Performance of Tumor Surveillance for Children With Cancer Predisposition.

Importance: Pediatric oncology patients are increasingly recognized as having an underlying cancer predisposition syndrome (CPS). Surveillance is often recommended to detect new tumors at their earliest and most curable stages. Data on the effectiveness and outcomes of surveillance for children with CPS are limited. Objective: To evaluate the performance of surveillance across a wide spectrum of CPSs. Design, Setting, and Participants: This cohort study reviewed surveillance outcomes for children and young adults from birth to age 23 years with a clinical and/or molecular CPS diagnosis from January 1, 2009, through September 31, 2021. Patients were monitored using standard surveillance regimens for their corresponding CPS at a specialty pediatric oncology center. Patients with hereditary retinoblastoma and bone marrow failure syndromes were excluded. Data were analyzed between August 1, 2021, and December 6, 2023. Exposure: Cancer predisposition syndrome. Main Outcomes and Measures: Outcomes of surveillance were reviewed to evaluate the incidence, spectrum, and clinical course of newly detected tumors. Surveillance modalities were classified for accuracy and assessed for common strengths and weaknesses. Results: A total of 274 children and young adults (mean age, 8 years [range, birth to 23 years]; 144 female [52.6%]) with 35 different CPSs were included, with a median follow-up of 3 years (range, 1 month to 12 years). During the study period, 35 asymptomatic tumors were detected in 27 patients through surveillance (9.9% of the cohort), while 5 symptomatic tumors were detected in 5 patients (1.8% of the cohort) outside of surveillance, 2 of whom also had tumors detected through surveillance. Ten of the 35 tumors (28.6%) were identified on first surveillance imaging. Malignant solid and brain tumors identified through surveillance were more often localized (20 of 24 [83.3%]) than similar tumors detected before CPS diagnosis (71 of 125 [56.8%]; P < .001). Of the 24 tumors identified through surveillance and surgically resected, 17 (70.8%) had completely negative margins. When analyzed across all imaging modalities, the sensitivity (96.4%), specificity (99.6%), positive predictive value (94.3%), and negative predictive value (99.6%) of surveillance were high, with few false-positive (6 [0.4%]) or false-negative (5 [0.3%]) findings. Conclusions and Relevance: These findings suggest that standardized surveillance enables early detection of new tumors across a wide spectrum of CPSs, allowing for complete surgical resection and successful treatment in the majority of patients.

Excitoprotective effects of conditional tau reduction in excitatory neurons and in adulthood.

Tau reduction is a promising therapeutic strategy for Alzheimer's disease. In numerous models, tau reduction via genetic knockout is beneficial, at least in part due to protection against hyperexcitability and seizures, but the underlying mechanisms are unclear. Here we describe the generation and initial study of a new conditional Tau flox model to address these mechanisms. Given the protective effects of tau reduction against hyperexcitability, we compared the effects of selective tau reduction in excitatory or inhibitory neurons. Tau reduction in excitatory neurons mimicked the protective effects of global tau reduction, while tau reduction in inhibitory neurons had the opposite effect and increased seizure susceptibility. Since most prior studies used knockout mice lacking tau throughout development, we crossed Tau flox mice with inducible Cre mice and found beneficial effects of tau reduction in adulthood. Our findings support the effectiveness of tau reduction in adulthood and indicate that excitatory neurons may be a key site for its excitoprotective effects. SUMMARY: A new conditional tau knockout model was generated to study the protective effects of tau reduction against hyperexcitability. Conditional tau reduction in excitatory, but not inhibitory, neurons was excitoprotective, and induced tau reduction in adulthood was excitoprotective without adverse effects.

Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration.

Parkinson's disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting an important role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.

Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

Genomes for Nurses: Understanding and Overcoming Barriers to Nurses Utilizing Genomics.

Background: Genomic testing is an increasingly important technology within pediatric oncology that aids in cancer diagnosis, provides prognostic information, identifies therapeutic targets, and reveals underlying cancer predisposition. However, nurses lack basic knowledge of genomics and have limited self-assurance in using genomic information in their daily practice. This single-institution project was carried out at an academic pediatric cancer hospital in the United States with the aim to explore the barriers to achieving genomics literacy for pediatric oncology nurses. Method: This project assessed barriers to genomic education and preferences for receiving genomics education among pediatric oncology nurses, nurse practitioners, and physician assistants. An electronic survey with demographic questions and 15 genetics-focused questions was developed. The final survey instrument consisted of nine sections and was pilot-tested prior to administration. Data were analyzed using a ranking strategy, and five focus groups were conducted to capture more-nuanced information. The focus group sessions lasted 40 min to 1 hour and were recorded and transcribed. Results: Over 50% of respondents were uncomfortable with or felt unprepared to answer questions from patients and/or family members about genomics. This unease ranked as the top barrier to using genomic information in clinical practice. Discussion: These results reveal that most nurses require additional education to facilitate an understanding of genomics. This project lays the foundation to guide the development of a pediatric cancer genomics curriculum, which will enable the incorporation of genomics into nursing practice.

