Association of Gene Expression and Tremor Network Structure.

BACKGROUND: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated. OBJECTIVE: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET. METHODS: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55). RESULTS: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ2 = 6.40, P = 0.006). CONCLUSIONS: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Transcriptomic imputation of genetic risk variants uncovers novel whole-blood biomarkers of Parkinson's disease.

Blood-based gene expression signatures could potentially be used as biomarkers for PD. However, it is unclear whether genetically-regulated transcriptomic signatures can provide novel gene candidates for use as PD biomarkers. We leveraged on the Genotype-Tissue Expression (GTEx) database to impute whole-blood transcriptomic expression using summary statistics of three large-scale PD GWAS. A random forest classifier was used with the consensus whole-blood imputed gene signature (IGS) to discriminate between cases and controls. Outcome measures included Area under the Curve (AUC) of Receiver Operating Characteristic (ROC) Curve. We demonstrated that the IGS (n = 37 genes) is conserved across PD GWAS studies and brain tissues. IGS discriminated between cases and controls in an independent whole-blood RNA-sequencing study (1176 PD, 254 prodromal, and 860 healthy controls) with mean AUC and accuracy of 64.8% and 69.4% for PD cohort, and 78.8% and 74% for prodromal cohort. PATL2 was the top-performing imputed gene in both PD and prodromal PD cohorts, whose classifier performance varied with biological sex (higher performance for males and females in the PD and prodromal PD, respectively). Single-cell RNA-sequencing studies (scRNA-seq) of healthy humans and PD patients found PATL2 to be enriched in terminal effector CD8+ and cytotoxic CD4+ cells, whose proportions are both increased in PD patients. We demonstrated the utility of GWAS transcriptomic imputation in identifying novel whole-blood transcriptomic signatures which could be leveraged upon for PD biomarker derivation. We identified PATL2 as a potential biomarker in both clinical and prodromic PD.

Treatment of apathy in Parkinson's disease: A bayesian network meta-analysis of randomised controlled trials.

Background: Apathy is an important but unrecognised aspect of Parkinson's disease (PD). The optimal therapeutic options for apathy remain unclear. Early recognition and treatment of apathy can reduce the significant burden of disease for patients and their caregivers. Here we conducted a meta-analysis to evaluate the comparative efficacy of different treatment modalities of apathy in PD (CRD42021292099). Methods: We screened Medline, Embase, and PsycINFO databases for articles on therapies for apathy in PD. The outcome of interest is the reduction in apathy scores post-intervention and is measured by standardised mean differences (SMD) with 95% credible intervals (CrI). We included only randomised controlled trials examining interventions targeted at reducing apathy. Results: Nineteen studies involving 2372 patients were included in the quantitative analysis. The network meta-analysis found pharmacotherapy to be the most efficacious treatment, significantly better than brain stimulation (SMD -0.43, 95% CrI -0.78 to -0.07), exercise-based interventions (SMD -0.66, 95% CrI -1.25 to -0.08), supplements (SMD -0.33, 95% CrI -0.67 to 0), and placebo (SMD -0.38, 95% CrI -0.56 to -0.23). Subgroup analysis of pharmacotherapy versus placebo found similar efficacy of dopamine agonists (SMD -0.36, 95% CI -0.59 to -0.12, P = 0.003) and alternative medications (SMD -0.42, 95% CI -0.61 to -0.23, P < 0.001). The remaining comparisons and subgroup analyses did not demonstrate any significant treatment effects. Conclusion: Our meta-analysis of randomised controlled trials showed that pharmacotherapy is the most efficacious treatment option, with dopamine agonists having similar efficacy as other medications. Further research is needed to determine the optimal management strategy.

Association between Type 1 Diabetes Mellitus and Parkinson's Disease: A Mendelian Randomization Study.

