Search

Patient notes contain shorthand and abbreviations that may be jargon or clinical vernacular. Here the authors train large machine learning models on public web data to decode such text by replacing abbreviations with their meanings.

Background: Pedophilic disorder (PD) entails sexual attraction to prepubertal children. A risk factor for committing child sexual abuse in PD is impaired cognitive control. However, the underlying neurocognitive mechanisms remain unclear. Methods: We performed a case-control study including 51 self-identified and help-seeking males with PD and 55 matched healthy control subjects. Functional magnetic resonance imaging and a pictorial-modified Stroop task involving computer-generated sexually implicit images were used to measure response time and brain activation. Increases in response time during the pictorial-modified Stroop task are presumably due to image-induced interference in executive functions required for task performance. Results: In PD, during the presentation of images of children compared with adults, we found increased response time (p = .005; 848 ± 92 ms vs. 826 ± 88 ms), and compared with healthy control subjects, we found increased activation in the occipital, temporal (bilateral hippocampus), parietal, frontal, cingulate, and left insular cortices; caudate (bilaterally); thalamus (mediodorsal); and cerebellum. Conclusions: Presentation of child images was associated with response interference in PD and increased engagement of brain regions involved in the processing of sexual stimuli, visual perception, self-referential thought, and executive function. We conclude that processing of child images is associated with functional and behavioral alterations in PD.

Background: Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of systemically administered hydroxypropyl-β-cyclodextrin (HP-β-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-β-CD, and biomarkers of NPC were assessed in pediatric and adult patients with NPC1. Methods: This was a multicenter, Phase I/II, randomized, double-blind, parallel-group, 48-week study (ClinicalTrials.gov identifier NCT02912793) to compare the PK of three different single intravenous (IV) doses of HP-β-CD in pediatric and adult patients with NPC1 and to evaluate the efficacy and tolerability of three different dosages of HP-β-CD in patients with NPC1 after long-term treatment. Twelve patients aged at least 2 years (2–39 years of age) with a confirmed diagnosis of NPC1 were randomized to receive one of three IV doses of HP-β-CD (1500 mg/kg, 2000 mg/kg, or 2500 mg/kg) every 2 weeks for 48 weeks. All patients received HP-β-CD; there was no placebo or other control. PK testing of plasma and cerebrospinal fluid (CSF) was at set times after the first infusion. Pharmacodynamic assessments included biomarkers of cholesterol metabolism (synthesis and breakdown products), N-palmitoyl-O-phosphocholineserine (PPCS), and specific biomarkers of CSF neurodegeneration (including total Tau), CNS inflammation (glial fibrillary acidic protein [GFAP] and tumor necrosis factor α [TNFα]), CNS cholesterol metabolism (24S-hydroxycholesterol) and inflammatory markers. Efficacy measures included clinical disease severity, neurologic symptoms, and clinical impressions of improvement. Safety assessment included physical examination, vital signs, clinical safety laboratory assessment and adverse events (AEs). Results: Nine patients completed the study, 2 in the 1500 mg/kg group, 4 in the 2000 mg/kg group and 3 in the 2500 mg/kg group. Three patients (all in the 1500 mg/kg group) discontinued the study because of either physician decision/site Principal Investigator (PI) discretion, withdrawal by subject/patient/parent/guardian, or other non-safety reasons. In 5 patients who underwent serial lumbar punctures, HP-β-CD was detected in the CSF. Of the 9 patients who completed the study, 8 (88.9%) improved in at least two domains of the 17-Domain Niemann-Pick disease Type C-Clinical Severity Scale (17D-NPC-CSS), and 6 of these patients improved in at least one domain viewed by patients and their caregivers to be key to quality of life, namely, speech, swallow, fine and gross motor skills, and cognition. Of the 9 patients who completed the study, 7 were viewed by their treating physicians as having improved to some degree at the end of the study, and 2 remained stable; both outcomes are highly relevant in a progressive neurodegenerative disease. Some patients and families reported improvement in quality of life.All three doses of HP-β-CD were well tolerated overall, with most treatment-emergent adverse events transient, mild-to-moderate in nature, and considered by the site PIs to be not related to study drug. Interpretation: This 48-week trial is the longest to date to evaluate the safety, tolerability, and efficacy across multiple clinical endpoints of IV administration of Trappsol® Cyclo™ (HP-β-CD) in NPC1 patients. In pediatric and adult patients with NPC, Trappsol® Cyclo™ IV improved clinical signs and symptoms and was generally well tolerated. The findings presented here demonstrate a favorable benefit-risk profile and support the global pivotal trial now underway to evaluate the long-term treatment benefits and the potential of Trappsol® Cyclo™ as a disease-modifying treatment in this patient population.

