Utility of microbial cell free DNA next-generation sequencing for diagnosis and management of infectious diseases.

Microbial cell-free DNA (mcfDNA) sequencing is a promising tool to identify infectious pathogens when traditional methods fail to identify the causative agent. We performed a retrospective observational cohort study to evaluate clinical outcomes among pediatric and adult patients who underwent mcfDNA testing. 127 mcfDNA tests were reviewed from 112 patients. Baseline characteristics included 61 (54.5 %) adults, 52 (40.9 %) tests were from female patients, and 67 (52.8 %) tests were obtained from patients designated as immunocompromised. Of all tests obtained, 59 (46.4 %) were deemed clinically relevant. 41 (32.3 %) of tests also led to a change in antimicrobial management for the corresponding patient. No statistically significant association was ascertained between patient-specific factors and clinically relevant test results. Testing in certain clinical scenarios or high-risk settings may be useful, however further studies are needed to assess the cost-benefit of this approach.

Epinephrine Dosing Intervals Are Associated With Pediatric In-Hospital Cardiac Arrest Outcomes: A Multicenter Study.

OBJECTIVES: Data to support epinephrine dosing intervals during cardiopulmonary resuscitation (CPR) are conflicting. The objective of this study was to evaluate the association between epinephrine dosing intervals and outcomes. We hypothesized that dosing intervals less than 3 minutes would be associated with improved neurologic survival compared with greater than or equal to 3 minutes. DESIGN: This study is a secondary analysis of The ICU-RESUScitation Project (NCT028374497), a multicenter trial of a quality improvement bundle of physiology-directed CPR training and post-cardiac arrest debriefing. SETTING: Eighteen PICUs and pediatric cardiac ICUs in the United States. PATIENTS: Subjects were 18 years young or younger and 37 weeks old or older corrected gestational age who had an index cardiac arrest. Patients who received less than two doses of epinephrine, received extracorporeal CPR, or had dosing intervals greater than 8 minutes were excluded. INTERVENTIONS: The primary exposure was an epinephrine dosing interval of less than 3 vs. greater than or equal to 3 minutes. MEASUREMENTS AND MAIN RESULTS: The primary outcome was survival to discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1-2 or no change from baseline. Regression models evaluated the association between dosing intervals and: 1) survival outcomes and 2) CPR duration. Among 382 patients meeting inclusion and exclusion criteria, median age was 0.9 years (interquartile range 0.3-7.6 yr) and 45% were female. After adjustment for confounders, dosing intervals less than 3 minutes were not associated with survival with favorable neurologic outcome (adjusted relative risk [aRR], 1.10; 95% CI, 0.84-1.46; p = 0.48) but were associated with improved sustained return of spontaneous circulation (ROSC) (aRR, 1.21; 95% CI, 1.07-1.37; p < 0.01) and shorter CPR duration (adjusted effect estimate, -9.5 min; 95% CI, -14.4 to -4.84 min; p < 0.01). CONCLUSIONS: In patients receiving at least two doses of epinephrine, dosing intervals less than 3 minutes were not associated with neurologic outcome but were associated with sustained ROSC and shorter CPR duration.

Osteogenesis Imperfecta: Skeletal and Non-skeletal Challenges in Adulthood.

Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which involves not only the skeleton, but also the cardiopulmonary and gastrointestinal system, soft tissues, tendons, muscle, and joints, hearing, eyesight, dental health, and women's health in OI and potentially adds negative affect to health-related quality of life. We aim to guide clinicians as well as draw attention to obvious knowledge gaps and the need for further research in adult OI.

Mechanistic and kinetic insights into Transcription factor biology via acute protein depletion.

Genetic downregulation of the BCL11A transcription factor reverses the switch from fetal to adult hemoglobin and is effective in treating ß-hemoglobinopathies. Genetic ablation results in gradual reduction in protein abundance and does not lend itself to analysis of immediate consequences of protein loss or determination of the direct interactors/targets of the protein of interest. We achieved acute degradation of the largely disordered and 'undruggable' BCL11A protein by fusing it with a conditional degradation (degron) tag, FKBP12F36V, called dTAG. Small molecules then depleted the BCL11A-dTAG through endogenous proteolytic pathways. By integrating acute depletion with nascent transcriptomics and cell cycle separation techniques, we demonstrate the necessity of BCL11A occupancy at target chromatin for sustained transcriptional repression in erythroid cells. We advocate for expanding the exploration of transcription factor function to include acute depletion, which holds the potential to unveil unprecedented kinetic insights into TF mechanisms of action.

