Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS: 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Plug-and-play DPC-based quantitative phase microscope.

Point-of-care testing (POCT) plays an increasingly important role in biomedical research and health care. Quantitative phase microscopes (QPMs) with good contrast, no invasion, no labeling, high speed and automation could be effectively applied for POCT. However, most QPMs are fixed on the optical platform with bulky size, lack of timeliness, which remained challenging in POCT solutions. In this paper, we proposed a plug-and-play QPM with multimode imaging based on the quantitative differential phase contrast (qDPC) method. The system employs a programmable LED array as the light source and uses the GPU to accelerate the calculation, which can realize multi-contrast imaging with six modes. Accurate phase measurement and real-time phase imaging are implemented by the proposed qDPC algorithms for quantitative phase targets and biomedical samples. A 3D electric control platform is designed for mechanical control of field of view and focusing without manual operations. The experimental results verify the robustness and high performance of the setup. Even a rookie could finish the POCT scheme for biomedical applications at the scene using the QPM with a compact size of 140 × 165 × 250 mm3.

The discrepancy in timing between synchronous signals and visual stimulation should not be underestimated.

Response latency is a critical parameter in studying human behavior, representing the time interval between the onset of stimulus and the response. However, different time between devices can introduce errors. Serial port synchronization signal can mitigate this, but limited information is available regarding their accuracy. Optical signals offer another option, but the difference in the positioning of optical signals and visual stimuli can introduce errors, and there have been limited reports of error reduction. This study aims to investigate methods for reducing the time errors. We used the Psychtoolbox to generate visual stimuli and serial port synchronization signals to explore their accuracy. Subsequently, we proposed a calibration formula to minimize the error between optical signals and visual stimuli. The findings are as follows: Firstly, the serial port synchronization signal presenting precedes visual stimulation, with a smaller lead time observed at higher refresh rates. Secondly, the lead time increases as the stimulus position deviates to the right and downwards. In Linux and IOPort(), serial port synchronization signals exhibited greater accuracy. Considering the poor accuracy and the multiple influencing factors associated with serial port synchronization signals, it is recommended to use optical signals to complete time synchronization. The results indicate that under the darkening process, the time error is - 0.23 ~ 0.08 ms (mean). This calibration formula can help measure the response latency accurately. This study provides valuable insights for optimizing experimental design and improving the accuracy of response latency. Although it only involves visual stimuli, the methods and results of this study can still serve as a reference.

An Advanced Gel Polymer Electrolyte for Solid-State Lithium Metal Batteries.

All-solid-state lithium metal batteries (LMBs) are regarded as one of the most viable energy storage devices and their comprehensive properties are mainly controlled by solid electrolytes and interface compatibility. This work proposes an advanced poly(vinylidene fluoride-hexafluoropropylene) based gel polymer electrolyte (AP-GPEs) via functional superposition strategy, which involves incorporating butyl acrylate and polyethylene glycol diacrylate as elastic optimization framework, triethyl phosphate and fluoroethylene carbonate as flameproof liquid plasticizers, and Li7La3Zr2O12 nanowires (LLZO-w) as ion-conductive fillers, endowing the designed AP-GPEs/LLZO-w membrane with high mechanical strength, excellent flexibility, low flammability, low activation energy (0.137 eV), and improved ionic conductivity (0.42 × 10-3 S cm-1 at 20 °C) due to continuous ionic transport pathways. Additionally, the AP-GPEs/LLZO-w membrane shows good safety and chemical/electrochemical compatibility with the lithium anode, owing to the synergistic effect of LLZO-w filler, flexible frameworks, and flame retardants. Consequently, the LiFePO4/Li batteries assembled with AP-GPEs/LLZO-w electrolyte exhibit enhanced cycling performance (87.3% capacity retention after 600 cycles at 1 C) and notable high-rate capacity (93.3 mAh g-1 at 5 C). This work proposes a novel functional superposition strategy for the synthesis of high-performance comprehensive GPEs for LMBs.

A voltage-controlled current source for temporal interference stimulation: Analysis, design, and study.