Background: The value of rapid reviews in informing health care decisions is more evident since the onset of the coronavirus disease 2019 (COVID-19) pandemic. While systematic reviews can be completed rapidly, rapid reviews are usually a type of evidence synthesis in which components of the systematic review process may be simplified or omitted to produce information more efficiently within constraints of time, expertise, funding or any combination thereof. There is an absence of high-quality evidence underpinning some decisions about how we plan, do and share rapid reviews. We will conduct a modified James Lind Alliance Priority Setting Partnership to determine the top 10 unanswered research questions about how we plan, do and share rapid reviews in collaboration with patients, public, reviewers, researchers, clinicians, policymakers and funders. Methods: An international steering group consisting of key stakeholder perspectives (patients, the public, reviewers, researchers, clinicians, policymakers and funders) will facilitate broad reach, recruitment and participation across stakeholder groups. An initial online survey will identify stakeholders’ perceptions of research uncertainties about how we plan, do and share rapid reviews. Responses will be categorised to generate a long list of questions. The list will be checked against systematic reviews published within the past three years to identify if the question is unanswered. A second online stakeholder survey will rank the long list in order of priority. Finally, a virtual consensus workshop of key stakeholders will agree on the top 10 unanswered questions. Discussion: Research prioritisation is an important means for minimising research waste and ensuring that research resources are targeted towards answering the most important questions. Identifying the top 10 rapid review methodology research priorities will help target research to improve how we plan, do and share rapid reviews and ultimately enhance the use of high-quality synthesised evidence to inform health care policy and practice.

Background: The value of rapid reviews in informing health care decisions is more evident since the onset of the coronavirus disease 2019 (COVID-19) pandemic. While systematic reviews can be completed rapidly, rapid reviews are usually a type of evidence synthesis in which components of the systematic review process may be simplified or omitted to produce information more efficiently within constraints of time, expertise, funding or any combination thereof. There is an absence of high-quality evidence underpinning some decisions about how we plan, do and share rapid reviews. We will conduct a modified James Lind Alliance Priority Setting Partnership to determine the top 10 unanswered research questions about how we plan, do and share rapid reviews in collaboration with patients, public, reviewers, researchers, clinicians, policymakers and funders. Methods: An international steering group consisting of key stakeholder perspectives (patients, the public, reviewers, researchers, clinicians, policymakers and funders) will facilitate broad reach, recruitment and participation across stakeholder groups. An initial online survey will identify stakeholders’ perceptions of research uncertainties about how we plan, do and share rapid reviews. Responses will be categorised to generate a long list of questions. The list will be checked against systematic reviews published within the past three years to identify if the question is unanswered. A second online stakeholder survey will rank the long list in order of priority. Finally, a virtual consensus workshop of key stakeholders will agree on the top 10 unanswered questions. Discussion: Research prioritisation is an important means for minimising research waste and ensuring that research resources are targeted towards answering the most important questions. Identifying the top 10 rapid review methodology research priorities will help target research to improve how we plan, do and share rapid reviews and ultimately enhance the use of high-quality synthesised evidence to inform health care policy and practice.

Abstract Background Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPβPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPβCD has been administered to NPC patients with approved INDs globally since 2009. Results Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPβCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPβCD following on average 13 months of IV HPβCD. Several patients transitioned to an alternate HPβCD. Moderately affected NPC patients treated with HPβCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. Conclusions These expanded access data support the safety and potential benefit of systemic IV administration of HPβCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPβCD in NPC patients.

Individuals from the 1945‐1965 birth cohort account for the majority of hepatocellular carcinoma (HCC) cases in the United States. Understanding trends in HCC among this birth cohort is vital given the increasing burden of chronic liver disease among this group. We retrospectively evaluated trends and disparities in HCC tumor stage at the time of diagnosis among the 1945‐1965 birth cohort in the United States using the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Tumor stage at the time of HCC diagnosis was assessed using Milan criteria and SEER HCC staging systems. Among 38,045 patients with HCC within the 1945‐1965 birth cohort (81.6% male, 50.1% non‐Hispanic white, 16.2% African American, 12.6% Asian, 19.8% Hispanic), 66.2% had Medicare or commercial insurance, 27.2% had Medicaid, and 6.6% were uninsured. During the period 2004‐2006 to 2013‐2014, the number of patients with HCC from the 1945‐1965 birth cohort increased by 58.7% (5.9% increase per year). While the proportion of patients with HCC within the Milan criteria increased with time (36.4% in 2003‐2006 to 46.3% in 2013‐2014; P

This study attempts to assess the innovation process based on innovation value chain model in footwear industry in East Java, Indonesia. A strength and weakness mapping analysis was performed and it included three factors related to company characteristics: operation scale based on number of employees, operational priod, and market orientation. The samples were 62 footwear industries, members of East Java Indonesian Footwear Association (Aprisindo). The questionnaire was sent via email. Thirty industries (48.38%) sent the questionnaire back. A focus group discussion (FGD) was conducted with several representatives from footwear industry before the questionnaire was sent. The study found that companies are relatively good at idea conversion (42,30%) but the companies have a little difficulties at diffusion (50,80%) and at idea generation (55,80%). From the result respose show (see table.2) that the weakest links (the innovation process bottleneck) is cross-pollination activity [in which the people typically don't collaborate on projects across units, businesses, or subsidiaries (88,6%)], while the strongest links is selection activity [the companies have a risk- averse attitude toward investing in novel ideas (39,3%)]. Based on p-value, the study found that company characteristics influencing a certain phase of innovation value chain significantly were company period (age of company) and market orientation. Specifically, both of them influenced idea generation phase.

