Deep Brain Stimulation and Levodopa Affect Gait Variability in Parkinson Disease Differently.

BACKGROUND: Both dopaminergic medication and subthalamic nucleus (STN) deep brain stimulation (DBS) can improve the amplitude and speed of gait in Parkinson disease (PD), but relatively little is known about their comparative effects on gait variability. Gait irregularity has been linked to the degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN). OBJECTIVES: The STN and PPN have reciprocal connections, and we hypothesized that STN DBS might improve gait variability by modulating PPN function. Dopaminergic medication should not do this, and we therefore sought to compare the effects of medication and STN DBS on gait variability. MATERIALS AND METHODS: We studied 11 patients with STN DBS systems on and off with no alteration to their medication, and 15 patients with PD without DBS systems on and off medication. Participants walked for two minutes in each state, wearing six inertial measurement units. Variability has previously often been expressed in terms of SD or coefficient of variation over a testing session, but these measures conflate long-term variability (eg, gradual slowing, which is not necessarily pathological) with short-term variability (true irregularity). We used Poincaré analysis to separate the short- and long-term variability. RESULTS: DBS decreased short-term variability in lower limb gait parameters, whereas medication did not have this effect. In contrast, STN DBS had no effect on arm swing and trunk motion variability, whereas medication increased them, without obvious dyskinesia. CONCLUSIONS: Our results suggest that STN DBS acts through a nondopaminergic mechanism to reduce gait variability. We believe that the most likely explanation is the retrograde activation of cholinergic PPN projection neurons.

Application of the aqueous two-phase system and nanozyme signal enhancement for the improved detection of Plasmodium lactate dehydrogenase in serum.

Malaria is an infectious disease that can cause severe sickness and death if not diagnosed and treated in a timely manner. The current gold standard technique for malaria diagnosis is microscopy, which requires a dedicated laboratory setting and trained personnel and can have a long time to result. These requirements can be alleviated using paper-based diagnostic devices that enable rapid and inexpensive diagnosis at the point of care, which can allow patients to receive treatment before their symptoms progress when used for early detection of diseases. The lateral-flow immunoassay (LFA) is one such device, but currently available LFAs are susceptible to false negative results caused by low parasite density. To improve sensitivity and detection, we utilized the aqueous two-phase system (ATPS) to concentrate and purify the sample, and nanozyme signal enhancement to increase the intensity of the visible signal on the test strip. We were able to achieve a limit of detection (LOD) of 0.01 ng/mL for the malaria biomarker Plasmodium lactate dehydrogenase (pLDH) in human serum using a multi-step assay combining the LFA format with the ATPS and nanozyme signal enhancement.

The current state of the evidence for the use of drains in spinal surgery: systematic review.

PURPOSE: Search for evidence pertaining to the effectiveness of drains used in spinal surgeries. METHOD: PubMed and EMBASE databases were searched for articles pertaining to the use of drains in all types of spinal surgery. The bibliographies of relevant studies were searched for additional papers that met the initial inclusion criteria. Level I and II studies were scored according to guidelines in the Cochrane Collaboration Back Review Group. We utilised the Population, Intervention, Comparison, Outcomes and Study design (PICOS) method to define our study eligibility criteria. RESULTS: Nineteen papers were identified: four level I studies, eight level III studies and seven level IV studies. The four level I, involving the randomization of patients into 'drain' and 'non-drain' groups, identified a total of 363 patients. Seven of the eight level III retrospective studies concluded that the use of drains did not reduce complications. Two of the seven level IV studies agreed with this conclusion. The remaining five level IV studies reported the benefits of lumbar drainage following dural tears. CONCLUSIONS: There is a paucity of published literature on the use of drains following spinal surgery. This is the first study to assess the evidence for the benefits of drains post-operatively in spinal surgery. The identified studies have shown that drains do not reduce the incidence of complications in anterior cervical discectomy and fusion, one and two level posterior cervical fusions, lumbar laminectomies, lumbar decompressions or discectomies and posterior spinal fusion for adolescent scoliosis. Further level I and II studies are needed.

Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.

OBJECTIVES: To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study. METHODS: In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1-Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates. RESULTS: Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1-Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group. CONCLUSIONS: In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab. TRIAL REGISTRATION NUMBER: NCT00929864.

Critical Changes in the Maternal Health Landscape: Community Care, Doulas, and Coverage.