The temporal interference stimulation is a new technique to modulate brain activity by applying multiple channels of voltage-controlled current source (VCCS) simultaneously to the receptor surface. In this paper, the envelopes of the overlapped current waves at several areas of the receptor were analyzed and discussed with different circuit structures of VCCS. A complementary differential current source (CDCS) was designed to fit the best circuit topology based on the analysis of the enhanced Howland current source structure. Experiments were conducted by injecting current to a swine tissue using the CDCS and conventional VCCS and acquiring the voltage waveform data from different parts of the tissue. The waveforms were compared and analyzed, revealing that the conventional VCCS may generate an interference envelope in unexpected regions, while the CDCS did not. The CDCS design approach in this paper provides a new solution for temporal interference stimulation VCCS.

Cardiovascular safety of Janus kinase inhibitors in patients with rheumatoid arthritis: systematic review and network meta-analysis.

Background: Janus kinase (JAK) inhibitors have emerged as a progressively utilized therapeutic approach for the management of rheumatoid arthritis (RA). However, the complete determination of their cardiovascular safety remains inconclusive. Hence, the primary objective of this network meta-analysis is to meticulously assess and juxtapose the cardiovascular risks linked to distinct JAK inhibitors employed in RA patients. Methods: A systematic review and network meta-analysis were meticulously conducted, encompassing a collection of randomized controlled trials (RCTs) that focused on investigating the incidence of major adverse cardiovascular events (MACE) and all-cause mortality associated with Janus kinase (JAK) inhibitors administered to patients with rheumatoid arthritis (RA). Extensive exploration was performed across multiple electronic databases, incorporating studies published until March 2023. To be included in this analysis, the RCTs were required to involve adult participants diagnosed with RA who received treatment with JAK inhibitors. To ensure accuracy, two authors independently undertook the selection of eligible RCTs and meticulously extracted aggregate data. In order to examine the outcomes of MACE and all-cause mortality, a frequentist graph theoretical approach within network meta-analyses was employed, utilizing random-effects models. Third study has been registered on PROSPERO under the reference CRD42022384611. Findings: A specific selection encompassing a total of 14 meticulously chosen randomized controlled trials was undertaken, wherein 13,524 patients were assigned randomly to distinct treatment interventions. The analysis revealed no notable disparity in the occurrence of major adverse cardiovascular events (MACE) between the interventions and the placebo group. However, in comparison to adalimumab, the employment of JAK inhibitors exhibited an association with higher rates of all-cause mortality [odds ratio (OR): 1.7, 95% confidence interval (CI): 1.02-2.81]. This observed increase in risk primarily stemmed from the usage of tofacitinib (OR: 1.9, 95% CI: 1.12-3.23). None of the other JAK inhibitors exhibited a statistically significant variance in all-cause mortality when compared to adalimumab. Interpretation: Our study suggests that JAK inhibitors may not increase the risk of MACE in RA patients but may be associated with a higher risk of all-cause mortality compared to adalimumab, primarily due to tofacitinib use. Rheumatologists should carefully consider the cardiovascular risks when prescribing JAK inhibitors, particularly tofacitinib, for RA patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384611, CRD42022384611.

Risk of diabetic ketoacidosis of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM. Methods: We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388). Conclusion: Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.

Efficacy, safety and immunogenicity of etanercept biosimilars versus reference biologics in patients with rheumatoid arthritis: A meta-analysis.

