Delphi panel to obtain clinical consensus about using long-acting injectable antipsychotics to treat first-episode and early-phase schizophrenia: treatment goals and approaches to functional recovery.

BACKGROUND: Schizophrenia is mostly a chronic disorder whose symptoms include psychosis, negative symptoms and cognitive dysfunction. Poor adherence is common and related relapse can impair outcomes. Long-acting injectable antipsychotics (LAIs) may promote treatment adherence and decrease the likelihood of relapse and rehospitalization. Using LAIs in first-episode psychosis (FEP) and early-phase (EP) schizophrenia patients could benefit them, yet LAIs have traditionally been reserved for chronic patients. METHODS: A three-step modified Delphi panel process was used to obtain expert consensus on using LAIs with FEP and EP schizophrenia patients. A literature review and input from a steering committee of five experts in psychiatry were used to develop statements about patient population, adverse event management, and functional recovery. Recruited Delphi process psychiatrists rated the extent of their agreement with the statements over three rounds (Round 1: paper survey, 1:1 interview; Rounds 2-3: email survey). Analysis rules determined whether a statement progressed to the next round and the level of agreement deemed consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists assess their previous responses in the context of those of the overall group. RESULTS: The Delphi panelists were 17 psychiatrists experienced in treating schizophrenia with LAIs, practicing in seven countries (France, Italy, US, Germany, Spain, Denmark, UK). Panelists were presented with 73 statements spanning three categories: patient population; medication dosage, management, and adverse events; and functional recovery domains and assessment. Fifty-five statements achieved ≥ 80% agreement (considered consensus). Statements with low agreement (40-79%) or very low agreement (< 39%) concerned initiating dosage in FEP and EP patients, and managing loss of efficacy and breakthrough episodes, reflecting current evidence gaps. The panel emphasized benefits of LAIs in FEP and EP patients, with consensus that LAIs can decrease the risk of relapse, rehospitalization, and functional dysfunction. The panel supported links between these benefits and multidimensional longer-term functional recovery beyond symptomatic remission. CONCLUSIONS: Findings from this Delphi panel support the use of LAIs in FEP and EP schizophrenia patients regardless of disease severity, number of relapses, or social support status. Gaps in clinician knowledge make generating evidence on using LAIs in FEP and EP patients critical.

MRI quantification of femoral neck version using the posterior lesser trochanteric line: a comparison of three measurements.

OBJECTIVE: To validate MRI for the quantification of the femoral neck version (FNV) using posterior lesser trochanteric Line (PLTL) and to compare reliability of the PLTL to the epicondylar and retrocondylar measurements. MATERIALS AND METHODS: A retrospective review of 3 T MRI scans performed for femoroacetabular impingement (FAI). Two musculoskeletal radiologists performed the measurements. MRI measurements of the PLTL were compared to CT using Bland Altman, Lin's concordance, and Lin's correlation coefficients. Interobserver reliability was determined using Bland Altman, Lin's concordance, and Lin's correlation coefficients. Intraobserver reliability was determined using Lin's concordance and Lin's correlation coefficients. RESULTS: Forty-five patients (90 lower extremities) met the inclusion criteria. Ages ranged from 20 to 41 years, with a mean of 31.5 years. There were 22 females and 23 males. Lin's concordance correlation coefficient for MRI and CT measurements of PLTL was substantial: 0.96 (95% CI: 0.94-0.98). PLTL Lin's correlation coefficient was 0.825 (95% CI 0.732-0.918) and indicated good interobserver reliability. Epicondylar and retrocondylar methods Lin's correlation coefficients demonstrated moderate interobserver reliability at 0.601 (0.415-0.786) and 0.632 (0.456-0.807), respectively. There was moderate 95% confidence interval overlap between the PLTL and the other measurements. Bland-Altman plots for each measurement were similar and demonstrated no bias. There was excellent intraobserver reliability (> 0.900) with significant 95% confidence interval overlap. CONCLUSION: MRI measurements of the PLTL are comparable to CT. The PLTL has good reliability between readers for the quantification of FNV using MRI, which could help avoid unnecessary radiation exposure using CT and reduce MRI scan time.

Video-based assessments of activities of daily living: generating real-world evidence in pediatric rare diseases.

