Directional electrodes in deep brain stimulation: Results of a survey by the European Association of Neurosurgical Societies (EANS).

Introduction: Directional Leads (dLeads) represent a new technical tool in Deep Brain Stimulation (DBS), and a rapidly growing population of patients receive dLeads. Research question: The European Association of Neurosurgical Societies(EANS) functional neurosurgery Task Force on dLeads conducted a survey of DBS specialists in Europe to evaluate their use, applications, advantages, and disadvantages. Material and methods: EANS functional neurosurgery and European Society for Stereotactic and Functional Neurosurgery (ESSFN) members were asked to complete an online survey with 50 multiple-choice and open questions on their use of dLeads in clinical practice. Results: Forty-nine respondents from 16 countries participated in the survey (n = 38 neurosurgeons, n = 8 neurologists, n = 3 DBS nurses). Five had not used dLeads. All users reported that dLeads provided an advantage (n = 23 minor, n = 21 major). Most surgeons (n = 35) stated that trajectory planning does not differ when implanting dLeads or conventional leads. Most respondents selected dLeads for the ability to optimize stimulation parameters (n = 41). However, the majority (n = 24), regarded time-consuming programming as the main disadvantage of this technology. Innovations that were highly valued by most participants included full 3T MRI compatibility, remote programming, and closed loop technology. Discussion and conclusion: Directional leads are widely used by European DBS specialists. Despite challenges with programming time, users report that dLeads have had a positive impact and maintain an optimistic view of future technological advances.

A randomized controlled trial of recovery management checkups for primary care patients: Twelve-month results.

BACKGROUND: Primary care settings like federally qualified health centers (FQHC) are optimal locations to identify individuals with substance use disorders (SUD) and link them to SUD treatment, yet successful linkage has proven difficult. Recovery management checkups for primary care (RMC-PC) is a promising method for increasing linkage to care, engagement in treatment, and reducing substance use. METHODS: Participants (n = 266) who received screening, brief intervention, and referral to treatment (SBIRT) at four FQHC sites and needed SUD treatment were randomized to receive SBIRT only or SBIRT+RMC-PC. All participants received SBIRT prior to randomization as part of usual care while those in the experimental group also received quarterly checkups. All participants completed research interviews at enrollment and 3, 6, 9, and 12 months post-enrollment. The primary outcome was whether participants received any days of SUD treatment. Key secondary outcomes were days of SUD treatment (total and by SUD level of care), days of alcohol or drug abstinence, and a reduction in days of specific substance use, all based on self-report. RESULTS: Relative to participants receiving SBIRT only, participants assigned to SBIRT+RMC-PC were significantly more likely to have received any SUD treatment over 12 months (adjusted odds ratio [AOR] = 3.85) and more days of SUD treatment over 12 months (Cohen's effect size d = +0.41). The SBIRT+RMC-PC group also reported significantly more days of abstinence over 12 months (d = +0.30), fewer days of alcohol use (d = -0.20) and cannabis use (d = -0.20), and lower combined substance use frequency (d = -0.25). Days of treatment were found to positively mediate the direct effect of SBIRT+RMC-PC on days of abstinence. CONCLUSION: This study provides further evidence of the effectiveness of the "referral to treatment" component of SBIRT when combined with RMC for patients in primary care settings, including those with drug use problems. Moreover, results demonstrate the value of repeated checkups on longer-term treatment and substance use outcomes.

High output power, single mode, and TEM00 operation of a multiple gain chip VECSEL using a twisted-mode configuration.

A vertical external cavity surface emitting laser (VECSEL) has been developed for a sodium guide star application. Stable single frequency operation with 21 W of output power near 1178 nm with multiple gain elements while lasing in the TEM00 mode has been achieved. Higher output power results in multimode lasing. For the sodium guide star application, the 1178 nm can be frequency doubled to 589 nm. The power scaling approach used involves using multiple gain mirrors in a folded standing wave cavity. This is the first demonstration of a high power single frequency VECSEL using a twisted-mode configuration and multiple gain mirrors located at the cavity folds.

Using recovery management checkups for primary care to improve linkage to alcohol and other drug use treatment: a randomized controlled trial three month findings.