Retrospective analyses evaluating the mortality risk associated with pimavanserin or other atypical antipsychotics in patients with Parkinson disease psychosis.

Introduction: Parkinson's disease (PD) is associated with increased mortality risk (MR), reflecting progression of motor and nonmotor symptoms. PD psychosis (PDP), a common nonmotor symptom, increases with prolonged disease and elevates the MR of PD even further. Pimavanserin is the only FDA-approved treatment for PDP. This review summarizes real-world evidence around the MR of patients with PDP treated with pimavanserin versus off-label atypical antipsychotics. Methods: A PubMed search was conducted using the following search terms: pimavanserin AND antipsychotic AND mortality AND Parkinson's disease AND psychosis. Inclusion criteria specified the entry of retrospective, observational, and open-label studies comparing pimavanserin to atypical antipsychotics or untreated controls. Results: A total of 10 of the 32 articles met inclusion criteria. Among five comparisons of pimavanserin with atypical antipsychotics, two were large (n = 21,719; n = 21,975), representative, Medicare-database studies, which demonstrated comparable or lower all-cause pimavanserin MR. Among three pimavanserin versus control studies, two reported lower or comparable pimavanserin MR and one, long-term care study reported higher MR for pimavanserin versus non-pimavanserin treated patients with unknown PDP status. Two open-label extensions reported pimavanserin mortality rates of 6.45 and 18.8 deaths per 100 patient-years, which are comparable to, or lower than, mortality rates for PD, PDP, and other atypical antipsychotics. Most studies (70 %; 7 of 10) demonstrated pimavanserin's MR was lower than or similar to other atypical antipsychotics or untreated controls. Conclusions: Pimavanserin did not increase the MR in PDP. Pimavanserin's MR appears to be comparable to or lower than other atypical antipsychotics prescribed for PDP, including quetiapine.

De Quervain's Tenosynovitis: As Seen from the Perspective of the Patient.

Purpose: Patient preferences and expectations following both nonsurgical and operative treatment of de Quervain's tenosynovitis are unclear. In this study, we aim to better delineate patient preferences for initial management of de Quervain's tenosynovitis. For patients considering surgical treatment, we hope to identify which factors of surgical care are most important for patients to receive counseling. Methods: An online crowdsourcing platform, Amazon Mechanical Turk, was used to recruit study participants. Study participants were then led through a clinical scenario pertaining to de Quervain's tenosynovitis. They were then asked a series of questions regarding initial treatment options, important factors to consider during surgery, and postoperative expectations. A Likert scale was used for responses. Descriptive statistics and one-way analysis of variance were used to assess survey responses. Results: In total, 199 survey responses were included, and 84% of respondents chose nonsurgical modalities for initial treatment of de Quervain's tenosynovitis. Survey items asking about the importance of cost, risks of surgery, expected recovery time, and expected pain level following surgery revealed that all factors were considered important to respondents. There were no differences between groups in the one-way analysis of variance. Conclusions: Providers should remain cognizant that patients presenting with de Quervain's tenosynovitis may favor initial nonsurgical management. The vast majority of respondents rated the importance of cost, risks of surgery, expected recovery time, and expected pain level as having some level of importance when considering surgical care. When discussing outcomes of surgery, respondents were nearly divided on what would be considered a successful outcome of surgery. This suggests that treating physicians may benefit from clarifying expected outcomes during surgical discussions. Type of study/level of evidence: Diagnostics IIb.

Protein phosphatase 6 activates NF-κB to confer sensitivity to MAPK pathway inhibitors in KRAS- and BRAF-mutant cancer cells.