An injection of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to mice lacking Niemann Pick type C (NPC) protein results in delayed neurodegeneration, decreased inflammation, and prolonged lifespan. Changes in sterol balance observed in Npc1−/− mice 24 h after HP-β-CD administration suggest that HP-β-CD facilitates the release of accumulated lysosomal cholesterol, the molecular hallmark of this genetic disorder. Current studies were performed to evaluate the time course of HP-β-CD effects. Within 3 h after HP-β-CD injection, decreases in cholesterol synthesis rates and increases in cholesteryl ester levels were detected in tissues of Npc1−/− mice. The levels of RNAs for target genes of sterol-sensing transcription factors were altered by 6 h in liver, spleen, and ileum. Despite the cholesterol-binding capacity of HP-β-CD, there was no evidence of increased cholesterol in plasma or urine of treated Npc1−/− mice, suggesting that HP-β-CD does not carry sterol from the lysosome into the bloodstream for ultimate urinary excretion. Similar changes in sterol balance were observed in cultured cells from Npc1−/− mice using HP-β-CD and sulfobutylether-β-CD, a variant that can interact with sterol but not facilitate its solubilization. Taken together, our results demonstrate that HP-β-CD works in cells of Npc1−/− mice by rapidly liberating lysosomal cholesterol for normal sterol processing within the cytosolic compartment.

Lipoprotein cholesterol taken up by cells is processed in the endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid lipase (LAL), Niemann-Pick C2 (NPC2), and Niemann-Pick C1 (NPC1). Inactivation of NPC2 in mouse caused sequestration of unesterified cholesterol (UC) and expanded the whole animal sterol pool from 2,305 to 4,337 mg/kg. However, this pool increased to 5,408 and 9,480 mg/kg, respectively, when NPC1 or LAL function was absent. The transport defect in mutants lacking NPC2 or NPC1, but not in those lacking LAL, was reversed by cyclodextrin (CD), and the ED50 values for this reversal varied from ∼40 mg/kg in kidney to >20,000 mg/kg in brain in both groups. This reversal occurred only with a CD that could interact with UC. Further, a CD that could interact with, but not solubilize, UC still overcame the transport defect. These studies showed that processing and export of sterol from the late E/L compartment was quantitatively different in mice lacking LAL, NPC2, or NPC1 function. In both npc2−/− and npc1−/− mice, the transport defect was reversed by a CD that interacted with UC, likely at the membrane/bulk-water interface, allowing sterol to move rapidly to the export site of the E/L compartment.

A mutation in NPC1 leads to sequestration of unesterified cholesterol in the late endosomal/lysosomal compartment of every cell culminating in the development of pulmonary, hepatic, and neurodegenerative disease. Acute administration of 2-hydroxypropyl-β-cyclodextrin (CYCLO) rapidly overcomes this transport defect in both the 7-day-old pup and 49-day-old mature npc1−/− mouse, even though this compound is cleared from the body and plasma six times faster in the mature mouse than in the neonatal animal. The liberated cholesterol flows into the cytosolic ester pool, suppresses sterol synthesis, down-regulates SREBP2 and its target genes, and reduces expression of macrophage-associated inflammatory genes. These effects are seen in the liver and brain, as well as in peripheral organs like the spleen and kidney. Only the lung appears to be resistant to these effects. Forty-eight h after CYCLO administration to the 49-day-old animals, fecal acidic, but not neutral, sterol output increases, whole-animal cholesterol burden is reduced, and the hepatic and neurological inflammation is ameliorated. However, lifespan is extended only when the CYCLO is administered to the 7-day-old animals. These studies demonstrate that CYCLO administration acutely reverses the cholesterol transport defect seen in the NPC1 mouse at any age, and this reversal allows the sequestered sterol to be excreted from the body as bile acid.