INTRODUCTION: Preserving function and independence to perform activities of daily living (ADL) is critical for patients and carers to manage the burden of care and improve quality of life. In children living with rare diseases, video recording ADLs offer the opportunity to collect the patients' experience in a real-life setting and accurately reflect treatment effectiveness on outcomes that matter to patients and families. AREAS COVERED: We reviewed the measurement of ADL in pediatric rare diseases and the use of video to develop at-home electronic clinical outcome assessments (eCOA) by leveraging smartphone apps and artificial intelligence-based analysis. We broadly searched PubMed using Boolean combinations of the following MeSH terms 'Rare Diseases,' 'Quality of Life,' 'Activities of Daily Living,' 'Child,' 'Video Recording,' 'Outcome Assessment, Healthcare,' 'Intellectual disability,' and 'Genetic Diseases, Inborn.' Non-controlled vocabulary was used to include human pose estimation in movement analysis. EXPERT OPINION: Broad uptake of video eCOA in drug development is linked to the generation of technical and clinical validation evidence to confidently assess a patient's functional abilities. Software platforms handling video data must align with quality regulations to ensure data integrity, security, and privacy. Regulatory flexibility and optimized validation processes should facilitate video eCOA to support benefit/risk drug assessment.

"Because it is a rare disease it needs to be brought to attention that there are things out of the norm": a qualitative study of patient and physician experiences of Wilson disease diagnosis and management in the US.

BACKGROUND: Wilson disease (WD) is a genetic disorder of copper metabolism that leads to copper accumulation in various organs, primarily the liver and brain, resulting in heterogenous hepatic, neurologic, and psychiatric symptoms. Diagnosis can occur at any age, requiring lifelong treatment, which can involve liver transplantation. This qualitative study aims to understand the wider patient and physician experience of the diagnosis and management of WD in the US. METHODS: Primary data were collected from 1:1 semi structured interviews with US-based patients and physicians and thematically analyzed with NVivo. RESULTS: Twelve WD patients and 7 specialist WD physicians (hepatologists and neurologists) were interviewed. Analysis of the interviews revealed 18 themes, which were organized into 5 overarching categories: (1) Diagnosis journey, (2) Multidisciplinary approach, (3) Medication, (4) The role of insurance, and (5) Education, awareness, and support. Patients who presented with psychiatric or neurological symptoms reported longer diagnostic journeys (range 1 to 16 years) than those presenting with hepatic symptoms or through genetic screening (range 2 weeks to 3 years). All were also affected by geographical proximity to WD specialists and access to comprehensive insurance. Exploratory testing was often burdensome for patients, but receipt of a definitive diagnosis led to relief for some. Physicians emphasized the importance of multidisciplinary teams beyond hepatology, neurology, and psychiatry and recommended a combination of chelation, zinc, and a low-copper diet; however, only half the patients in this sample were on a chelator, and some struggled to access prescription zinc due to insurance issues. Caregivers often advocated for and supported adolescents with their medication and dietary regimen. Patients and physicians recommended more education and awareness for the healthcare community. CONCLUSIONS: WD requires the coordination of care and medication among several specialists due to its complex nature, but many patients do not have access to multiple specialties due to geographical or insurance barriers. Because some patients cannot be treated in Centers of Excellence, easy access to reliable and up-to-date information is important to empower physicians, patients, and their caregivers in managing the condition, along with general community outreach programs.

Delphi panel to obtain clinical consensus about using long-acting injectable antipsychotics to treat first-episode and early-phase schizophrenia: Treatment goals and approaches to functional recovery.

Background Schizophrenia is mostly a chronic disorder whose symptoms include psychosis, negative symptoms and cognitive dysfunction. Poor adherence is common and related relapse can impair outcomes. Long-acting injectable antipsychotics (LAIs) may promote treatment adherence and decrease the likelihood of relapse and rehospitalization. Using LAIs in first-episode psychosis (FEP) and early-phase (EP) schizophrenia patients could benefit them, yet LAIs have traditionally been reserved for chronic patients. Methods A three-step modified Delphi panel process was used to obtain expert consensus on using LAIs with FEP and EP schizophrenia patients. A literature review and input from a steering committee of five experts in psychiatry were used to develop statements about patient population, adverse event management, and functional recovery. Recruited Delphi process psychiatrists rated the extent of their agreement with the statements over three rounds (Round 1: paper survey, 1:1 interview; Rounds 2-3: email survey). Analysis rules determined whether a statement progressed to the next round and the level of agreement deemed consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists assess their previous responses in the context of those of the overall group. Results The Delphi panelists were 17 psychiatrists experienced in treating schizophrenia with LAIs, practicing in seven countries (France, Italy, US, Germany, Spain, Denmark, UK). Panelists were presented with 73 statements spanning three categories: patient population; medication dosage, management, and adverse events; and functional recovery domains and assessment. Fifty-five statements achieved ≥ 80% agreement (considered consensus). Statements with low agreement (40%-79%) or very low agreement (< 39%) concerned initiating dosage in FEP and EP patients, and managing loss of efficacy and breakthrough episodes, reflecting current evidence gaps. The panel emphasized benefits of LAIs in FEP and EP patients, with consensus that LAIs can decrease the risk of relapse, rehospitalization, and functional dysfunction. The panel supported links between these benefits and multidimensional longer-term functional recovery beyond symptomatic remission. Conclusions Findings from this Delphi panel support the use of LAIs in FEP and EP schizophrenia patients regardless of disease severity, number of relapses, or social support status. Gaps in clinician knowledge make generating evidence on using LAIs in FEP and EP patients critical.