Constitutional balanced translocations involving SMARCB1: A rare cause of rhabdoid tumor predisposition syndrome.

Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1. RTPS1 should be evaluated in all individuals with rhabdoid tumor and is more likely in those with a young age at presentation (occasionally congenital presentation), multiple primary tumors, or a family history of rhabdoid tumor or RTPS1. Proband genetic testing is the standard method for diagnosing RTPS1. Most known RTPS1-related SMARCB1 gene mutations are copy number variants (CNVs) or single nucleotide variants/indels, but structural variant analysis (SVA) is not usually included in the molecular evaluation. Here, we report two children with RTPS1 presenting with atypical teratoid/rhabdoid tumor (ATRT) who had constitutional testing showing balanced chromosome translocations involving SMARCB1. Patient 1 is a 23-year-old female diagnosed with pineal region ATRT at 7 months who was found to have a de novo, constitutional t(16;22)(p13.3;q11.2). Patient 2 is a 24-month-old male diagnosed with a posterior fossa ATRT at 14 months, with subsequent testing showing a constitutional t(5;22)(q14.1;q11.23). These structural rearrangements have not been previously reported in RTPS1. While rare, these cases suggest that structural variants should be considered in the evaluation of children with rhabdoid tumors to provide more accurate genetic counseling on the risks of developing tumors, the need for surveillance, and the risks of passing the disorder on to future children. Further research is needed to understand the prevalence, clinical features, and tumor risks associated with RTPS1-related constitutional balanced translocations.

Parental Understanding of Their Child's Germline Genomic Testing: Intent of Disclosure to Their Child and Family.

Genomic testing is becoming increasingly common in the care of pediatric patients with cancer. Parental understanding of germline results and their intent and timing of results disclosure to their child and family may have significant implications on the family unit. The purpose of this study was to examine parental understanding of germline genomic results and plans for disclosure to their child and other relatives. Semi-structured interviews were conducted with 64 parents of children with cancer, approximately eight weeks after parents had received their child's results. Parents of children with negative results (n = 20), positive results (n = 15), or variants of uncertain significance (n = 29), were interviewed. Fifty-three parents (83%) correctly identified their child's results as negative, uncertain, or positive. Most parents had disclosed results to family members; however, only 11 parents (17%) acknowledged discussing results with their child. Most parents delayed disclosure due to the young age of their child at the time of testing. In summary, most parents appropriately described their child's germline genomic results, yet few discussed the results with their child due to age. Families should be followed with supportive counseling to assist parents in the timing and content of result disclosure to their children.

Parent Quality of Life After Disclosure of Pediatric Oncology Germline Sequencing Results.

PURPOSE: To characterize parents' quality of life (QoL) after germline genomic sequencing for their children with cancer. METHODS: Participants were n = 104 parents of children with cancer enrolled in a prospective study of clinical tumor and germline genomic sequencing. Parents completed surveys at study consent (T0), before disclosure of their child's germline results (T1), and again ≥5 weeks after results disclosure (T2). Bivariate associations with QoL were examined, followed by a multivariable regression model predicting parents' psychological distress. RESULTS: At T2, parental distress significantly differed by their children's germline result type (positive, uncertain, negative; P = .038), parent relationship status (P = .04), predisclosure genetics knowledge (P = .006), and predisclosure worry about sequencing (P < .001). Specifically, parents of children with positive (ie, pathogenic or likely pathogenic) results experienced greater distress than those of children with negative results (P = .029), as did parents who were single, more knowledgeable about genetics, and with greater worry. In the adjusted regression model, a positive germline result remained significantly associated with parents' lower QoL at T2 follow-up (F [4,92] = 9.95; P < .001; R2 = .30; ß = .19; P = .031). CONCLUSION: Germline genomic sequencing for children with cancer is associated with distress among parents when revealing an underlying cancer predisposition among their affected children. Genetic education and counseling before and after germline sequencing may help attenuate this impact on QoL by addressing parents' concerns about test results and their health implications. Assessing parents' worry early in the testing process may also aid in identifying those most likely in need of psychosocial support.

Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response.

Severe infections with coronaviruses are often accompanied with hyperinflammation, requiring therapeutic strategies to simultaneously tackle the virus and inflammation. By screening a safe-in-human broad-spectrum antiviral agents library, we identified that indomethacin can inhibit pan-coronavirus infection in human cell and airway organoids models. Combining indomethacin with oral antiviral drugs authorized for treating COVID-19 results in synergistic anti-coronavirus activity. Coincidentally, screening a library of FDA-approved drugs identified indomethacin as the most potent potentiator of interferon response through increasing STAT1 phosphorylation. Combining indomethacin with interferon-alpha exerted synergistic antiviral effects against multiple coronaviruses. The anti-coronavirus activity of indomethacin is associated with activating interferon response. In a co-culture system of lung epithelial cells with macrophages, indomethacin inhibited both viral replication and inflammatory response. Collectively, indomethacin is a pan-coronavirus inhibitor that can simultaneously inhibit virus-triggered inflammatory response. The therapeutic potential of indomethacin can be further augmented by combining it with oral antiviral drugs or interferon-alpha.