The Ras-mitogen-activated protein kinase (MAPK) pathway is a major target for cancer treatment. To better understand the genetic pathways that modulate cancer cell sensitivity to MAPK pathway inhibitors, we performed a CRISPR knockout screen with MAPK pathway inhibitors on a colorectal cancer (CRC) cell line carrying mutant KRAS. Genetic deletion of the catalytic subunit of protein phosphatase 6 (PP6), encoded by PPP6C, rendered KRAS- and BRAF-mutant CRC and BRAF-mutant melanoma cells more resistant to these inhibitors. In the absence of MAPK pathway inhibition, PPP6C deletion in CRC cells decreased cell proliferation in two-dimensional (2D) adherent cultures but accelerated the growth of tumor spheroids in 3D culture and tumor xenografts in vivo. PPP6C deletion enhanced the activation of nuclear factor κB (NF-κB) signaling in CRC and melanoma cells and circumvented the cell cycle arrest and decreased cyclin D1 abundance induced by MAPK pathway blockade in CRC cells. Inhibiting NF-κB activity by genetic and pharmacological means restored the sensitivity of PPP6C-deficient cells to MAPK pathway inhibition in CRC and melanoma cells in vitro and in CRC cells in vivo. Furthermore, a R264 point mutation in PPP6C conferred loss of function in CRC cells, phenocopying the enhanced NF-κB activation and resistance to MAPK pathway inhibition observed for PPP6C deletion. These findings demonstrate that PP6 constrains the growth of KRAS- and BRAF-mutant cancer cells, implicates the PP6-NF-κB axis as a modulator of MAPK pathway output, and presents a rationale for cotargeting the NF-κB pathway in PPP6C-mutant cancer cells.

Gut Microbiota Shape Oligodendrocyte Response after Traumatic Brain Injury.

White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the modulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI.

Assessing the variation and drivers of cost in 1-level lumbar fusion: a time-driven activity-based costing analysis.

BACKGROUND CONTEXT: As value-based health care arrangements gain traction in spine care, understanding the true cost of care becomes critical. Historically, inaccurate cost proxies have been used, including negotiated reimbursement rates or list prices. However, time-driven activity-based costing (TDABC) allows for a more accurate cost assessment, including a better understanding of the primary drivers of cost in 1-level lumbar fusion. PURPOSE: To determine the variation of total hospital cost, differences in characteristics between high-cost and non-high-cost patients, and to identify the primary drivers of total hospital cost in a sample of patients undergoing 1-level lumbar fusion. STUDY DESIGN/SETTING: Retrospective, multicenter (one academic medical center, one community-based hospital), observational study. PATIENT SAMPLE: A total of 383 patients undergoing elective 1-level lumbar fusion for degenerative spine conditions between November 2, 2021 and December 2, 2022. OUTCOME MEASURES: Total hospital cost of care (normalized); preoperative, intraoperative, and postoperative cost of care (normalized); ratio of most to least expensive 1-level lumbar fusion. METHODS: Patients undergoing a 1-level lumbar fusion between November 2, 2021 and December 2, 2022 were identified at two hospitals (one quaternary referral academic medical center and one community-based hospital) within our health system. TDABC was used to calculate total hospital cost, which was also broken up into: pre-, intra-, and postoperative timeframes. Operating surgeon and patient characteristics were also collected and compared between high- and non-high-cost patients. The correlation of surgical time and cost was determined. Multivariable linear regression was used to determine factors associated with total hospital cost. RESULTS: The most expensive 1-level lumbar fusion was 6.8x more expensive than the least expensive 1-level lumbar fusion, with the intraoperative period accounting for 88% of total cost. On average. the implant cost accounted for 30% of the total, but across the patient sample, the implant cost accounted for a range of 6% to 44% of the total cost. High-cost patients were younger (55 years [SD: 13 years] vs.63 years [SD: 13 years], p=.0002), more likely to have commercial health insurance (24 out of 38 (63%) vs. 181 out of 345 (52%), p=.003). There was a poor correlation between time of surgery (i.e., incision to close) and total overall cost (ρ: .26, p<.0001). Increase age (RC: -0.003 [95% CI: -0.006 to -0.000007], p=.049) was associated with decreased cost. Surgery by certain surgeons was associated with decreased total cost when accounting for other factors (p<.05). CONCLUSIONS: A large variation exists in the total hospital cost for patients undergoing 1-level lumbar fusion, which is primarily driven by surgeon-level decisions and preferences (e.g., implant and technology use). Also, being a "fast" surgeon intraoperatively does not mean your total cost is meaningfully lower. As efforts continue to optimize patient value through ensuring appropriate clinical outcomes while also reducing cost, spine surgeons must use this knowledge to lead, or at least be active participants in, any discussions that could impact patient care.