Background: Although with the application of etanercept biosimilars in the field of rheumatoid arthritis, the evidences of their efficacy, safety, and immunogenicity are still limited. We conducted this meta-analysis to evaluate the efficacy, safety and immunogenicity of etanercept biosimilars for treating active rheumatoid arthritis compared to reference biologics (Enbrel®). Methods: PubMed, Embase, Central, and ClinicalTrials.gov were searched for randomized controlled trials of etanercept biosimilars treated in adult patients diagnosed with rheumatoid arthritis from their earliest records to 15 August 2022. The outcomes included ACR20, ACR50, and ACR70 response rate at different time points from FAS or PPS, adverse events, and proportion of patients developed anti-drug antibodies. The risk of bias of each included study was assessed using the revised Cochrane Risk of Bias in Randomised Trials tool, and the certainty of evidence was rated according to the Grading of Recommendation Assessment, Development, and Evaluation. Results: Six RCTs with 2432 patients were included in this meta-analysis. Etanercept biosimilars showed more benefits in ACR50 at 24 weeks from PPS [5 RCTs, OR = 1.22 (1.01, 1.47), p = 0.04, I 2 = 49%, high certainty], ACR50 at 1 year from PPS [3 RCTs, OR = 1.43 (1.10, 1.86), p < 0.01, I 2 = 0%, high certainty] or FAS [2 RCTs, OR = 1.36 (1.04, 1.78), p = 0.03, I 2 = 0%, high certainty], and ACR70 at 1 year from PPS [3 RCTs, OR = 1.32 (1.01, 1.71), p = 0.04, I 2 = 0%, high certainty]. In terms of other outcomes about efficacy, safety, and immunogenicity, the results showed that there was no significant difference between etanercept biosimilars and reference biologics, and the certainty of evidences ranged from low to moderate. Conclusion: Etanercept biosimilars showed more benefits in ACR50 response rate at 1 year than reference biologics (Enbrel®), other outcomes for clinical efficacy, safety, and immunogenicity of etanercept biosimilars were comparable with originator in patients with rheumatoid arthritis. Systematic Review Registration: PROSPERO, identifier CRD42022358709.

Square wave reference digital lock-in detection using non-orthogonal demodulation.

Digital lock-in detection technique is commonly used to measure the amplitude and phase of a selected frequency signal. The technique which uses a square wave as the reference signal has an advantage of easier implementation and higher computational efficiency compared to that uses a sine wave. However, one constraint for a square wave reference digital lock-in is that the sampling rate must be the integral multiple of 4 of all the signal frequencies. As the sampling clock may not always be able to set to the integral multiple of 4 of the signal frequencies, the constraint brings inconvenient for the implementation. Presented in this paper is a novel algorithm for square wave digital lock-in detection in which the sampling frequency doesn't have to meet the constraint. The algorithm allows frequency sweep measurements with a fixed sampling rate. For different relationships between the sampling rate and the signal frequency, different calculation equations are provided in this paper. Simulations and actual experiments show the feasibility of the proposed algorithm.

Temperature measurement of aqueous solution in miniature sample chamber in microscopic system based on near-infrared spectrum.

Measurement of the sample temperature in biophysics research is challenging, as the samples are commonly placed in a miniature sample chamber under a microscope. In this study, we proposed a method to measure the temperature of an aqueous solution in miniature sample chambers in a microscopic system. Existing studies show that the absorption coefficient spectrum of water shifts with temperature, especially in the near-infrared (NIR) band. We measured the absorption spectra of water with different temperatures and analyzed them, to build a mathematical model relating the temperature and the spectrum. A setup for temperature measurement in a microscopic system was designed and implemented by coupling a spectrometer and a light source to a microscope. The temperature could be calculated by the spectral data and the mathematical model while simultaneously observing the micro-image of the sample. A series of liquid samples at different temperatures were tested using the setup, and the root mean square error of the calculated temperature is less than 0.5 °C. The results demonstrate that the method based on the NIR spectrum can be used for noncontact and quick measurement of the liquid sample temperature in a microscopic system.

Chirality and frequency measurement of longitudinal rolling of human sperm using optical trap.

Motility is one of the most critical features to evaluate sperm quality. As longitudinal rolling of human sperm has long been ignored until recently, its detailed dynamics and cellular biological mechanisms are still largely unknown. Here we report an optical-tweezers-based method to evaluate the chirality and frequency of sperm rotation. According to the intensity distribution patterns of off-focus micron-size particles, we established a method to judge the orientation of the sperm head along the optical axis in the optical trap. Together with the rotation direction of the projection of the sperm head, the chirality of longitudinal rolling of sperm can be measured without the application of three-dimensional tracking techniques or complex optical design. By video tracking optically trapped sperm cells from different patients, both rolling chirality and rolling frequency were analyzed. In this study, all the vertically trapped human sperm cells adopt a right-hand longitudinal rolling. The orientation and rolling frequency but not the rolling chirality of sperm in the optical trap are affected by the trap height. The rotation analysis method developed in this study may have clinical potential for sperm quality evaluation.

'Stress hyperglycemia ratio and in-hospital prognosis in non-surgical patients with heart failure and type 2 diabetes.