While much evidence suggests that type 2 diabetes mellitus increases the risk of Parkinson's disease (PD), the relationship between type 1 diabetes mellitus (T1DM) and PD is unclear. To study their association, we performed a two-sample Mendelian randomization (MR) using the following statistical methods: inverse variance weighting (IVW), MR-Egger, weight median, and weighted mode. Independent datasets with no sample overlap were retrieved from the IEU GWAS platform. All the MR methods found a lower risk of PD in T1DM (IVW-OR 0.93, 95% CI 0.91-0.96, p = 3.12 × 10-5; MR-Egger-OR 0.93, 95% CI 0.88-0.98, p = 1.45 × 10-2; weighted median-OR 0.93, 95% CI 0.89-0.98, p = 2.76 × 10-3; and weighted mode-OR 0.94, 95% CI 0.9-0.98, p = 1.58 × 10-2). The findings were then replicated with another independent GWAS dataset on T1DM (IVW-OR 0.97, 95% CI 0.95-0.99, p = 3.10 × 10-3; MR-Egger-OR 0.96, 95% CI 0.93-0.99, p = 1.08 × 10-2; weighted median-OR 0.97, 95% CI 0.94-0.99, p = 1.88 × 10-2; weighted mode-OR 0.97, 95% CI 0.94-0.99, p = 1.43 × 10-2). Thus, our study provides evidence that T1DM may have a protective effect on PD risk, though further studies are needed to clarify the underlying mechanisms.

Risk of Suicidal Ideation and Behavior in Individuals With Parkinson Disease: A Systematic Review and Meta-Analysis.

Importance: Suicide risk may be increased in patients with Parkinson disease (PD), a common neurodegenerative condition. Mood disorders, especially depression, are prevalent in patients with PD who report suicidality. Objective: To address inconsistent results from studies of suicidal ideation and behavior in patients with PD. Data Sources: The study team searched MEDLINE and Embase from inception to June 14, 2023, and further screened the bibliographies of relevant studies to ensure a comprehensive search. Study Selection: Original studies, published in English, discussing either suicidal ideation, behavior, or both in adults with PD were included. Accepted study designs included cross-sectional, case-control, and cohort studies. Studies that only included patients with PD after deep brain stimulation were excluded. Data Extraction and Synthesis: This meta-analysis was conducted in line with the PRISMA guidelines. Two authors reviewed each study and extracted the data independently, with discrepancies referred to a third independent author. Main Outcomes and Measures: Outcomes included the prevalence of suicidal ideation and behavior, measured as proportions, and the risk of suicidal behavior in patients with PD relative to controls, measured in both odds ratio (OR) and hazards ratio (HR). Results: A total of 28 studies comprising 505 950 PD patients were included in the final analysis. The prevalence of suicidal ideation was evaluated in 14 studies (22.2%; 95% CI, 14.6-32.3) and suicidal behavior in 21 studies (1.25%; 95% CI, 0.64-2.41). Excluding 4 outliers, prevalence of suicidal behavior was significantly higher in prospective studies (1.75%; 95% CI, 1.03-2.95) than retrospective studies (0.50%; 95% CI, 0.24-1.01). Excluding 1 outlier, OR of suicidal behavior was pooled across 10 studies and significant (OR, 2.15; 95% CI, 1.22-3.78; P = .01). HR of suicidal behavior was assessed in 9 studies (HR, 1.73; 95% CI, 1.40-2.14; P < .001). Conclusions and Relevance: This meta-analysis involving more than 500 000 patients with PD found 22.2% and 1.25% of patients with PD to have suicidal ideation and behavior, respectively. Patients with PD had 2 times the risk of suicidal behavior than controls. Early recognition and management of suicidality in PD can help reduce mortality.

Tamoxifen in breast cancer and risk of Parkinson's disease: A meta-analysis.