The positive impact of conservation action.

Governments recently adopted new global targets to halt and reverse the loss of biodiversity. It is therefore crucial to understand the outcomes of conservation actions. We conducted a global meta-analysis of 186 studies (including 665 trials) that measured biodiversity over time and compared outcomes under conservation action with a suitable counterfactual of no action. We find that in two-thirds of cases, conservation either improved the state of biodiversity or at least slowed declines. Specifically, we find that interventions targeted at species and ecosystems, such as invasive species control, habitat loss reduction and restoration, protected areas, and sustainable management, are highly effective and have large effect sizes. This provides the strongest evidence to date that conservation actions are successful but require transformational scaling up to meet global targets.

Cost-Effectiveness of the ACR TIRADS Compared to the ATA 2015 Risk Stratification Systems in the Evaluation of Incidental Thyroid Nodules.

RATIONALE AND OBJECTIVES: Thyroid nodules are a common incidental imaging finding and prone to overdiagnosis. Several risk stratification systems have been developed to reduce unnecessary work-up, with two of the most utilized including the American Thyroid Association 2015 (ATA2015) and the newer American College of Radiology Thyroid Imaging, Reporting and Data System (TIRADS) guidelines. The purpose of this study is to evaluate the cost-effectiveness of the ATA2015 versus the TIRADS guidelines in the management of incidental thyroid nodules. METHODS: A cost-utility analysis was conducted using decision tree modeling, evaluating adult patients with incidental thyroid nodules < 4 cm. Model inputs were populated using published literature, observational data, and expert opinion. Single-payer perspective, Canadian dollar currency, five-year time horizon, willingness to pay (WTP) threshold of $50,000, and discount rate of 1.5% per annum were utilized. Scenario, deterministic and probabilistic sensitivity analyses were performed. The primary outcome was the incremental cost-effectiveness ratio (ICER) expressed as incremental cost per quality-adjusted life year (QALY) gained. RESULTS: For the base case scenario, TIRADS dominated the ATA2015 strategy by a slim margin, producing 0.005 more QALYs at $25 less cost. Results were sensitive to the malignancy rate of biopsy and the utilities of a patient with a benign nodule/subclinical malignancy or under surveillance. Probabilistic sensitivity analysis showed that TIRADS was the more cost-effective option 79.7% of the time. CONCLUSION: The TIRADS guidelines may be the more cost-effective strategy by a small margin compared to ATA2015 in most scenarios when used to risk stratify incidental thyroid nodules.

Post-operative Patient Portal Messaging is Associated With Return to the Emergency Department After Lumbar Spine Surgery.

STUDY DESIGN: Retrospective study. OBJECTIVE: To explore the association between patients undergoing lumbar spine surgery who message their care team via an electronic patient portal (EPP) post-operatively and emergency department (ED) visits within 90 days of surgery. SUMMARY OF BACKGROUND DATA: Secure patient messaging through electronic patient portals has grown over recent years. Despite its frequent utilization by patients to engage with their care team, its association with clinical outcomes remains unknown in spine surgery. METHODS: This study was approved by our Institutional Review Board. Inclusion criteria were adults who underwent single-stage lumbar spine surgery between January 2016-June 2023. Patients with incomplete information, multi-stage surgeries, and those who died within 90 days of surgery were excluded. Patient sociodemographic, surgical, hospital readmission, and patient-provider engagement data were collected. RESULTS: A total of 13,135 patients were included. A total of 1,711 patients (13%) had a post-operative ED visit, and 4,791 patients (36%) used the patient portal to send a message after surgery. Sending a post-operative patient message after undergoing lumbar spine surgery was associated with an increased likelihood of having an ED visit that does not lead to readmission (1.29 (1.10-1.53), P = 0.002). Patients with high school degrees were more likely to have an ED visit without readmission (1.33 (1.08-1.65), P = 0.008). CONCLUSION: Patients at a higher risk of presenting to the ED post-operatively should be identified and may benefit from additional counseling and access to the care team virtually to limit unnecessary healthcare utilization. Focusing on patients who reach out via EPP messaging post-operatively may be a good target patient group to address first. Future research is needed to investigate the possible health literacy and other socioeconomic barriers affecting these patients so that appropriate, more cost-effective resources can be utilized to avoid clinically unnecessary and costly ED visits.