OBJECTIVE: To evaluate the impact of stress hyperglycemia on the in-hospital prognosis in non-surgical patients with heart failure and type 2 diabetes. RESEARCH DESIGN AND METHODS: We identified non-surgical hospitalized patients with heart failure and type 2 diabetes from a large electronic medical record-based database of diabetes in China (WECODe) from 2011 to 2019. We estimated stress hyperglycemia using the stress hyperglycemia ratio (SHR) and its equation, say admission blood glucose/[(28.7 × HbA1c)- 46.7]. The primary outcomes included the composite cardiac events (combination of death during hospitalization, requiring cardiopulmonary resuscitation, cardiogenic shock, and the new episode of acute heart failure during hospitalization), major acute kidney injury (AKI stage 2 or 3), and major systemic infection. RESULTS: Of 2875 eligible Chinese adults, SHR showed U-shaped associations with composite cardiac events, major AKI, and major systemic infection. People with SHR in the third tertile (vs those with SHR in the second tertile) presented higher risks of composite cardiac events ([odds ratio, 95% confidence interval] 1.89, 1.26 to 2.87) and major AKI (1.86, 1.01 to 3.54). In patients with impaired kidney function at baseline, both SHR in the first and third tertiles anticipated higher risks of major AKI and major systemic infection. CONCLUSIONS: Both high and low SHR indicates poor prognosis during hospitalization in non-surgical patients with heart failure and type 2 diabetes.

Glycated Haemoglobin A1c Variability Score Elicits Kidney Function Decline in Chinese People Living with Type 2 Diabetes.

Our aim was to investigate the association of glycated haemoglobin A1c (HbA1c) variability score (HVS) with estimated glomerular filtration rate (eGFR) slope in Chinese adults living with type 2 diabetes. This cohort study included adults with type 2 diabetes attending outpatient clinics between 2011 and 2019 from a large electronic medical record-based database of diabetes in China (WECODe). We estimated the individual-level visit-to-visit HbA1c variability using HVS, a proportion of changes in HbA1c of ≥0.5% (5.5 mmol/mol). We estimated the odds of people experiencing a rapid eGFR annual decline using a logistic regression and differences across HVS categories in the mean eGFR slope using a mixed-effect model. The analysis involved 2397 individuals and a median follow-up of 4.7 years. Compared with people with HVS ≤ 20%, those with HVS of 60% to 80% had 11% higher odds of experiencing rapid eGFR annual decline, with an extra eGFR decline of 0.93 mL/min/1.73 m2 per year on average; those with HVS > 80% showed 26% higher odds of experiencing a rapid eGFR annual decline, with an extra decline of 1.83 mL/min/1.73 m2 per year on average. Chinese adults with type 2 diabetes and HVS > 60% could experience a more rapid eGFR decline.

Cardiovascular safety of febuxostat and allopurinol in patients with gout: A meta-analysis.

Background: Gout is a common disease and is usually treated with uric acid-lowering drugs (the most commonly used of which are febuxostat and allopurinol). However, the cardiovascular safety of febuxostat and allopurinol is still controversial. The purpose of our study is to evaluate the cardiovascular safety of the two drugs in patients with gout using one-stage and two-stage meta-analysis. Methods: PubMed, Embase, CBM, CNKI, WanFang, Central, and VIP were searched from inception to 30 January 2022. Randomized controlled trials which evaluated the cardiovascular safety of febuxostat or allopurinol for treating patients with gout were included. Based on the Kaplan-Meier curves of the two studies, individual patient data (IPD) were extracted and reconstructed. We used time-varying risk ratios (RRs) to summarize time-to-event outcomes, and the RRs of MACE incidence, cardiovascular mortality, and all-cause mortality were calculated by a multi-level flexible hazard regression model in 1-stage meta-analyses. p values were calculated using a log-rank test. At the same time, using the reconstructed IPD, we performed 2-stage meta-analyses to inform the quantitative estimates of time-specific relative risks at the six time points (1 , 2, 3, 4, 5, and 6 years) based on a random-effects model. Results: Two RCTs with 12,318 participants were included. In the incidence of major adverse cardiovascular events between the two regimens, there was no significant difference [RR = 0.99 (95% CI, 0.89-1.11), p = 0.87]; at the same time, there was no significant difference in cardiovascular mortality [RR = 1.17 (95% CI, 0.98-1.40),p = 0.08] or all-cause mortality [RR = 1.03 (95% CI, 0.91-1.17),p = 0.62]. In terms of 2-stage meta-analyses, there was no significant difference in any outcomes at any time point (moderate-to low-certainty evidence). Conclusion: In patients without atherosclerotic disease, febuxostat likely has a similar cardiovascular profile to allopurinol. However, in patients with a history of cardiovascular disease, allopurinol treatment is associated with less cardiovascular mortality as compared with febuxostat. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#loginpage, identifier PROSPERO, CRD42022325656.

