Streamlined Clinical Management Pathways May Reduce Major Amputations in Patients with Chronic Limb Threatening Ischaemia: A Prospective Cohort Study with Historical Controls.

OBJECTIVE: Patient characteristics and patterns of disease in chronic limb threatening ischaemia (CLTI) have changed markedly in recent years. Urgent specialist referral and timely revascularisation are recommended in international guidelines. UK guidelines now recommend revascularisation within 5 days of referral for inpatients and 2 weeks in outpatients. This study compared the contemporary one year major amputation incidence in patients with CLTI with a historical cohort at a single UK centre. METHODS: This was a single centre, observational cohort study with historical controls. A prospective cohort was recruited between May 2019 and March 2022. A historical cohort presenting between 2013 and 2015 inclusive was identified retrospectively. Significant changes in management pathways, including establishing a rapid access limb salvage clinic, occurred between these periods aiming to expedite time from referral to revascularisation. The one year primary outcome was major amputation, and the secondary outcome was death. Major amputation was analysed by Fine-Gray competing risks models (death as the competing risk), presented as subdistribution hazard ratios (SHRs). One year mortality was analysed by Cox regression, presented as hazard ratios. Analyses were adjusted for propensity score. RESULTS: A total of 928 patients were included (432 prospective and 496 historical). Proportions of patients presenting with tissue loss (72.2% vs. 71.6%; p = .090) were similar in both cohorts. At one year, 48 patients (11.1%) in the prospective cohort and 124 patients (25.0%) in the historical cohort had undergone a major amputation (p < .001). Risk of major amputation was 57.0% lower in the prospective cohort compared with the historical cohort after adjustment for propensity score (SHR 0.43, 95% confidence interval 0.29 - 0.63; p < .001). CONCLUSION: An encouraging reduction in major amputation incidence was observed after improvements to CLTI management pathways, but residual confounding is likely. The generalisability of these results is uncertain.

C1ql1 expression in oligodendrocyte progenitor cells promotes oligodendrocyte differentiation.

Myelinating oligodendrocytes arise from the stepwise differentiation of oligodendrocyte progenitor cells (OPCs). Approximately 5% of all adult brain cells are OPCs. Why would a mature brain need such a large number of OPCs? New myelination is possibly required for higher-order functions such as cognition and learning. Additionally, this pool of OPCs represents a source of new oligodendrocytes to replace those lost during injury, inflammation, or in diseases such as multiple sclerosis (MS). How OPCs are instructed to differentiate into oligodendrocytes is poorly understood, and for reasons presently unclear, resident pools of OPCs are progressively less utilized in MS. The complement component 1, q subcomponent-like (C1QL) protein family has been studied for their functions at neuron-neuron synapses, but we show that OPCs express C1ql1. We created OPC-specific conditional knockout mice and show that C1QL1 deficiency reduces the differentiation of OPCs into oligodendrocytes and reduces myelin production during both development and recovery from cuprizone-induced demyelination. In vivo over-expression of C1QL1 causes the opposite phenotype: increased oligodendrocyte density and myelination during recovery from demyelination. We further used primary cultured OPCs to show that C1QL1 levels can bidirectionally regulate the extent of OPC differentiation in vitro. Our results suggest that C1QL1 may initiate a previously unrecognized signaling pathway to promote differentiation of OPCs into oligodendrocytes. This study has relevance for possible novel therapies for demyelinating diseases and may illuminate a previously undescribed mechanism to regulate the function of myelination in cognition and learning.

Modular synthesis of aryl amines from 3-alkynyl-2-pyrones.

The synthesis of aryl amines from 3-alkynyl-2-pyrones and various amines is described. Mechanistically, the aryl amines are proposed to arise from the 3-alkynyl-2-pyrone substrates through their selective opening in a 1,6-fashion by secondary amines followed by decarboxylation and an unexpected rearrangement. The proposed mechanism is supported by quantum chemical transition-state calculations, which are consistent with the regiochemical outcome. The scope of this transformation spans a variety of 3-alkynyl-2-pyrones and a range of secondary amines. The influence of the secondary amine coupling partners on reaction efficiency was elucidated through data-driven modeling as well as scope exploration. These latter studies revealed that the steric bulk of the secondary amine coupling partner under the reaction conditions serves as a strong indicator of overall reaction efficiency.