BACKGROUND: Tamoxifen is widely used for hormone-sensitive breast cancer, achieved by modulating the estrogen receptor activity in a tissue-specific manner. There is evidence to support the protective effects of estrogen against Parkinson's disease (PD), a common neurodegenerative condition. Some epidemiologic studies suggest the use of tamoxifen may modulate the PD risk. We conducted a meta-analysis to examine the association between tamoxifen and risk of PD. METHODS: A search of PubMed using search terms synonymous with "tamoxifen" and "Parkinson's disease" was conducted. Outcomes of interest were the odds ratio (OR) of PD comparing tamoxifen-exposed to -unexposed women, as well as the incidence rate of PD in tamoxifen-exposed women. RESULTS: A total of 37,932 subjects with breast cancer, comprising 17,233 tamoxifen-exposed subjects and 20,699 tamoxifen-unexposed subjects, satisfied the inclusion criteria. The exposure to tamoxifen ranged from 30-96 months. Using the common-effect model, the pooled OR of PD was 2.4, with (95% CI 1.91-3.01, P < 0.0001), with high heterogeneity (I2 = 81.5%, Cochran's Q test P = 0.001). Pooling 28,640 tamoxifen-exposed patients under the common-effect model found an incidence rate of 5.86 events per 10,000 person-years (95% CI 4.82-7.12) with minimal heterogeneity (I2 = 26%, Cochran's Q test P = 0.258). CONCLUSIONS: Our meta-analysis suggests that tamoxifen use may be associated with an increased PD risk in women. However, due to heterogeneity and potential limitations of some of the studies, further clinical and functional validation will be needed. Longitudinal studies supported by imaging and biomarkers evaluation will be useful to identify the mechanisms linking tamoxifen and PD risk.

Cardiovascular Risk in Patients with Hematological Malignancies: A Systematic Review and Meta-Analysis.

Patients with hematologic malignancies (HMs) are at risk of future cardiovascular (CV) events. We therefore conducted a systematic review and meta-analysis to quantify their risk of future CV events. We searched Medline and EMBASE databases from inception until January 31, 2023 for relevant articles using a combination of keywords and medical subject headings. Studies examining CV outcomes in patients with HM versus controls without HM were included. The outcomes of interest included acute myocardial infarction (AMI), heart failure (HF), and stroke. The outcomes were expressed as hazard ratios (HRs) and their 95% confidence intervals (CIs). This study is registered with PROSPERO at CRD42022307814. A total of 15 studies involving 1,960,144 cases (178,602 patients with HM and 1,781,212 controls) were included in the quantitative analysis. A total of 10 studies examined the risk of AMI, 5 examined HF, and 11 examined stroke. Compared with the control group, the HRs for HM for AMI, HF, and stroke were 1.65 (95% CI 1.29 to 2.09, p <0.001), 4.82 (95% CI 3.72 to 6.25, p <0.001), and 1.60 (95% CI 1.30 to 1.97, p <0.001), respectively. The sensitivity analysis of stroke risk based on lymphoma type showed an increased risk of stroke in patients with non-Hodgkin lymphoma compared with controls (HR 1.31, 95% CI 1.04 to 1.64, p = 0.03) but no significant difference for Hodgkin lymphoma (HR 1.67, 95% CI 0.86 to 3.23, p = 0.08). Patients with HM are at increased risk of future AMI, HF, and stroke, and these findings suggest that CV care of patients with HM should be considered as a growing priority.

Risk of Parkinson's disease in hepatitis B and C populations: a systematic review and meta-analysis.

Parkinson's disease (PD) is a common neurodegenerative disorder, and its association with viral hepatitis has been debated. We performed a meta-analysis to examine the association between PD risk and viral hepatitis. Medline, EMBASE, and the Cochrane library were searched from inception till July 2022. Meta-analysis was conducted using a fixed-effect model with the inverse variance method. Three groups were compared to controls: infection with either hepatitis B or C virus (HBV and HCV, respectively), or coinfection with both viruses. We found 551 records, and six studies comprising of 2,566,947 patients were included in the analysis. PD risk was increased in HCV-infected population (OR 1.10, 95% CI 1.03-1.17, p = 0.005) and (HR 1.37, 95% CI 1.26-1.49, p < 0.001). This increase was not observed for the HBV-infected and HBV-HCV-coinfected coinfection populations. For pooled OR, the risk was significantly lower in HBV-infected (OR 0.79, 95% CI 0.76-0.83, p < 0.001) but not significantly different in HBV-HCV-coinfected populations (OR 0.96, 95% CI 0.82-1.12, p = 0.57). For pooled HR, the risk was significantly higher in both HBV-infected (HR 1.22, 95% CI 1.14-1.31, p < 0.001) and HBV-HCV-coinfected populations (HR 1.29, 95% CI 1.05-1.58, p = 0.013). We found that the risk of PD was increased in the HCV-infected population, but results were inconsistent in those with HBV and HBV-HCV infections. Our findings provide impetus for further clinical and functional studies to unravel the role of the adaptive immune system in PD.