BACKGROUND AND AIMS: Recovery management checkups (RMC) have established efficacy for linking patients to substance use disorder (SUD) treatment. This study tested whether using RMC in combination with screening, brief intervention, and referral to treatment (SBIRT), versus SBIRT alone, can improve linkage of primary care patients referred to SUD treatment. DESIGN: A randomized controlled trial of SBIRT as usual (n = 132) versus SBIRT plus recovery management checkups for primary care (RMC-PC) (n = 134) with follow-up assessments at 3 months post-baseline. SETTING: Four federally qualified health centers in the United States serving low-income populations. PARTICIPANTS: Primary care patients (n = 266, 64% male, 80% Black, mean age, 48.3 [range, 19-53]) who were referred to SUD treatment after SBIRT. INTERVENTIONS: SBIRT alone (control condition) compared with SBIRT + RMC-PC (experimental condition). MEASUREMENT: The primary outcome was any days of SUD treatment in the past 3 months. Key secondary outcomes were days of SUD treatment overall and by level of care, days of alcohol and other drug (AOD) abstinence, and days of using specific substances, all based on self-report. FINDINGS: At 3-month follow-up, those assigned to SBIRT + RMC-PC (n = 134) had higher odds of receiving any SUD treatment (46% vs 20%; adjusted odds ratio = 4.50 [2.49, 8.48]) compared with SBIRT only, including higher rates of entering residential and intensive outpatient treatment. They also reported more days of treatment (14.45, vs 7.13; d = +0.26), more days abstinent (41.3 vs 31.9; d = +0.22), and fewer days of using alcohol (27.14, vs 36.31; d = -0.25) and cannabis (19.49, vs 28.6; d = -0.20). CONCLUSIONS: Recovery management checkups in combination with screening, brief intervention, and referral to treatment are an effective strategy for improving linkage of primary care patients in need to substance use disorder treatment over 3 months.

Increased variance in second electrode accuracy during deep brain stimulation and its relationship to pneumocephalus, brain shift, and clinical outcomes: A retrospective cohort study.

•Overall electrode accuracy was 0.22+/-0.4 â€‹mm with only 3 (4%) electrodes out with 2 â€‹mm from the intended target.•Accuracy was significantly worse in the GPi versus the STN and on the second side implanted.•Inaccuracy occurred in the X (lateral) plane but was not related to pneumocephalus or brain shift.

Rapid quasi-periodic oscillations in the relativistic jet of BL Lacertae.

Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales1-3. This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet5, plasma instabilities6,7 or orbital motion in an accretion disc7,8. Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref. 9). BL Lac, the prototype of a subclass of blazars10, is powered by a 1.7 × 108 MSun (ref. 11) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref. 12)). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image.

Strong host-specific selection and over-dominance characterize arbuscular mycorrhizal fungal root colonizers of coastal sand dune plants of the Mediterranean region.

Sand dunes of the Mediterranean region constitute drought-stressed, low-fertility ecosystems. Arbuscular mycorrhizal fungi (AMF) are regarded as key components of their biota, that contribute to plant host adaptation and fitness. However, AMF community assembly rules in the roots of the psammophilous plants of coastal sand dunes have not been investigated. We studied the root colonizing AMF communities of four characteristic native plants of eastern Mediterranean coastal foredunes, in nine locations in Greece. Host-specificity (plant identity) was the major driver of AMF community assembly in the plant roots, while geographical distance between locations was not related to differences in the AMF communities. Additionally, colonizer AMF communities were characterized by over-dominance of a single operational taxanomic unit (OTUs), which was remarkably host-specific among locations. Wider dissimilarity in AMF communities was observed in small and disturbed (SD) sites compared to large and undisturbed (LU) sites, a trait that may be attributed to relaxed environmental filtering and facilitated AMF dispersal/immigration in SD sites from surrounding habitats. Overall, our results indicate that the assembly of root-colonizing AMF communities in the eastern Mediterranean sand dunes is characterized by strong biotic filtering (host identity), suggesting that co-adaptation processes may be more pronounced than previously proposed, under extreme environmental conditions.

Laboratory biomarkers associated with COVID-19 severity and management.

The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokines implicated in COVID-19 for their potential application as biomarkers of disease severity, respiratory failure and need of higher-level care. From analysis of 203 samples, CRP, IL-6, IL-10 and LDH were most strongly correlated with the WHO ordinal scale of illness severity, the fraction of inspired oxygen delivery, radiological evidence of ARDS and level of respiratory support (p ≤ 0.001). IL-6 levels of ≥3.27 pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for a requirement of ventilation, and a CRP of ≥37 mg/l of 0.91 and 0.66. Reliable stratification of high-risk cases has significant implications on patient triage, resource management and potentially the initiation of novel therapies in severe patients.

