic review and network meta-analyses of RCTs of individuals with type 2 diabetes randomized to FRCs or to their components for ≥24 weeks. All reports were obtained from PubMed or ClinicalTrials.gov up to February 28, 2022. The primary outcome was glycated hemoglobin (A1C) level attained. Secondary outcomes included fasting plasma glucose, change in body weight, and incident hypoglycemia. Treatment effects were estimated as mean difference (MD) and standard error (SE), or as odds ratio (OR) with 95% confidence interval (CI) using the fixed combination of insulin glargine 100 IU/mL and lixisenatide (iGlarLixi) as reference. RESULTS: We included 29 RCTs from among the 1,404 articles identified. No direct comparisons between FRCs were found. After excluding some insulin-capped trials to reach model consistency, both FRCs were more efficacious regarding A1C than their components, but no difference between FRCs was found (MD, -0.10%; SE, 0.10%). The effect of the fixed combination of insulin degludec and liraglutide (IDegLira) (MD, -0.47 mmol/L; SE, 0.24 mmol/L) and basal insulins was similar to that of iGlarLixi (reference) on fasting glucose, whereas GLP-1RAs had lower efficacy than iGlarLixi. Weight gain was lower with GLP-1RAs and IDegLira (MD, -0.72 kg; SE, 0.32 kg) than with iGlarLixi (reference) and higher with basal insulins. Incident hypoglycemia (based on different definitions) was least frequent with GLP-1RAs, followed by IDegLira (OR, 0.78; 95% CI, 0.39 to 1.57), iGlarLixi (reference), and basal insulins. CONCLUSIONS: For A1C, both FRCs were more efficacious over their individual components, with similar efficacies of the 2 FRCs.

The association between distal symmetric polyneuropathy in diabetes with all-cause mortality - a meta-analysis.

Background: Distal symmetric polyneuropathy (DSPN) is a common microvascular complication of both type 1 and 2 diabetes with substantial morbidity burden and reduced quality of life. Its association with mortality is equivocal. Purpose: To describe the association between DSPN and all-cause mortality in people with diabetes and further stratify by the type of diabetes based on a meta-analysis of published observational studies. Data Sources: We searched Medline from inception to May 2021. Study Selection: Original data were collected from case-control and cohort studies that reported on diabetes and DSPN status at baseline and all-cause mortality during follow-up. Data Extraction: was completed by diabetes specialists with clinical experience in neuropathy assessment. Data Synthesis: Data was synthesized using random-effects meta-analysis. The difference between type 1 and 2 diabetes was investigated using meta-regression. Results: A total of 31 cohorts (n=155,934 participants, median 27.4% with DSPN at baseline, all-cause mortality 12.3%) were included. Diabetes patients with DSPN had an almost twofold mortality (HR: 1.96, 95%CI: 1.68-2.27, I2 = 91.7%), I2 = 91.7%) compared to those without DSPN that was partly explained by baseline risk factors (adjusted HR: 1.60, 95%CI: 1.37-1.87, I2 = 78.86%). The association was stronger in type 1 compared to type 2 diabetes (HR: 2.22, 95%CI: 1.43-3.45). Findings were robust in sensitivity analyses without significant publication bias. Limitations: Not all papers reported multiple adjusted estimates. The definition of DSPN was heterogeneous. Conclusions: DSPN is associated with an almost twofold risk of death. If this association is causal, targeted therapy for DSPN could improve life expectancy of diabetic patients.