These studies investigated the role of gangliosides in governing the steady-state concentration and turnover of unesterified cholesterol in normal tissues and in those of mice carrying the NPC1 mutation. In animals lacking either GM2/GD2 or GM3 synthase, tissue cholesterol concentrations and synthesis rates were normal in nearly all organs, and whole-animal sterol pools and turnover also were not different from control animals. Mice lacking both synthases, however, had small elevations in cholesterol concentrations in several organs, and the whole-animal cholesterol pool was marginally elevated. None of these three groups, however, had changes in any parameter of cholesterol homeostasis in the major regions of the central nervous system. When either the GM2/GD2 or GM3 synthase activity was deleted in mice lacking NPC1 function, the clinical phenotype was not changed, but lifespan was shortened. However, the abnormal cholesterol accumulation seen in the tissues of the NPC1 mouse was unaffected by loss of either synthase, and clinical and molecular markers of hepatic and cerebellar disease also were unchanged. These studies demonstrate that hydrophobic interactions between cholesterol and various gangliosides do not play an important role in determining cellular cholesterol concentrations in the normal animal or in the mouse with the NPC1 mutation.

Niemann-Pick type C (NPC) disease is a multisystem disorder caused primarily by a mutation in the npc1 gene. These studies evaluated the effect of genetic background, deletion of additional genes, and administration of several agents on the age at death in a murine model of this disorder. Such factors as differing strain background or genetic drift within a given background in the npc1−/− mouse significantly altered the age at death and the degree of organ disease. Genetic deletion of Siat9 (GM3 synthetase) or Nr1h2 [liver X receptor (LXR)β] shortened the life of the npc1−/− animals. Daily treatment of the npc1−/− mice with an LXR agonist or administration of a single dose of cyclodextrin, with or without the neurosteroid allopregnanolone, significantly slowed neurodegeneration and increased the lifespan of these animals. These data illustrate that the age at death of the npc1−/− mouse can be significantly influenced by many factors, including differences in strain background, other inactivating gene mutations (Siat9 and lxrβ), and administration of agents such as LXR agonists and, particularly, cyclodextrin. It is currently not clear which of these effects is nonspecific or which might relate directly to the molecular defect present in the NPC1 syndrome.

These studies explored the roles of receptor-mediated and bulk-phase endocytosis as well as macrophage infiltration in the accumulation of cholesterol in the mouse with Niemann-Pick type C (NPC) disease. Uptake of LDL-cholesterol varied from 514 μg/day in the liver to zero in the central nervous system. In animals lacking LDL receptors, liver uptake remained about the same (411 μg/day), but more cholesterol was taken up in extrahepatic organs. This uptake was unaffected by the reductive methylation of LDL and consistent with bulk-phase endocytosis. All tissues accumulated cholesterol in mice lacking NPC1 function, but this accumulation was decreased in adrenal, unchanged in liver, and increased in organs like spleen and lung when LDL receptor function was also deleted. Over 56 days, the spleen and lung accumulated amounts of cholesterol greater than predicted, and these organs were heavily infiltrated with macrophages. This accumulation of both cholesterol and macrophages was increased by deleting LDL receptor function. These observations indicate that both receptor-mediated and bulk-phase endocytosis of lipoproteins, as well as macrophage infiltration, contribute to the cholesterol accumulation seen in NPC disease. These macrophages may also play a role in parenchymal cell death in this syndrome.

Niemann-Pick type C (NPC) disease is a multisystem disorder resulting from mutations in the NPC1 gene that encodes a protein involved in intracellular cholesterol trafficking. Significant liver dysfunction is frequently seen in patients with this disease. The current studies used npc1 mutant mice to investigate the association between liver dysfunction and unesterified cholesterol accumulation, a hallmark of NPC disease. Data from 92 npc1−/− mice (age range, 9–56 days) revealed a significant positive correlation between the plasma activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and whole liver cholesterol content. In 56 day old npc1−/− mice that had been fed from 35 days of age a rodent diet or the same diet containing either cholesterol (1.0%, w/w) or ezetimibe (a sterol absorption inhibitor; 0.0125%, w/w), whole liver cholesterol content averaged 33.5 ± 1.1, 87.9 ± 1.7, and 20.8 ± 0.9 mg, respectively. Again, plasma ALT and AST activities were positively correlated with hepatic cholesterol content. In contrast, plasma transaminase levels remained in the normal range in npc1+/+ mice, in which hepatic esterified cholesterol content had been increased by 72-fold by feeding a high-cholesterol, high-fat diet. These studies suggest that the late endosomal/lysosomal content of unesterified cholesterol correlates with cell damage in NPC disease.

Recently, cinemas, home theater systems and game consoles have undergone a rapid evolution towards stereoscopic representation with recipients gradually becoming accustomed to these changes. Stereoscopy techniques in most media present two offset images separately to the left and right eye of the viewer (usually with the help of glasses separating both images) resulting in the perception of three-dimensional depth. In contrast to these mass market techniques, true 3D volumetric displays or holograms that display an image in three full dimensions are relatively uncommon. The visual quality and visual comfort of stereoscopic representation is constantly being improved by the industry.