Association of Three-Month Radiographic Union Score for Tibia Fractures (RUST) with Nonunion in Tibial Shaft Fracture Patients.

Objectives Nonunions of tibial shaft fractures have profound implications on patient quality of life and are associated with physical and mental suffering. Radiographic Union Score for Tibia Fractures (RUST) may serve as an important prognostic tool for identifying patients at a high risk of nonunion. Design We used data from the Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) and Fluid Lavage of Open Wounds (FLOW) trials to explore the association of three-month RUST scores with nonunion in patients with tibial shaft fractures treated with intramedullary nailing. We performed a retrospective cohort study nested within two multi-center, randomized controlled trials. Participants The patients included in the current study: (1) sustained a tibial shaft fracture and were enrolled in the SPRINT or FLOW randomized trials, (2) had initial operative management with intramedullary nailing, (3) showed radiographic evidence of an unhealed fracture at the three-month follow-up, and (4) their healing status (union or nonunion) was captured at 12-months postoperatively. Intervention Multivariable binary logistic regression was carried out to identify factors associated with nonunion, including open versus closed injury, fracture severity, fracture gap, and three-month RUST score. We determined the concordance statistic (c statistic) for our regression model both with and without the RUST score. Outcome Measurements and Results Of the 155 tibial fracture patients with complete data available for analysis, the overall rate of nonunion at 12 months was 30% (n=47). The mean three-month RUST score in patients with nonunion at 12 months was 4.8 (standard deviation (SD) 1.1) as compared to 6.3 (SD 1.7) for those healed at 12 months. In our multivariable regression analysis, open fractures conferred five-fold greater odds of nonunion at 12 months as compared to closed fractures (odds ratio (OR) 4.76, 95% confidence interval (CI):1.71-13.30). Further, three-month RUST scores of 4 and 5-6 were associated with a 47% (95% CI: 18%-73%) and 23% (4.5-51.5%) absolute risk increase of nonunion as compared to a score of ≥ 7, respectively. The addition of RUST scores to our adjusted regression model improved the c statistic from 0.70 (95%CI: 0.61-0.79) to 0.81 (95%CI: 0.74-0.88). Conclusion A third of patients with tibial shaft fractures who have failed to heal by three months will show nonunion at one year. Open fractures and lower three-month RUST scores are strongly associated with a higher risk of nonunion at one year. Further research is needed to establish whether prognosis in this high-risk group can be modified.

Posterior ankle labral changes at MRI: A preliminary study.

INTRODUCTION: The transverse ligament in the ankle joint has been described as a labrum-like structure in a previous cadaveric study. The purpose of this study is to assess the spectrum of abnormal changes related to this structure on imaging/MRI, and correlate these findings with other ankle joint findings and patient symptoms. METHOD: A retrospective observational review of 172 ankle MRI scans was carried out independently by two fellowship trained musculoskeletal Radiologists. Correlation between abnormal labral changes, other ankle joint findings and patient symptomatology was performed. RESULTS: Abnormal labral changes were seen in 26% of the MRI scans (n = 44/172) and included signal change, contour abnormality with heterogeneous signal change, linear fluid filled clefts, multidirectional fluid filled clefts, and a macerated labrum. There was a statistically significant association between abnormal labral changes and the presence of Stieda process/os trigonum (P = 0.001), talocrural joint osteoarthritis (P = 0.0003), paralabral cysts (P = 0.0001), imaging features of posterior impingement (P = 0.01), and both medial (P = 0.005) and lateral (P = 0.01) ankle ligament injuries. However, there was no statistically significant association between abnormal labral changes and patient symptoms. CONCLUSION: The posterior ankle labrum can develop a spectrum of abnormal MRI appearances in patients with other ankle joint abnormalities. Although this study showed no correlation between patients' symptoms and posterior ankle labral changes, larger studies are needed to examine the biomechanical alterations that may arise from these labral changes.

Loss of Nek11 Prevents G2/M Arrest and Promotes Cell Death in HCT116 Colorectal Cancer Cells Exposed to Therapeutic DNA Damaging Agents.