Linking autism spectrum disorders and parkinsonism: clinical and genetic association.

BACKGROUND: Autism spectrum disorders (ASD) comprise many complex and clinically distinct neurodevelopmental conditions, with increasing evidence linking them to parkinsonism. METHODS: We searched Medline and Embase from inception to 21 March 2022 and reviewed the bibliographies of relevant articles. Studies were screened and reviewed comprehensively by two independent authors. RESULTS: Of 863 references from our search, we included eight clinical studies, nine genetic studies, and five case reports. Regardless of age group, Parkinson's disease (PD) and parkinsonian syndromes were more frequently observed in patients with ASD, though the evidence for increased rates of parkinsonism is less clear for children and adolescents. Parkinsonian features and hypokinetic behavior were common in Rett syndrome, with prevalence estimates ranging from 40% to 80%. Frequently observed parkinsonian features include bradykinesia, rigidity, hypomimia, and gait freezing. PD gene PARK2 copy number variations appear more frequently in ASD cases than controls. Evidence suggests that RIT2 and CD157/BST1 are implicated in ASD and PD, while the evidence for other PD-related genes (DRD2, GPCR37, the SLC gene family, and SMPD1) is less clear. Rare mutations, such as ATP13A2, CLN3, and WDR45, could result in autistic behavior and concomitant parkinsonism. CONCLUSION: The prevalence of parkinsonism in ASD is substantially greater than in the general population or matched controls. Various PD-associated gene loci, especially PARK2, could confer susceptibility to ASD as well. Important future directions include conducting prospective cohort studies to understand how parkinsonian symptoms may progress, genetic studies to reveal relevant gene loci, and pathophysiologic studies to identify potential therapeutic targets.

The genetic basis of multiple system atrophy.

Multiple system atrophy (MSA) is a heterogenous, uniformly fatal neurodegenerative ɑ-synucleinopathy. Patients present with varying degrees of dysautonomia, parkinsonism, cerebellar dysfunction, and corticospinal degeneration. The underlying pathophysiology is postulated to arise from aberrant ɑ-synuclein deposition, mitochondrial dysfunction, oxidative stress and neuroinflammation. Although MSA is regarded as a primarily sporadic disease, there is a possible genetic component that is poorly understood. This review summarizes current literature on genetic risk factors and potential pathogenic genes and loci linked to both sporadic and familial MSA, and underlines the biological mechanisms that support the role of genetics in MSA. We discuss a broad range of genes that have been associated with MSA including genes related to Parkinson's disease (PD), oxidative stress, inflammation, and tandem gene repeat expansions, among several others. Furthermore, we highlight various genetic polymorphisms that modulate MSA risk, including complex gene-gene and gene-environment interactions, which influence the disease phenotype and have clinical significance in both presentation and prognosis. Deciphering the exact mechanism of how MSA can result from genetic aberrations in both experimental and clinical models will facilitate the identification of novel pathophysiologic clues, and pave the way for translational research into the development of disease-modifying therapeutic targets.

The clinical impact of anti-hypertensive treatment drug-gene pairs in the asian population: a systematic review of publications in the past decade.

Pharmacogenetics play an important role in determining the anti-hypertensive effects of blood pressure-lowering medications and have the potential to improve future patient care. Current literature on the topic, however, has a heavy focus on Caucasians and may not be generalisable to the Asian populations. Therefore, we have conducted this systematic review to summarise and evaluate the literature of the past decade. PubMed, Embase, and the Cochrane Register of Controlled Trials were searched for relevant studies from 1 January 2011 to 23 July 2021. The outcome of interest was the response to anti-hypertensive treatment in Asians according to each genetic polymorphism. A total of 26 studies with a total of 8837 patients were included in our review, covering five classes of anti-hypertensive agents-namely, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta-blockers (BB), calcium channel blockers (CCB), and thiazide-like diuretics. Response to ACEI therapy was most susceptible to genotypic variations, while the efficacy of ARB and CCB were affected by pharmacogenetic differences to varying extent. For BB, only variations in the ADRB1 genotype significantly affects therapeutic response, while the therapeutic efficacy of thiazide-like diuretics was correlated with genotypic variations in the REN and ACE. This systematic review evaluated the impact of pharmacogenetic variations on the therapeutic efficacy of anti-hypertensive treatment in Asians and has described numerous drug-gene pairs that are potentially clinically important. Future prospective studies with larger sample sizes and longer follow-up periods are needed to better elucidate the impact of these drug-gene pairs.