In this commentary, we present an overview of the accelerating trend toward community-based models for pregnancy care. Doula services, as part of community care programs, are the major target for new coverage changes. Obstetric professionals who include community care providers in their treatment plans can benefit from these local resources in the prenatal, birthing, and postpartum stages of patient management. Including community care programs may help achieve goals of improving health outcomes and health equity.

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease.

BACKGROUND AND OBJECTIVES: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort. METHODS: This cross-sectional analysis used data from 2 studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. RESULTS: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 µm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 µm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. DISCUSSION: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.

Oculomotor deficits in Parkinson's disease: Increasing sensitivity using multivariate approaches.

Parkinson's disease (PD) affects several domains of neurological function, from lower-level motor programs to higher cognitive processing. As certain types of eye movements (saccades) are fast, non-fatiguing, and can be measured objectively and non-invasively, they are a promising candidate for quantifying motor and cognitive dysfunction in PD, as well as other movement disorders. In this pilot study, we evaluate the latency (reaction time), damping (resistance to oscillation), and amplitude of saccadic movements in two tasks performed by 25 PD patients with mild to moderate disease and 26 age-matched healthy controls. As well as general increases in reaction time caused by PD, the damping of saccadic eye movements was found to be task-dependent and affected by disease. Finally, we introduce a proof-of-concept multivariate model to demonstrate how information from saccadometry can be combined to infer disease status.

Parkinson's disease deficits in time perception to auditory as well as visual stimuli - A large online study.

Cognitive deficits are common in Parkinson's disease (PD) and range from mild cognitive impairment to dementia, often dramatically reducing quality of life. Physiological models have shown that attention and memory are predicated on the brain's ability to process time. Perception has been shown to be increased or decreased by activation or deactivation of dopaminergic neurons respectively. Here we investigate differences in time perception between patients with PD and healthy controls. We have measured differences in sub-second- and second-time intervals. Sensitivity and error in perception as well as the response times are calculated. Additionally, we investigated intra-individual response variability and the effect of participant devices on both reaction time and sensitivity. Patients with PD have impaired sensitivity in discriminating between durations of both visual and auditory stimuli compared to healthy controls. Though initially designed as an in-person study, because of the pandemic the experiment was adapted into an online study. This adaptation provided a unique opportunity to enroll a larger number of international participants and use this study to evaluate the feasibility of future virtual studies focused on cognitive impairment. To our knowledge this is the only time perception study, focusing on PD, which measures the differences in perception using both auditory and visual stimuli. The cohort involved is the largest to date, comprising over 800 participants.

Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to autoimmune pancreatitis.

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) underlies 5%-11% of cases of chronic pancreatitis. An association between AIP and the human leukocyte antigen (HLA)-DRB1*0405/DQB1*0401 haplotype has been reported, but linkage disequilibrium has precluded the identification of predisposing HLA gene(s). We studied the role of single HLA genes in the development of AIP in transgenic mice. METHODS: CD4(+) T-cell-negative I-Abeta chain(-/-) (Ab0) mice develop AIP spontaneously, likely due to dysregulation of CD8(+) T- cell responses. We generated Ab0 nonobese diabetic (NOD) mice transgenic for HLA-DR*0405, leading to rescue of CD4(+) T cells; we compared their susceptibility to AIP with HLA-DQ8 or HLA-DR*0401 (single) transgenic, or HLA-DR*0405/DQ8 (double) transgenic mice. RESULTS: CD4(+) T-cell-competent HLA-DR*0405 transgenic Ab0 NOD mice develop AIP with high prevalence after sublethal irradiation and adoptive transfer of CD90(+) T cells, leading to complete pancreatic atrophy. HLA-DR*0405 transgenic mice can also develop unprovoked AIP, whereas HLA-DR*0401, HLA-DQ8, and HLA-DR*0405/DQ8 transgenic Ab0 NOD controls all remained normal, even after irradiation and adoptive transfer of CD90(+) T cells. Pancreas histology in HLA-DR*0405 transgenic mice was characterized by destructive infiltration of the exocrine tissue with CD4(+) and CD8(+) T cells, B cells, and macrophages. Mice with complete pancreatic atrophy lost weight, developed fat stools, and had reduced levels of serum lipase activity. CONCLUSIONS: Because HLA-DR*0405 expression fails to protect mice from AIP, the HLA-DRB1*0405 allele appears to be an important risk factor for AIP on the HLA-DRB1*0405/DQB1*0401 haplotype. This humanized mouse model should be useful for studying immunopathogenesis, diagnostic markers, and therapy of human AIP.