The Nek11 kinase is a potential mediator of the DNA damage response whose expression is upregulated in early stage colorectal cancers (CRCs). Here, using RNAi-mediated depletion, we examined the role of Nek11 in HCT116 WT and p53-null CRC cells exposed to ionizing radiation (IR) or the chemotherapeutic drug, irinotecan. We demonstrate that depletion of Nek11 prevents the G2/M arrest induced by these genotoxic agents and promotes p53-dependent apoptosis both in the presence and absence of DNA damage. Interestingly, Nek11 depletion also led to long-term loss of cell viability that was independent of p53 and exacerbated following IR exposure. CRC cells express four splice variants of Nek11 (L/S/C/D). These are predominantly cytoplasmic, but undergo nucleocytoplasmic shuttling mediated through adjacent nuclear import and export signals in the C-terminal non-catalytic domain. In HCT116 cells, Nek11S in particular has an important role in the DNA damage response. These data provide strong evidence that Nek11 contributes to the response of CRC cells to genotoxic agents and is essential for survival either with or without exposure to DNA damage.

Nek5 promotes centrosome integrity in interphase and loss of centrosome cohesion in mitosis.

Nek5 is a poorly characterized member of the NIMA-related kinase family, other members of which play roles in cell cycle progression and primary cilia function. Here, we show that Nek5, similar to Nek2, localizes to the proximal ends of centrioles. Depletion of Nek5 or overexpression of kinase-inactive Nek5 caused unscheduled separation of centrosomes in interphase, a phenotype also observed upon overexpression of active Nek2. However, separated centrosomes that resulted from Nek5 depletion remained relatively close together, exhibited excess recruitment of the centrosome linker protein rootletin, and had reduced levels of Nek2. In addition, Nek5 depletion led to loss of PCM components, including γ-tubulin, pericentrin, and Cdk5Rap2, with centrosomes exhibiting reduced microtubule nucleation. Upon mitotic entry, Nek5-depleted cells inappropriately retained centrosome linker components and exhibited delayed centrosome separation and defective chromosome segregation. Hence, Nek5 is required for the loss of centrosome linker proteins and enhanced microtubule nucleation that lead to timely centrosome separation and bipolar spindle formation in mitosis.

Computerized clinical decision support systems for acute care management: a decision-maker-researcher partnership systematic review of effects on process of care and patient outcomes.

BACKGROUND: Acute medical care often demands timely, accurate decisions in complex situations. Computerized clinical decision support systems (CCDSSs) have many features that could help. However, as for any medical intervention, claims that CCDSSs improve care processes and patient outcomes need to be rigorously assessed. The objective of this review was to systematically review the effects of CCDSSs on process of care and patient outcomes for acute medical care. METHODS: We conducted a decision-maker-researcher partnership systematic review. MEDLINE, EMBASE, Evidence-Based Medicine Reviews databases (Cochrane Database of Systematic Reviews, DARE, ACP Journal Club, and others), and the Inspec bibliographic database were searched to January 2010, in all languages, for randomized controlled trials (RCTs) of CCDSSs in all clinical areas. We included RCTs that evaluated the effect on process of care or patient outcomes of a CCDSS used for acute medical care compared with care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. RESULTS: Thirty-six studies met our inclusion criteria for acute medical care. The CCDSS improved process of care in 63% (22/35) of studies, including 64% (9/14) of medication dosing assistants, 82% (9/11) of management assistants using alerts/reminders, 38% (3/8) of management assistants using guidelines/algorithms, and 67% (2/3) of diagnostic assistants. Twenty studies evaluated patient outcomes, of which three (15%) reported improvements, all of which were medication dosing assistants. CONCLUSION: The majority of CCDSSs demonstrated improvements in process of care, but patient outcomes were less likely to be evaluated and far less likely to show positive results.

Identification by high-throughput screening of viridin analogs as biochemical and cell-based inhibitors of the cell cycle-regulated nek2 kinase.

Nek2 is a serine/threonine protein kinase that localizes to the centrosome and is implicated in mitotic regulation. Overexpression of Nek2 induces premature centrosome separation and nuclear defects indicative of mitotic errors, whereas depletion of Nek2 interferes with cell growth. As Nek2 expression is upregulated in a range of cancer cell lines and primary human tumors, inhibitors of Nek2 may have therapeutic value in cancer treatment. The authors used a radiometric proximity assay in a high-throughput screen to identify small-molecule inhibitors of Nek2 kinase activity. The assay was based on the measurement of the radiolabeled phosphorylated product of the kinase reaction brought into contact with the surface of wells of solid scintillant-coated microplates. Seventy nonaggregating hits were identified from approximately 73,000 compounds screened and included a number of toxoflavins and a series of viridin/wortmannin-like compounds. The viridin-like compounds were >70-fold selective for Nek2 over Nek6 and Nek7 and inhibited the growth of human tumor cell lines at concentrations consistent with their biochemical potencies. An automated mechanism-based microscopy assay in which centrosomes were visualized using pericentrin antibodies confirmed that 2 of the viridin inhibitors reduced centrosome separation in a human tumor cell line. The data presented show that pharmacological inhibition of Nek2 kinase results in the expected phenotype of disruption to centrosome function associated with growth inhibition and further supports Nek2 as a target for cancer drug discovery.