The association between cancer diagnosis, care, and outcomes in 1 million patients hospitalized for acute pulmonary embolism.

OBJECTIVES: To evaluate the clinical care provided to cancer patients hospitalized for acute pulmonary embolism (PE), as well as the association between type of cancer, in-hospital care, and clinical outcomes. METHODS: This study examined the in-hospital care (systemic thrombolysis, catheter-directed thrombolysis, and surgical thrombectomy/embolectomy) and clinical outcomes (mortality, major bleeding, and hemorrhagic stroke) among adults hospitalized due to acute PE between October 2015 to December 2018 using the National Inpatient Sample (NIS). Multivariable logistic regression analysis was used to determine adjusted odds ratios (aOR) with 95% confidence interval (95% CI). RESULTS: Of 1,090,130 hospital records included in the analysis, 216,825 (19.9%) had current cancer diagnoses, including lung (4.7%), hematological (2.5%), colorectal (1.6%), breast (1.3%), prostate (0.8%), and 'other' cancer (9.0%). Cancer patients had lower adjusted odds of receiving systemic thrombolysis, catheter-directed therapy, and surgical thrombectomy/embolectomy compared with their non-cancer counterparts (P < 0.001), except for systemic thrombolysis (aOR 0.96, 95% CI 0.85-1.09, P = 0.553) and catheter-directed therapy (aOR 0.82, 95% CI 0.67-1.00, P = 0.053) for prostate cancer. Cancer patients had greater odds of mortality (P < 0.05). Lung cancer patients had the highest odds of mortality (aOR 2.68, 95% CI 2.61-2.76, P < 0.001) and hemorrhagic stroke (aOR 1.75, 95% CI 1.61-1.90, P < 0.001), while colorectal cancer patients had the greatest odds of bleeding (aOR 2.04, 95% CI 1.94-2.15, P < 0.001). CONCLUSION: Among those hospitalized for PE, cancer diagnoses were associated with lower odds of invasive management and poorer in-hospital outcomes, with metastatic status being an especially important determinant. Appropriateness of care could not be assessed in this study.

Transcranial alternating current stimulation and its effects on cognition and the treatment of psychiatric disorders: a systematic review and meta-analysis.

Background: Transcranial alternating current stimulation (TACS) is a non-invasive method of brain stimulation that is hypothesised to alter cortical excitability and brain electrical activity, modulating functional connectivity within the brain. Several trials have demonstrated its potential in treating psychiatric disorders such as depression and schizophrenia. Objectives: To study the efficacy of TACS in ameliorating symptoms of depression and schizophrenia in patients and its effects on cognition in patients and healthy subjects compared to sham stimulation. Design: Systematic review with meta-analysis. Data Sources and Methods: This PROSPERO-registered systematic review (CRD42022331149) is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, EMBASE, CENTRAL and PsycINFO were searched from inception to March 2022. Only randomised-controlled trials were included. Results: A total of 12 randomised-controlled trials are reviewed for meta-analysis, with three randomised-controlled trials reporting only effects on cognition in psychiatric and cognitively impaired patients, three trials on cognition in healthy subjects, one trial on cognition in both patients and healthy subjects, one trial on only depression, two on both cognition and depression in patients and two on schizophrenia symptoms. No studies were at significant risk of bias. For cognition, TACS showed significant improvement [positive standardised mean differences (SMD) denoting improvement] over sham stimulation in those with psychiatric disorders with an SMD of 0.60 (95% confidence interval [CI]: 0.14, 1.06). Similarly, among patients with depression, an SMD of 1.14 (95% CI: 0.10, 2.18) was found significantly favouring TACS over sham stimulation. Two studies assessed the effect of TACS on schizophrenia symptoms with mixed results. Conclusion: TACS has shown promise in ameliorating symptoms of both schizophrenia and depression in patients. TACS also improves cognition in both patients and healthy subjects. However, these findings are limited by the sample size of included studies, and future studies may be required to better our understanding of the potential of TACS. Registration: PROSPERO (CRD42022331149).