An apparatus for qualitative assessment of the shading ratio of oblique illumination and real-time high-contrast imaging.

Oblique illumination imaging can significantly improve the contrast of transparent thin samples. However, in traditional oblique illumination methods, either the condenser is offset or a block is added to the condenser, which makes it complicated and challenged to build a stable oblique illumination imaging. Herein, we present a method to measure the optimal shading ratio of oblique illumination in an inverted microscope, and develop an apparatus for stable high-speed high-contrast imaging with uniform brightness. At optimal shading ratio, the oblique illumination imaging has better imaging quality than differential interference contrast, which characteristic is independent on sample. In oblique illumination with low magnification objective, the images have uneven brightness. According to target brightness, we have developed a brightness unevenness correction algorithm to form uniform background brightness for oblique illumination. Integrating the algorithm with imaging acquisition, corrected oblique illumination microscopy is appropriate to observe living cells with high contrast.

Efficacy and Safety of Bevacizumab Biosimilars Compared With Reference Biologics in Advanced Non-small Cell Lung Cancer or Metastatic Colorectal Cancer Patients: A Network Meta-Analysis.

Background: Bevacizumab biosimilars are slowly making their way into cancer treatment, but the data on their efficacy and safety in cancer patients are still poor. We systematically summarized the current evidence for the efficacy and safety of bevacizumab biosimilars in patients with advanced non-small cell lung cancer (NSCLC) or metastatic colorectal cancer (CRC). Methods: This review searched CNKI, VIP, PubMed, Medline (Ovid), Embase, and Cochrane Library (Ovid) for randomized controlled trials of bevacizumab biosimilars treated in adults with advanced NSCLC or metastatic CRC. A pairwise meta-analysis and a Bayesian network meta-analysis based on the random-effect model were performed to summarize the evidence. We rated the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation framework. Results: Ten eligible trials with a total of 5526 patients were included. Seven trials (n = 4581) were for the NSCLC population, while three trials (n = 945) were for patients with CRC. According to the pairwise meta-analysis, the efficacy (objective response rate: risk ratio (RR) 0.98 [0.92-1.04], p = 0.45; progression-free survival: hazard ratio (HR) 1.01 [0.92-1.10], p = 0.85; and overall survival: HR 1.06 [0.94-1.19], p = 0.35) and safety (incidence of grade 3-5 adverse events: odds ratio (OR) 1.03 [0.91-1.16], p = 0.65) of bevacizumab biosimilars performed no significant difference with reference biologics in patients with NSCLC as well as metastatic CRC patients (objective response rate: RR 0.97 [0.87-1.09], p = 0.60; overall survival: HR 0.94 [0.70-1.25], p = 0.66; incidence of grade 3-5 adverse events: OR 0.78 [0.59-1.02], p = 0.73). Network estimates displayed 7 types of bevacizumab biosimilars in the medication regime of NSCLC patients who had no significant difference among each other in terms of efficacy and safety. The certainty of the evidence was assessed as low to moderate. Three types of biosimilars were found to be clinically equivalent to each other in the patients with CRC, which were evaluated with very low to moderate certainty. Conclusion: In patients with advanced NSCLC or metastatic CRC, the efficacy and safety of bevacizumab biosimilars were found to be comparable with those of reference biologics and each other.

Novel Non-invasive Transcranial Electrical Stimulation for Parkinson's Disease.