Projected Cost-Effectiveness for 2 Gene-Drug Pairs Using a Multigene Panel for Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: For patients undergoing percutaneous coronary intervention, gene-drug associations exist relevant to first-line treatment options-antiplatelet agent, clopidogrel, and pain medication, tramadol. Knowledge of genotype information may allow for avoidance of adverse drug events during critical clinical windows. OBJECTIVE: This evaluation estimated cost-effectiveness associated with a multi-gene panel pre-emptively testing two genes providing CYP2C19 genotype-guided strategy for antiplatelet therapy, with CYP2D6 genotype-guided pain management, compared to single gene test for CYP2C19 with random assignment for pain treatment, and to no testing (empiric clopidogrel with random assignment for pain treatment). METHODS: Decision analysis modeling was used to project costs from a payer perspective and patient quality-adjusted life years (QALYs) from the three strategies. The model captured composite risks of major adverse cardiovascular events and pain therapy-related adverse drug events and associated utility estimates. We conducted sensitivity analyses to assess influential input parameters. RESULTS: Over 15 months, multi-gene testing was least costly and yielded more QALYs compared to both single gene and no testing; total incremental costs were $1646 lower with incremental gains of 0.04 QALYs for multi-gene compared with single gene and $11 368 lower with 0.17 QALY gains compared to no test. Base case analyses revealed multi gene was dominant compared to both single gene and no test, as it demonstrated cost savings with increased QALYs. CONCLUSIONS: For these patients, a multi-gene-guided strategy yields a favorable incremental cost-effectiveness ratio compared to the other two treatment strategies. Pre-emptively ascertaining additional gene-drug pair information can inform clinical and economic decision-making at the point of care.

Insurance coverage does not predict outcomes of genetic testing: The search for meaning in payer decisions for germline cancer tests.

In this work, we explore the results of germline cancer genetic tests in individuals whose insurance would not cover this testing. We enrolled 31 patients with a personal history of cancer whose health insurer denied coverage for a clinical germline cancer panel genetic test recommended by a medical genetics provider into a study providing exome sequencing and return of cancer-related results. Five participants (16%) had a pathogenic variant identified related to increased cancer risk. Three participants (10%) had a variant of uncertain significance (VUS) in a gene related to their cancer history. These rates are not significantly different than the 12% rate of pathogenic or likely pathogenic (P/LP) variants and VUS in 1,462 patients approved by insurance to have a similar clinical germline cancer test (p = .59 for P/LP variants; p = .87 for VUS; Shirts et al., Genet Med, 18:974, 2016). Health insurance guidelines may not meaningfully differentiate between patients with cancer who are likely to benefit from germline cancer genetic testing and those who will not. Failure to identify pathogenic variants in this research cohort would have led to suboptimal care. Strategic evaluation of current germline cancer genetic testing coverage policies is needed to appropriately deliver precision medicine.

Consideration for Employer-Based and Geographic Attributes Included in Value Assessment Methods of Next-Generation Sequencing Tests.

There is a need for formal cost-effectiveness evidence to better model the real-world payer decision context in which general economic models are currently being used, specifically regarding clinical genomics health services (for next-generation sequencing (NGS) tests). We reviewed literature focused on cost-effectiveness studies after completion of the Human Genome Project within the Tufts Cost-Effectiveness Analysis (CEA) Registry and found that only 33% of eligible studies were conducted from the U.S. payer perspective. Additional interpretation challenges include economic models that do not account for true payer-negotiated costs, limits in internal expertise for quality-adjusted life-year inferences, and limited internal policies to use CEA research in decision making. This Viewpoints article highlights numerous opportunities to increase the translational effect of economic modeling work. Specifically, geographically relevant cost and outcomes data should be considered for integration within best practices for economic evaluations of NGS tests. Such data integration may provide more informed decision making regarding the allocation of constrained resources for health care services and technology. DISCLOSURES: No outside funding supported the writing of this article. Hart is supported by an unrestricted gift from Pfizer, which played no role in the study referred to in this article. The authors have no conflicts of interest to report.

Psychological outcomes related to exome and genome sequencing result disclosure: a meta-analysis of seven Clinical Sequencing Exploratory Research (CSER) Consortium studies.