Impact of COVID-19 pandemic on patients with Parkinson's disease: A meta-analysis of 13,878 patients.

BACKGROUND: The clinical, neuropsychological, and socioeconomic factors affecting Parkinson's disease (PD) during COVID-19 pandemic across different populations have not been systematically studied. To address this, we conducted a meta-analysis of factors that impact the well-being of PD patients during the pandemic. METHODS: Medline and Embase were searched for articles published between 2020 and 2022. We conducted random-effects pooling of estimates and meta-regression. RESULTS: Twenty-seven studies involving 13,878 patients from America, Europe, Asia, and Africa were included. There is a high prevalence of decreased physical activity and exercise, and worsening motor and neuropsychiatric symptoms (17-56%). Patients in lower-income countries more frequently reported worsening anxiety (adjusted OR [aOR] 8.94, 95% confidence interval [CI] 1.62-49.28, p = 0.012), sleep (aOR 5.16, 95% CI 1.15-23.17, p = 0.032), and PD symptoms (aOR 3.57, 95% CI 0.96-13.34, p = 0.058). Lockdown was associated with decreased exercise levels (aOR 0.13, 95% CI 0.02-0.78, p = 0.025) and worsening mood (aOR 0.48, 95% CI 0.24-0.95, p = 0.035). Younger age correlated with decreased physical activity (ß -0.30, 95% CI -0.53 to -0.07, p = 0.012), exercise (ß -0.11, 95% CI -0.15 to -0.07, p < 0.001), worsening PD symptoms (ß -0.08, 95% CI -0.15 to -0.01, p = 0.018), and sleep (ß -0.14, 95% CI -0.27 to 0, p = 0.044). Female PD patients reported a greater decrease in physical activity (ß 11.94, 95% CI 2.17-21.71, p = 0.017) and worse sleep (ß 10.76, 95% CI 2.81-18.70, p = 0.008). CONCLUSION: This large meta-analysis of PD patients in diverse populations identified a high prevalence of physical and mental worsening during the COVID-19 pandemic, with patients in lower-income countries being exceptionally vulnerable.

Topical Biological Agents as Adjuncts to Improve Wound Healing in Chronic Diabetic Wounds: A Systematic Review of Clinical Evidence and Future Directions.

Diabetes is a leading chronic illness in the modern world and 19-34% develop chronic diabetic foot ulcers (DFUs) in their lifetime, often necessitating amputation. The reduction in tissue growth factors and resulting imbalance between proteolytic enzymes and their inhibitors, along with systemic factors impairing healing appear particularly important in chronic wounds. Growth factors applied topically have thus been suggested to be a non-invasive, safe, and cost-effective adjunct to improve wound healing and prevent complications. Comprehensive database searches of MEDLINE via PubMed, EMBASE, Cochrane, and ClinicalTrials.gov were performed to identify clinical evidence and ongoing trials. The risk of bias analysis included randomized controlled trials (RCTs) was performed using the Cochrane Risk of Bias 2.0 tool. We included randomized controlled trials that compared the use of a topical biologic growth factor-containing regimen to any other regimen. Primary outcomes of interest were time to wound closure, healing rate, and time. Secondary outcomes included the incidence of adverse events such as infection. A total of 41 trials from 1992-2020 were included in this review, with a total recorded 3,112 patients. Platelet-derived growth factors (PDGF) in the form of becaplermin gel are likely to reduce the time of closure, increase the incidence of wound closure, and complete wound healing. Human umbilical cord-related treatments, dehydrated human amnion and chorion allograft (dHACA), and hypothermically stored amniotic membrane (HSAM), consistently increased the rates and incidence of complete ulcer healing while reducing ulcer size and time to complete ulcer healing. Fibroblast growth factor-1 (FGF1) showed only a slight benefit in multiple studies regarding increasing complete ulcer healing rates and incidence while reducing ulcer size and time to complete ulcer healing, with a few studies showing no statistical difference from placebo. Platelet-rich fibrin (PRF) is consistent in reducing the time to complete ulcer healing and increasing wound healing rate but may not reduce ulcer size or increase the incidence of complete ulcer healing. Targeting the wound healing pathway via the extrinsic administration of growth factors is a promising option to augment wound healing in diabetic patients. Growth factors have also shown promise in specific subgroups of patients who are at risk of significantly impaired wound healing such as those with a history of secondary infection and vasculopathy. As diabetes impairs multiple stages of wound healing, combining growth factors in diabetic wound care may prove to be an area of interest. Evidence from this systematic literature review suggests that topical adjuncts probably reduce time to wound closure, reduce healing time, and increase the healing rate in patients with chronic DFUs.