Lateral Epicondylitis: Treatment Preferences from the Potential Patient Perspective.

Background: Knowing the questions and concerns that patients have regarding treatment options for lateral epicondylitis may allow for shared-decision making and potentially superior patient outcomes and satisfaction. In the present study, we aimed to further delineate patient preferences with treatment of lateral epicondylitis. Methods: An online, survey-based, descriptive study was conducted through Amazon Mechanical Turk. Survey participants were presented with a clinical scenario regarding lateral epicondylitis and asked four questions regarding treatment preferences for nonoperative treatment, whether they would consider platelet-rich plasma (PRP) injection, and whether they would consider surgical intervention for recalcitrant symptoms. A Likert scale was used for responses. McNemar chi-square test was used for paired nominal data for statistical analysis. Results: A total of 238 survey responses were included. A majority (63%) of respondents elected to proceed with formal physical therapy. When given additional information regarding corticosteroid injections, 50.8% of respondents reported preferring physical therapy. There were no differences between groups for questions 1 and 2 (P = 0.90). Of the respondents, 75.2% were "likely" or "extremely likely" to consider PRP injection. When asked about surgical intervention, 74.8% of respondents were "likely" or "extremely likely" to proceed with continued symptoms. Conclusions: It is important to include patient preferences in treatment discussions of lateral epicondylitis. Survey respondents preferred formal physical therapy for initial treatment. A surprising majority of respondents were likely to consider a PRP injection. With prolonged symptoms, respondents were interested in discussions of surgical intervention and thus, it should continue to be offered to patients with recalcitrant symptoms.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Safety of fluconazole in kidney transplant recipients for prevention of coccidioidomycosis.

Coccidioides is an endemic fungus that causes infections ranging from mild respiratory illness to life-threatening disease, and immunocompromised hosts such as solid organ transplant recipients are at higher risk for disseminated infection and mortality. Our center administers fluconazole prophylaxis to kidney transplant recipients residing in geographic areas with higher incidences of coccidioidomycosis. However, because drug-drug interactions occur between triazoles and immunosuppressants used in transplant medicine, we undertook a study to ascertain whether fluconazole prophylaxis was associated with any important safety outcomes in kidney transplant recipients. This retrospective study evaluated patients who had undergone kidney transplantation between 2016 and 2019. Data on patient demographics, transplant-related clinical information, use of fluconazole prophylaxis (200 mg daily for 6-12 months post-transplant), and patient outcomes were obtained. The primary outcome was mean estimated glomerular filtration rate (eGFR) at 12 months, comparing those who received fluconazole prophylaxis to those who did not. Secondary outcomes included mean eGFR at 3 months, 6 months, and 9 months post-transplant, patient survival, biopsy-proven graft rejection, graft loss, or a new requirement for post-transplant dialysis, all within 12 months post-transplant. The mean eGFR at 12 months was similar between both groups, with 66.4 ml/min/1.73 m² in the fluconazole prophylaxis group vs. 64.3 ml/min/1.73 m² in the non-fluconazole prophylaxis group (P = 0.55). Secondary outcomes were similar across both groups. Multivariable linear regression found no significant association between fluconazole use and graft function. Fluconazole prophylaxis for prevention of coccidioidomycosis was not associated with adverse graft outcomes in kidney transplant recipients.

Solid organ transplant recipients can be highly immune suppressed, and infection with Coccidioides (valley fever) after transplant can lead to severe infections in these patients. Our study showed that fluconazole was safe and effective for preventing Coccidioides in kidney transplant recipients.

Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.

Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study.

BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

Association of Pediatric Postcardiac Arrest Ventilation and Oxygenation with Survival Outcomes.