Enantioconvergent Cross-Nucleophile Coupling: Copper-Catalyzed Deborylative Cyanation.

Organoboron compounds are widely utilized in organic synthesis for their diverse reactivity, modular preparation, and stability compared to other classes of organometallic reagents. While organoboron species are commonly employed as nucleophiles in cross-coupling reactions, their potential as racemic building blocks in enantioconvergent transformations remains largely untapped. Herein, we demonstrate the direct utilization of alkylboronic pinacol esters in intermolecular enantioconvergent transformations. Specifically, this work describes the development and mechanistic study of an enantioconvergent deborylative cyanation enabled by Cu catalysis. This method imparts a high degree of enantioselectivity and tolerates a wide range of common functional groups and heterocycles. The reaction is proposed to proceed through a radical-relay mechanism. Aniline-assisted homolysis of the carbon-boron bond results in prochiral alkyl radicals that are functionalized by in situ generated Cu(II)(CN)2 species in an enantioselective fashion. The Cu(II)(CN)2 intermediate was characterized by electron paramagnetic resonance (EPR) spectroscopy, and its electronic structure was probed using density functional theory (DFT) calculations. Computational studies were carried out to corroborate the proposed radical-relay mechanism.

Elevated osmol gaps in patients with alcoholic ketoacidosis.

INTRODUCTION: The use of the osmol gap as a surrogate marker of toxic alcohol poisoning is common. Unfortunately, many patients with alcoholic ketoacidosis have elevated osmol gaps and are misdiagnosed with toxic alcohol poisoning. We aimed to characterize the range of osmol gaps in patients with alcoholic ketoacidosis. METHODS: This was a retrospective poison center study. Data from 24 years were reviewed using the following case definition of alcoholic ketoacidosis: (1) documented alcohol use disorder; (2) presence of urine or serum ketones or an elevated blood beta-hydroxybutyrate concentration; (3) an anion gap ≥14 mmol/L. Potential cases of alcoholic ketoacidosis that failed to fulfill all three criteria were adjudicated by three toxicologists. Exclusion criteria included (1) detectable toxic alcohol concentration, (2) hemodialysis and/or multiple doses of fomepizole, (3) no osmol gap documented, (4) other diagnoses that lead to a metabolic acidosis. Demographics, pH, anion gap, lactate concentration, and osmol gap were extracted. RESULTS: Of 1,493 patients screened, 55 met criteria for alcoholic ketoacidosis. Sixty-four percent were male, and their median age was 52 years. The median osmol gap was 27 [IQR 18-36]. The largest anion gap was 57 mmol/L, and the lowest pH was 6.8. Forty-five (82%) of the patients with alcoholic ketoacidosis had osmol gaps >10; 38 (69%) had osmol gaps >20; 24 (44%) had osmol gaps >30; 11 (20%) had osmol gaps > 40. DISCUSSION: The large range of osmol gaps in patients with alcoholic ketoacidosis often reaches values associated with toxic alcohol poisoning. The study is limited by the potential for transcribing errors and the inability to identify the cause of the osmol gap. CONCLUSIONS: In this retrospective study, patients with alcoholic ketoacidosis had a median osmol gap of 26. Given that alcoholic ketoacidosis is easily and inexpensively treated, proper identification may prevent costly and invasive treatment directed at toxic alcohol poisoning.

Sources of Rapid and Delayed New Lower Jaw Input in the Forepaw Barrel Subfield (FBS) in Rat Primary Somatosensory Cortex (SI) Following Forelimb Deafferentation.