Non-invasive electrical stimulation in patients with neurodegenerative ataxia and spasticity: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: There are limited treatment options for patients with neurodegenerative ataxia and spasticity. Non-invasive electrostimulation (NES) is receiving increasing interest because of its ease of implementation, cost-effectiveness and safety. A meta-analysis was conducted to evaluate the efficacy of NES. METHODS: MEDLINE and Embase were screened for studies using NES in ataxias and spasticity. Key outcome measurements of effectiveness included changes in (1) Modified Ashworth Scale (MAS) scores, (2) cerebellar brain inhibition (CBI), (3) the nine-hole peg test (9HPT), (4) the 8-m walking time (8MWT), (5) International Cooperative Ataxia Rating Scale (ICARS) score and (6) the Scale for Assessment and Rating of Ataxia (SARA) scores. RESULTS: Seven randomized controlled trials involving 203 patients were included. There were significant improvements in MAS (mean difference [MD] -0.42, 95% confidence interval [CI] -0.76 to -0.08, p = 0.015), CBI (MD -0.35%, 95% CI -0.42 to -0.28, p < 0.001), 8MWT (MD -1.88 s, 95% CI -3.26 to -0.49, p = 0.008), ICARS (MD -7.84, 95% CI -11.90 to -3.78, p < 0.001) and SARA (MD -3.01, 95% CI -4.74 to -1.28, p < 0.001). There was almost no heterogeneity across all outcomes except for CBI (I2  = 79%). No significant changes in the 9HPT were observed comparing NES to a sham procedure (MD -3.52 s, 95% CI -9.15 to 2.10, p = 0.220). Most included studies were at low risk of bias, and no severe adverse effects were reported. CONCLUSION: It was demonstrated that NES is an effective treatment for improving coordination and balance and increased exercise capacity in patients with ataxia and spasticity. There was also a significant modulation of CBI in ataxic patients.

Booster doses of COVID-19 vaccines for patients with haematological and solid cancer: a systematic review and individual patient data meta-analysis.

IMPORTANCE: Patients with cancer have an increased risk of severe disease and mortality from COVID-19, as the disease and antineoplastic therapy cause reduced vaccine immunogenicity. Booster doses have been proposed to enhance protection, and efficacy data are emerging from several studies. OBJECTIVE: To evaluate the proportion of COVID-19 primary vaccination non-responders with cancer who seroconvert after a booster dose. METHODS: PubMed, EMBASE, CENTRAL and medRxiv were searched from 1st January 2021 to 10th March 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal checklist. RESULTS: After the eligibility assessment, 22 studies were included in this systematic review and 17 for meta-analysis of seroconversion in non-responders, pooling a total of 849 patients with haematological cancer and 82 patients with solid cancer. Haematological cancer non-responders exhibited lower seroconversion at 44% (95% CI 36-53%) than solid cancer at 80% (95% CI 69-87%). Individual patient data meta-analysis found the odds of having a meaningful rise in antibody titres to be significantly associated with increased duration between the second and third dose (OR 1.02, 95% CI 1.00-1.03, P ≤ 0.05), age of patient (OR 0.960, 95% CI 0.934-0.987, P ≤ 0.05) and cancer type. With patients with haematological cancer as a reference, patients with lung cancer had 16.8 times the odds of achieving a meaningful increase in antibody titres (OR 16.8, 95% CI 2.95-318, P ≤ 0.05) and gastrointestinal cancer patients had 25.4 times the odds of achieving a meaningful increase in antibody titres (OR 25.4, 95% CI 5.26-492.21, P ≤ 0.05). CONCLUSIONS: administration of a COVID-19 vaccine booster dose is effective in improving seroconversion and antibody levels. Patients with haematological cancer consistently demonstrate poorer response to booster vaccines than patients with solid cancer.