Wandering Atrial Pacemaker Wire: Migration of a Temporary Epicardial Pacing Wire Into the Left Heart.

Temporary epicardial pacing, routinely used after cardiac surgery, employs wires anchored to the epicardium allowing removal via traction. In cases of resistance, the temporary wires are cut flush at the skin. We present a rare noninfectious case of a migrated retained temporary pacing wire into the left heart. (Level of Difficulty: Beginner.).

Oculomotor effects of medical and surgical treatments of Parkinson's disease.

Oculomotor abnormalities are fast becoming a proxy for disease diagnosis and progression. Saccades-ballistic eye movements-are known to be affected by dopaminergic cell loss in the basal ganglia, caused by Parkinson's disease. Pharmaceutical and neurosurgical interventions such as deep brain stimulation and functional neurosurgery have both been noted to have an effect on saccades. Comparing and contrasting these effects may yield insights into Parkinson's disease pathophysiology, and the mechanisms of pharmacological and neurosurgical treatments. Computational models of saccadic control, such as the LATER model, can help to interpret the distribution of saccadic latencies, providing a framework for objectively comparing the effects of pharmaceutical interventions and deep brain stimulation.

Prognostic implications of negative dobutamine stress echocardiography in African Americans compared to Caucasians.

BACKGROUND: African Americans (AA) have higher rates of cardiovascular morbidity and mortality than Caucasians (CA). Despite its excellent negative predictive value, the influence of race on the prognostic implications of negative dobutamine echocardiography in predicting major cardiac problems is largely unknown. METHODS: We studied 387 AA and 340 CA patients with negative dobutamine stress echocardiography (NDSE). Kaplan-Meier survival analysis was used to create freedom-from-event curves for major adverse cardiac events over a 36-month period, and a Cox proportional-hazards multivariable model to examine the influence of race on cardiac outcomes. RESULTS: AA patients were younger (69.4 +/- 12.6 vs. 74.2 +/- 10.7, p < .001), had higher incidence of diabetes mellitus (37% vs. 29%, p = .01), hypertension (91% vs. 85%, p = .006), left ventricular hypertrophy (70% vs. 49%, p < .001) and lower incidence of prior coronary artery disease (27% vs. 34%, p = .05) compared to CA patients. Ejection fraction > or = 50% was comparable (81% vs. 82%, p = .8). At 3-years, AA patients had a lower freedom from nonfatal myocardial infarction (92% vs. 96%, p = .006) and any cardiac event (cardiac death, myocardial infarction) (91% vs. 95%, p = .005) compared to CA patients. CONCLUSION: This is the first study to demonstrate that AA patients have higher rates of nonfatal MI and MACE compared to CA patients with a NDSE. These patients require closer follow-up and aggressive preventive and treatment strategies should be employed to help reduce cardiovascular morbidity and mortality despite negative ischemic workup.

Embolic protection: the FilterWire EZ Embolic Protection System.

The field of interventional cardiology has grown dramatically over the past 30 years, including recent advances in the area of peripheral vascular intervention. The phenomenon of no-reflow, characterized by a reduction in coronary blood flow during vascular intervention, has been associated with adverse outcomes in both saphenous vein graft and carotid artery interventions. Distal embolic protection devices, such as the FilterWire EZ System, have been shown to reduce the incidence of no-reflow and adverse cardiac events in patients undergoing saphenous vein graft interventions. Recently approved indications for the FilterWire EZ System include carotid artery stenting. With the definite reduction in adverse events from the use of distal protection, future advancements will focus on improved deliverability of such devices.

Inferior vena cava filters for recurrent thrombosis: current evidence.

Inferior vena cava filters are often used as alternatives to anticoagulant therapy for the prevention of pulmonary embolism. Many of the clinical data that support the use of these devices stem from relatively limited retrospective studies. The dual purpose of this review is to examine the incidence of thrombotic complications associated with inferior vena cava filters and to discuss the role of anticoagulant therapy concurrent with filter placement. Device-associated morbidity and overall efficacy can be considered only in the context of rates of vena cava thrombosis, insertion-site thrombosis, recurrent deep venous thrombosis, and recurrent pulmonary embolism.

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016.

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.