Previously, we reported an immediate emergence of new lower jaw input to the anterior forepaw barrel subfield (FBS) in primary somatosensory cortex (SI) following forelimb deafferentation. However, a delay of 7 weeks or more post-amputation results in the presence of this new input to both anterior and posterior FBS. The immediate change suggests pre-existing latent lower jaw input in the FBS, whereas the delayed alteration implies the involvement of alternative sources. One possible source for immediate lower jaw responses is the neighboring lower jaw barrel subfield (LJBSF). We used anatomical tracers to investigate the possible projection of LJBSF to the FBS in normal and forelimb-amputated rats. Our findings are as follows: (1) anterograde tracer injection into LJBSF in normal and amputated rats labeled fibers and terminals exclusively in the anterior FBS; (2) retrograde tracer injection in the anterior FBS in normal and forelimb-amputated rats, heavily labeled cell bodies predominantly in the posterior LJBSF, with fewer in the anterior LJBSF; (3) retrograde tracer injection in the posterior FBS in normal and forelimb-amputated rats, sparsely labeled cell bodies in the posterior LJBSF; (4) retrograde tracer injection in anterior and posterior FBS in normal and forelimb-amputated rats, labeled cells exclusively in ventral posterior lateral (VPL) nucleus and posterior thalamus (PO); (5) retrograde tracer injection in LJBSF-labeled cell bodies exclusively in ventral posterior medial thalamic nucleus and PO. These findings suggest that LJBSF facilitates rapid lower jaw reorganization in the anterior FBS, whereas VPL and/or other subcortical sites provide a likely substrate for delayed reorganization observed in the posterior FBS.

Does the Primary Tumor Site Drive Biology for Patients With Synovial Sarcoma?

OBJECTIVE: We evaluated survival outcomes by primary tumor site in synovial sarcoma (SS) patients with localized and metastatic disease at diagnosis. METHODS: We conducted a retrospective review of 504 SS patients diagnosed from 1974 to 2020. Kaplan-Meier method, log-rank test, and Cox-proportional hazards regression were used. RESULTS: Among 504 patients, 401 (79.6%) presented with localized disease, and 103 (20.4%) with metastases. For patients with localized disease, (1) 5-year OS by tumor site was as follows: 80% (95% CI, 67%-89%) for head/neck, 30% (95% CI, 18%-42%) for intrathoracic, 51% (95% CI, 35%-65%) for abdomen/pelvis, 71% (95% CI, 62%-79%) for proximal-extremity, and 83% (71%, 91%) for distal-extremity. (2) On multivariable analysis, tumor site (compared with proximal-extremity: intrathoracic tumors [HR: 1.95; 95% CI, 1.22-3.16]; hand/foot [HR: 0.52; 95% CI, 0.28-0.97]), tumor size (compared with <5 cm, 5-10 cm [HR: 1.80; 95% CI, 1.14-2.85]; ≥10 cm [HR: 4.37; 95% CI, 2.69-7.11]), and use of neo/adjuvant radiation (HR: 0.54; 95% CI, 0.37-0.79) remained significantly associated with OS. For patients with metastatic disease, (1) 5-year OS was 12% (95% CI, 6%-21%) and (2) the only factor that remained significantly associated with OS on multivariable analysis was surgical resection for the primary tumor (HR: 0.14; 95% CI, 0.08-0.26). CONCLUSIONS: The primary tumor location plays a significant role in predicting outcomes for patients with localized SS. Even though patients present with metastatic disease, surgical resection of the primary tumor improves their survival. These findings are critical for patient counseling and designing a personalized treatment plan that reflects the corresponding outcomes.

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk.

BACKGROUND: Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. METHODS: In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis. RESULTS: At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline. CONCLUSIONS: Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).

A comparative study of influenza surveillance systems and administrative data in England during the 2022-2023 season.