Conventional transcranial electrical stimulation (tES) is a non-invasive method to modulate brain activity and has been extensively used in the treatment of Parkinson's disease (PD). Despite promising prospects, the efficacy of conventional tES in PD treatment is highly variable across different studies. Therefore, many have tried to optimize tES for an improved therapeutic efficacy by developing novel tES intervention strategies. Until now, these novel clinical interventions have not been discussed or reviewed in the context of PD therapy. In this review, we focused on the efficacy of these novel strategies in PD mitigation, classified them into three categories based on their distinct technical approach to circumvent conventional tES problems. The first category has novel stimulation modes to target different modulating mechanisms, expanding the rang of stimulation choices hence enabling the ability to modulate complex brain circuit or functional networks. The second category applies tES as a supplementary intervention for PD hence amplifies neurological or behavioral improvements. Lastly, the closed loop tES stimulation can provide self-adaptive individualized stimulation, which enables a more specialized intervention. In summary, these novel tES have validated potential in both alleviating PD symptoms and improving understanding of the pathophysiological mechanisms of PD. However, to assure wide clinical used of tES therapy for PD patients, further large-scale trials are required.

Heparin and Related Substances for Treating Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis.

Background: Diabetic foot ulcers are a major complication of diabetes mellitus (DM), when heparin and heparin related substances may be potentially used as an adjuvant treatment. We aimed to evaluate the efficacy and safety of heparin and heparin related substances for the treatment of diabetic foot ulcers. Methods: We searched up to March 2021 in the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; EBSCO CINAHL; VIP Chinese Science and Technique Journals Database; China National Knowledge Infrastructure (CNKI) Database and Wan Fang Database investigating heparin or heparin-related substances in patients with diabetic foot ulcers. The primary outcomes included proportion of ulcers completely healed and time to complete ulcer healing. We assessed each included study with the Cochrane 'Risk of bias' tool and used the GRADE approach to assess the overall quality of the evidence. Results: We included nine randomized studies involving 620 participants in the meta-analysis, involving two different heparin and heparin-related substances, low molecular weight heparin (LMWH) and hyaluronic acid. Our study did not show the benefits from LMWH on increasing chance of the ulcer healing (RR: 1.26; 95% CI: 0.78 to 2.04; P=0.35; very low) or shortening the time to complete ulcer healing (SMD: 0.13 d; 95% CI: -0.29 to 0.56; P=0.54; very low). Hyaluronic acid may improve the complete ulcer healing (RR: 1.57; 95% CI: 1.29 to 1.91; P˂0.00001; very low) and shorten the time to complete ulcer healing (SMD -0.84, 95% CI -1.15 to -0.53; P<0.00001; low). Hyaluronic acid and LMWH were generally well tolerated for treating diabetic foot ulcers in this review. Conclusion: Hyaluronic acid may improve diabetic foot ulcer with very low quality evidence but not LMWH. However, the benefits and harms need further validation in larger trials with different population. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [PROSPERO, CRD42021269212].

Morphology analysis of unlabeled red blood cells based on quantitative differential phase contrast microscopy.

The current classical blood smear technique to observe the morphology of single red blood cells (RBCs) for classification is a laborious and error-prone process. To objectively evaluate the morphology of blood cells, we established a method of computational imaging based on a programmable light emitting diode array. By using quantitative differential phase contrast (qDPC), we characterized the morphology of unlabeled RBCs as well as blood smears. By focusing on comparing the difference of imaging between unlabeled RBCs and stained RBCs under multimode microscopic imaging technology, we demonstrated that qDPC could clearly differentiate discocytes and spherocytes in both unlabeled RBCs and blood smears. The phase map provided by quantitative phase imaging further enhanced the classification accuracy. According to statistical analysis from morphological indexes, the qDPC imaging has a significantly improvement in non-circularity, texture inhomogeneity and equivalent diameters of cells. Thus, this method has a significant superiority in the capability to analyze the morphology of RBCs and could be applied to clinical assays for determining morphological, functional, and structural deterioration of RBCs.

Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS: 14 605 citations were identified by our search, of which 143 eligible trials enrolled 49 810 participants. Except for levocarnitine, all drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·97, 95% CI -9·28 to -6·66) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·76, 95% CI -6·30 to -5·21). Naltrexone-bupropion (OR 2·69, 95% CI 2·11 to 3·43), phentermine-topiramate (2·40, 1·69 to 3·42), GLP-1 receptor agonists (2·17, 1·71 to 2·77), and orlistat (1·72, 1·44 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·41, 95% CI -12·54 to -10·27). INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.