Rationale: Adult and pediatric studies provide conflicting data regarding whether post-cardiac arrest hypoxemia, hyperoxemia, hypercapnia, and/or hypocapnia are associated with worse outcomes. Objectives: We sought to determine whether postarrest hypoxemia or postarrest hyperoxemia is associated with lower rates of survival to hospital discharge, compared with postarrest normoxemia, and whether postarrest hypocapnia or hypercapnia is associated with lower rates of survival, compared with postarrest normocapnia. Methods: An embedded prospective observational study during a multicenter interventional cardiopulmonary resuscitation trial was conducted from 2016 to 2021. Patients ⩽18 years old and with a corrected gestational age of ≥37 weeks who received chest compressions for cardiac arrest in one of the 18 intensive care units were included. Exposures during the first 24 hours postarrest were hypoxemia, hyperoxemia, or normoxemia-defined as lowest arterial oxygen tension/pressure (PaO2) <60 mm Hg, highest PaO2 ⩾200 mm Hg, or every PaO2 60-199 mm Hg, respectively-and hypocapnia, hypercapnia, or normocapnia, defined as lowest arterial carbon dioxide tension/pressure (PaCO2) <30 mm Hg, highest PaCO2 ⩾50 mm Hg, or every PaCO2 30-49 mm Hg, respectively. Associations of oxygenation and carbon dioxide group with survival to hospital discharge were assessed using Poisson regression with robust error estimates. Results: The hypoxemia group was less likely to survive to hospital discharge, compared with the normoxemia group (adjusted relative risk [aRR] = 0.71; 95% confidence interval [CI] = 0.58-0.87), whereas survival in the hyperoxemia group did not differ from that in the normoxemia group (aRR = 1.0; 95% CI = 0.87-1.15). The hypercapnia group was less likely to survive to hospital discharge, compared with the normocapnia group (aRR = 0.74; 95% CI = 0.64-0.84), whereas survival in the hypocapnia group did not differ from that in the normocapnia group (aRR = 0.91; 95% CI = 0.74-1.12). Conclusions: Postarrest hypoxemia and hypercapnia were each associated with lower rates of survival to hospital discharge.

A new genus and four new species of Darnini (Hemiptera: Membracidae) from South America.

The new genus Polyodontotrochus is described and illustrated with four new species: P. auriculatus from French Guiana, P. elevatus (type species) from Ecuador, P. extentapalaestrus from French Guiana, and P. inpa from Brazil, the genus differs from all other membracids in having the inner sides of their metathoracic trochanters developed into apposed, sclerotized studlike, flattened plates distributed throughout. Their metathoracic tibiae have cucullate setal rows II and III incomplete, row I missing. A key to all species is provided.

Prescribed safer supply during dual public health emergencies: a qualitative study examining service providers perspectives on early implementation.

BACKGROUND: Within North America and worldwide, drug related overdoses have increased dramatically over the past decade. COVID-19 escalated the need for a safer supply to replace unregulated substances and to reduce toxicity and overdoses. Service providers play an integral role in the delivery of safer supply but there is little empirical evidence that conceptualizes effective safer supply from their perspectives. This study explored early implementation and impacts of a safer supply program, capturing the perspectives of an interdisciplinary team of service providers on tensions and issues encountered in the development of the SAFER program. METHODS: Using a community-based participatory approach, we conducted individual interviews with program providers (n = 9). The research team was composed of researchers from a local drug user organization, a local harm reduction organization, and academic researchers. The Consolidated Framework for Implementation Research (CFIR) informed the interview guide. Data was analyzed using thematic analysis. RESULTS: There are six themes describing early implementation: (1) risk mitigation prescribing as context for early implementation; (2) developing SAFER specific clinical protocols; (3) accessibility challenges and program innovations; (4) interdisciplinary team and wraparound care; (5) program tensions between addiction medicine and harm reduction; (6) the successes of safer supply and future visions. CONCLUSION: Early implementation issues and tensions included prescriber concerns about safer supply prescribing in a highly politicized environment, accessibility challenges for service users such as stigma, encampment displacement, OAT requirements, program capacity and costs, and tensions between addiction medicine and harm reduction. Navigating these tensions included development of clinical protocols, innovations to reduce accessibility challenges such as outreach, wraparound care, program coverage of medication costs and prescribing safer supply with/without OAT. These findings contribute important insights for the development of prescribed safer supply programs.