Accurate and representative surveillance is essential for understanding the impact of influenza on healthcare systems. During the 2022-2023 influenza season, the Northern Hemisphere experienced its most significant epidemic wave since the onset of the COVID-19 pandemic in 2020. Concurrently, new surveillance systems, developed in response to the pandemic, became available within health services. In this study, we analysed per capita admission rates from National Health Service hospital Trusts across four surveillance systems in England during the winter of 2022-2023. We examined differences in reporting timeliness, data completeness, and regional coverage, modelling key epidemic metrics including the maximum admission rates, cumulative seasonal admissions, and growth rates by fitting generalised additive models at national and regional levels. From modelling the admission rates per capita, we find that different surveillance systems yield varying estimates of key epidemiological metrics, both spatially and temporally. While national data from these systems generally align on the maximum admission rate and growth trends, discrepancies emerge at the subnational level, particularly in the cumulative admission rate estimates, with notable issues observed in London and the East of England. The rapid growth and decay phases of the epidemic contributed to higher uncertainty in these estimates, especially in regions with variable data quality. The study highlights that the choice of surveillance system can significantly influence the interpretation of influenza trends, especially at the subnational level, where regional disparities may mask true epidemic dynamics. Comparing multiple data sources enhances our understanding of the impact of seasonal influenza epidemics and highlights the limitations of relying on a single system.

Reduced Stroke Volume and Brain Perfusion Drive Postural Hyperventilation in Postural Orthostatic Tachycardia Syndrome.

Postural hyperventilation has been implicated as a cause of postural orthostatic tachycardia syndrome (POTS), yet the precise mechanisms underlying the heightened breathing response remain unclear. This study challenges current hypotheses by revealing that exaggerated peripheral chemoreceptor activity is not the primary driver of postural hyperventilation. Instead, significant contributions from reduced stroke volume and compromised brain perfusion during orthostatic stress were identified. These findings shed light on our understanding of POTS pathophysiology, emphasizing the critical roles of systemic hemodynamic status. Further research should explore interventions targeting stroke volume and brain perfusion for more effective clinical management of POTS.

Single and two-dose typhoid conjugate vaccine safety and immunogenicity in HIV-exposed uninfected and HIV-unexposed uninfected Malawian children.

Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

Long guidewire peripheral intravenous catheters in emergency departments for management of difficult intravenous access: A multicenter, pragmatic, randomized controlled trial.

BACKGROUND: A quarter of patients who present to emergency departments (EDs) have difficult intravenous access (DIVA), making it challenging for clinicians to successfully place a peripheral intravenous catheter (PIVC). Some literature suggests that guidewire PIVC improves first-insertion success rate. AIM: The aim was to determine the clinical and cost-effectiveness of a novel long PIVC (5.8 cm) with a retractable coiled guidewire (GW-PIVC) for patients with DIVA, compared with standard care PIVCs. METHODS: A pragmatic randomized controlled trial was conducted in two Australian EDs. Eligible participants were adults assessed as meeting DIVA criteria. Participants were randomized (1:1 ratio; stratified by hospital) to either GW-PIVC (long) or standard care group (short or long PIVC). The use of ultrasound was discretionary in the standard care group and was recommended in the GW-PIVC group due to the pragmatic design that was primarily testing the GW-PIVC rather than the ultrasound use. Primary outcome was first-insertion success and secondary outcomes included all-cause device failure, patient and staff satisfaction, and cost-effectiveness. The analysis was intention to treat. RESULTS: A total of 446 participants were randomized and 409 received PIVCs. The use of GW-PIVC, compared with standard PIVC, had a lower first-insertion success rate (68% vs. 77%, odds ratio [OR] 0.65, 95% confidence interval [CI] 0.43-0.99, p < 0.05). There was no difference in PIVC failure (134.0 per 1000 catheter days [GW-PIVC] vs. 111.8 [standard PIVC] per 1000 catheter days, hazard ratio 1.18, 95% CI 0.72-1.95). Both participant (8/10 vs. 9/10, median difference [MD] -1.00, 95% CI -1.37 to -0.63) and clinician (8/10 vs. 10/10, MD -2.00, 95% CI -2.37 to -1.63) satisfaction was lower with GW-PIVCs compared with standard PIVCs. More nurses inserted standard PIVCs than GW-PIVCs (56.9% vs. 36.5%) and had less confidence in their ultrasound skills (28.0% vs. 46.6% self-claimed as advanced/expert users). The cost per participant of GW-PIVC insertions was 2.46 times greater than standard PIVC insertions ($AU80.24 vs. $AU32.57). CONCLUSIONS: GW-PIVCs had significantly lower first-insertion success and non-significantly higher all-cause catheter failure. Additional training and device design familiar to clinicians are vital factors to enhance the likelihood of successful future implementation of GW-PIVCs.