PURPOSE: As exome and genome sequencing (ES/GS) enters the clinic, there is an urgent need to understand the psychological effects of test result disclosure. Through a Clinical Sequencing Exploratory Research (CSER), phase 1 (CSER1) Consortium collaboration, we evaluated participants' psychological outcomes across multiple clinical settings. METHODS: We conducted a random effects meta-analysis of state anxiety (Hospital Anxiety and Depression Scale [HADS]/Generalized Anxiety Disorder 7-item), depressive symptoms (HADS/Personal Health Questionnaire 9-item), and multidimensional impact (i.e., test-related distress, uncertainty and positive impact: modified Multidimensional Impact of Cancer Risk Assessment/Feelings About Genomic Testing Results scale). RESULTS: Anxiety and depression did not increase significantly following test result disclosure. Meta-analyses examining mean differences from pre- to postdisclosure revealed an overall trend for a decrease in participants' anxiety. We observed low levels of test-related distress and perceptions of uncertainty in some populations (e.g., pediatric patients) and a wide range of positive responses. CONCLUSION: Our findings across multiple clinical settings suggest no clinically significant psychological harms from the return of ES/GS results. Some populations may experience low levels of test-related distress or greater positive psychological effects. Future research should further investigate the reasons for test-related psychological response variation.

Reduced vancomycin susceptibility and increased macrophage survival in Staphylococcus aureus strains sequentially isolated from a bacteraemic patient during a short course of antibiotic therapy.

PURPOSE: The purpose of the present study was to determine the relatedness of Staphylococcus aureus strains successively isolated over a 7-day period from a single bacteraemic patient undergoing antibiotic treatment with vancomycin. METHODS: The S. aureus strains had been isolated and sequenced previously. Antibiotic susceptibility testing, population analysis profiling, and lysostaphin sensitivity and phagocytic killing assays were used to characterize these clonal isolates. RESULTS: The seven isolates (MEH1-MEH7) were determined to belong to a common multilocus sequence type (MLST) and spa type. Within the third and fifth day of vancomycin treatment, mutations were observed in the vraS and rpsU genes, respectively. Population analysis profiles revealed that the initial isolate (MEH1) was vancomycin-susceptible S. aureus (VSSA), while those isolated on day 7 were mostly heteroresistant vancomycin-intermediate S. aureus (hVISA). Supporting these findings, MEH7 was also observed to be slower in growth, to have an increase in cell wall width and to have reduced sensitivity to lysostaphin, all characteristics of VISA and hVISA strains. In addition, MEH7, although phagocytosed at numbers comparable to the initial isolate, MEH1, survived in higher numbers in RAW 264.7 macrophages. Macrophages infected with MEH7 also released more TNF-α and IFN-1ß. CONCLUSION: We report an increasing resistance to vancomycin coupled with daptomycin that occurred within approximately 3 days of receiving vancomycin and steadily increased until the infection was cleared with an alternative antibiotic therapy. This study reiterates the need for rapid, efficient and accurate detection of hVISA and VISA infections, especially in high-bacterial load, metastatic infections like bacteraemia.

The Feelings About genomiC Testing Results (FACToR) Questionnaire: Development and Preliminary Validation.

The purpose of this study was to develop a brief instrument, the Feelings About genomiC Testing Results (FACToR), to measure the psychosocial impact of returning genomic findings to patients in research and clinical practice. To create the FACToR, we modified and augmented the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire based on findings from a literature review, two focus groups (N = 12), and cognitive interviews (N = 6). We evaluated data from 122 participants referred for evaluation for inherited colorectal cancer or polyposis from the New EXome Technology in (NEXT) Medicine Study, an RCT of exome sequencing versus usual care. We assessed floor and ceiling effects of each item, conducted principal component analysis to identify subscales, and evaluated each subscale's internal consistency, test-retest reliability, and construct validity. After excluding items that were ambiguous or demonstrated floor or ceiling effects, 12 items forming four distinct subscales were retained for further analysis: negative emotions, positive feelings, uncertainty, and privacy concerns. All four showed good internal consistency (0.66-0.78) and test-retest reliability (0.65-0.91). The positive feelings and the uncertainty subscales demonstrated known-group validity. The 12-item FACToR with four subscales shows promising psychometric properties on preliminary evaluation in a limited sample and needs to be evaluated in other populations.

Correction: Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

The originally published version of this Article contained errors in Fig. 2. The numbers below the black arrowheads were incorrect; please see incorrect Figure in associated Correction. These errors have now been corrected in the PDF and HTML versions of the Article.

Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

PURPOSE: Clinical sequencing emerging in health care may result in secondary findings (SFs). METHODS: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. RESULTS: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. CONCLUSION: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.

Plasma cell depletion with bortezomib in the treatment of refractory N-methyl-d-aspartate (NMDA) receptor antibody encephalitis. Rational developments in neuroimmunological treatment.

BACKGROUND AND PURPOSE: The aim was to assess the therapeutic potential of bortezomib in the treatment of refractory N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis and its potential in other immune-mediated, B-cell-driven neurological diseases. METHODS: Two cases of severe NMDAR antibody encephalitis, resistant to first and second line therapy with steroids, intravenous immunoglobulins, plasma exchange, cyclophosphamide and rituximab, were treated with four and five cycles of 1.3 mg/m2 bortezomib at 350 and 330 days following initial presentation. RESULTS: Both patients showed significant clinical improvement with reductions of NMDAR antibody titres following bortezomib treatment. This is the first case in the literature where the NMDAR antibody level was undetectable following treatment with bortezomib. CONCLUSION: Bortezomib's unique ability to target long-lived autoreactive plasma cells appears to be a useful adjunct to standard second line immunosuppressive therapy in treatment-refractory NMDAR antibody encephalitis. The drug's pharmacodynamics, cell targeting and mechanism of action are reviewed, and it is postulated that bortezomib may be useful in a host of B-cell-driven neuroimmunological diseases.

Monitoring Theileria orientalis (Ikeda)-associated bovine anaemia in affected cattle over time.

The aim of the study was to observe changes in haematocrit (HCT) over time in a New Zealand South Island dairy herd affected by an outbreak of Theileria-associated bovine anaemia (TABA; Ikeda). A secondary aim was to relate individual cow HCTs to the amount of Theileria orientalis Ikeda DNA present in the blood, as measured by cycle threshold values, using a quantitative PCR (qPCR). Over a 6 month period, blood samples from 19 randomly selected cattle were monitored from a herd of 600 dairy cows. The sampling interval was approximately fortnightly for the first six weeks, followed by sampling at between four and six week intervals. At the initial report of the outbreak, two from six cattle were anaemic (HCT<0.25L/L). Blood collected from 14 cattle 11 days later showed that 57% (95% CI 33-77%) of the cattle sampled were anaemic. Of the 19 cattle that went on to be monitored, 12 (63% 95% CI=41-81%) developed anaemia at some point during the period of monitoring. One of the anaemic animals did not meet the case definition for TABA Ikeda. For individual cattle, the average number of days between when cattle were first detected as anaemic and when HCT returned to normal was 53days (median=47 days, range=6-92 days). At the point of notification the amount of T. orientalis Ikeda DNA in the blood of the six cattle tested was low (Cq median=36), but 11days later the amount of DNA in blood of 14 additional cows tested was relatively high (Cq median=24). Levels of all 19 cows monitored continued to remain moderately high through the period of testing (Cq median=29). This was despite a general improvement in the HCT of affected cattle. In four of the 15 cattle positive to T. orientalis Ikeda where blood fractions (plasma and whole blood) were tested, it appeared that T. orientalis Ikeda (as measured by qPCR) dropped more rapidly in plasma fractions than in whole blood at the point that HCT started to return to normal levels. Despite the assumption that tick populations were low in the Canterbury region of the South Island the impact of TABA (proportion of herd affected and the average period that animals remained anaemic) on the case herd was still relatively high.

Draft Genome Sequences of Two Staphylococcus aureus Strains Isolated in Succession from a Case of Bacteremia.

Staphylococcus aureus strains MEH1 and MEH7 were successively isolated from the blood of a patient with recurrent bacteremia. The submitted draft genomes of strains MEH1 and MEH7 are 2,914,972 and 2,911,704 bp, respectively.

Processing two-dimensional X-ray diffraction and small-angle scattering data in DAWN 2.

A software package for the calibration and processing of powder X-ray diffraction and small-angle X-ray scattering data is presented. It provides a multitude of data processing and visualization tools as well as a command-line scripting interface for on-the-fly processing and the incorporation of complex data treatment tasks. Customizable processing chains permit the execution of many data processing steps to convert a single image or a batch of raw two-dimensional data into meaningful data and one-dimensional diffractograms. The processed data files contain the full data provenance of each process applied to the data. The calibration routines can run automatically even for high energies and also for large detector tilt angles. Some of the functionalities are highlighted by specific use cases.