Population genomics of Streptococcus mitis in UK and Ireland bloodstream infection and infective endocarditis cases.

Streptococcus mitis is a leading cause of infective endocarditis (IE). However, our understanding of the genomic epidemiology and pathogenicity of IE-associated S. mitis is hampered by low IE incidence. Here we use whole genome sequencing of 129 S. mitis bloodstream infection (BSI) isolates collected between 2001-2016 from clinically diagnosed IE cases in the UK to investigate genetic diversity, antimicrobial resistance, and pathogenicity. We show high genetic diversity of IE-associated S. mitis with virtually all isolates belonging to distinct lineages indicating no predominance of specific lineages. Additionally, we find a highly variable distribution of known pneumococcal virulence genes among the isolates, some of which are overrepresented in disease when compared to carriage strains. Our findings suggest that S. mitis in patients with clinically diagnosed IE is not primarily caused by specific hypervirulent or antimicrobial resistant lineages, highlighting the accidental pathogenic nature of S. mitis in patients with clinically diagnosed IE.

An Analysis of the Interplay and Mutual Benefits of Grounded Theory and Visualization.

Grounded theory (GT) is a research methodology that entails a systematic workflow for theory generation grounded on emergent data. In this paper, we juxtapose GT workflows with typical workflows in visualization and visual analytics (VIS), unveiling the characteristics shared by these workflows. We explore the research landscape of VIS to study where GT is applied to generate VIS theories, explicitly as well as implicitly. We discuss "why" GT can potentially play a significant role in VIS. We outline a "how" methodology for conducting GT research in VIS, which addresses the need for theoretical advancement in VIS while benefiting from other methods and techniques in VIS. We illustrate this "how" methodology with a use case of adopting GT approaches in studying visualization guidelines.

Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease.

BACKGROUND: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION: Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. HIGHLIGHTS: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE-𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families.

Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose.

In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with CYP3A5 (rs776746) and DRD2 (rs4436578), and decreased odds with NKIR (rs6715729). Homozygotic CYP3A5 (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic NK1R (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that CYP3A5 (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. NK1R regulates the expression of the neurokinin-1 receptor, a regulator of respiration and NK1R (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.

Movement-related activity in the internal globus pallidus of the parkinsonian macaque.

Although the basal ganglia (BG) plays a central role in the motor symptoms of Parkinson's disease, few studies have investigated the influence of parkinsonism on movement-related activity in the BG. Here, we studied the perimovement activity of neurons in globus pallidus internus (GPi) of non-human primates before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal responses were equally common in the parkinsonian brain as seen prior to MPTP and the distribution of different response types was largely unchanged. The slowing of behavioral reaction times and movement durations following the induction of parkinsonism was accompanied by a prolongation of the time interval between neuronal response onset and movement initiation. Neuronal responses were also reduced in magnitude and prolonged in duration after the induction of parkinsonism. Importantly, those two effects were more pronounced among decrease-type responses, and they persisted after controlling for MPTP-induced changes in the trial-by-trial timing of neuronal responses. Following MPTP The timing of neuronal responses also became uncoupled from the time of movement onset and more variable from trial-to-trial. Overall, the effects of MPTP on temporal features of neural responses correlated most consistently with the severity of parkinsonian motor impairments whereas the changes in response magnitude and duration were either anticorrelated with symptom severity or inconsistent. These findings point to a potential previously underappreciated role for abnormalities in the timing of GPi task-related activity in the generation of parkinsonian motor signs.