A case of diffuse panbronchiolitis caused by Mycoplasma amphoriforme.

Mycoplasma amphoriforme is a novel specie which was discovered in 2003 and associated with congenital immune deficiency. It has been described as an underlying cause of bronchopneumonia. There is limited description of the in vitro sensitivities. In this article, we present the first description of M. amphoriforme as the causative agent of diffuse panbronchiolitis in a patient with X-linked hypogammaglobulinema and bronchiectasis, with symptoms improved by treatment with azithromycin. We also describe the difficulty obtaining this organism through routine culture and the need to consider culture independent methods of recovery when the suspicion is high.

How is fish market waste managed in the Philippines?

Improper management of fish waste is one of the factors that makes Philippine fisheries unsustainable. A considerable portion of fish waste is produced in wet markets where bulk of fish products are sold. A comparison of existing practices in different municipalities can indicate the best points of intervention and identify existing traditional practices that can be promoted. This study interviewed stakeholders of the fisheries industry and collected information at the market level to determine existing fish waste management systems. From the responses gathered, the average daily production of fish waste in Philippine wet markets was 70.3 + 0.93 kg, with no significant differences across locations (p = 0.2501). Of the fish waste produced, 32.3 + 1.33 kg per wet market were disposed of, 18.9 + 0.81 kg were sold, and 19.1 + 1.15 kg were given away to stakeholders who re-use the fish waste. A significantly greater proportion of fish waste in rural areas were re-used compared to Metro Manila (p = 0.0311). Incentivizing innovations that maximize the use of derived fish waste at the municipal level, and promoting existing traditional practices, can prove effective in contributing to the Philippine circular economy while providing alternative sources of income for the stakeholders of the fisheries industry.

Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management.

PURPOSE: Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution. EXPERIMENTAL DESIGN: This is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 preselected aoCPGs. Available tumor whole-genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference. RESULTS: Thirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibiting a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline-positive patients were counseled regarding future cancer risks, surveillance, and risk-reducing measures. No patients had immediate cancer therapy changed due to aoCPG data. CONCLUSIONS: AoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of tumor aoCPG variants examined exhibited a second hit and/or conferred an abnormal DNA mutational profile suggesting a role in tumor formation. aoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.

Screening for Perinatal OCD: A Comparison of the DOCS and the EPDS.

Screening for perinatal-occurring obsessive-compulsive disorder (OCD) is rare. We sought to evaluate the Dimensional Obsessive-Compulsive Scale (DOCS) as a screening tool for perinatal OCD and compare the screening accuracy of the DOCS with the commonly recommended Edinburgh Postnatal Depression Scale (EPDS). English-speaking, pregnant individuals aged 19+ (N = 574) completed online questionnaires and diagnostic interviews to assess for OCD prenatally and twice postpartum. The DOCS total score demonstrated the highest level of accuracy. Neither the EPDS-Full nor the three-item Anxiety subscale of the EPDS (EPDS-3A) met the criteria of a sufficiently accurate screening tool for OCD at any of the assessment points. Findings provide support for the DOCS as a screening tool for perinatal OCD and indicate a need for disorder-specific screening for perinatal anxiety and their related disorders (AD). Generalizability of findings is limited to Canada only. Future research would benefit from comparisons with measures of perinatal OCD (e.g., the Perinatal Obsessive-Compulsive Scale).

Patterns of Prenatal Care Delivery and Obstetric Outcomes before and during the COVID-19 Pandemic.

OBJECTIVE: Health care providers and health systems confronted new challenges to deliver timely, high-quality prenatal care during the coronavirus disease 2019 (COVID-19) pandemic as the pandemic raised concerns that care would be delayed or substantively changed. This study describes trends in prenatal care delivery in 2020 compared with 2018 to 2019 in a large, commercially insured population and investigates changes in obstetric care processes and outcomes. STUDY DESIGN: This retrospective cohort study uses de-identified administrative claims for commercially insured patients. Patients whose entire pregnancy took place from March 1 to December 31 in years 2018, 2019, and 2020 were included. Trends in prenatal care, including in-person, virtual, and emergency department visits, were evaluated, as were prenatal ultrasounds. The primary outcome was severe maternal morbidity (SMM). Secondary outcomes included preterm birth and stillbirth. To determine whether COVID-19 pandemic-related changes in prenatal care had an impact on maternal outcomes, we compared the outcome rates during the pandemic period in 2020 to equivalent periods in 2018 and 2019. RESULTS: In total, 35,112 patients were included in the study. There was a significant increase in the prevalence of telehealth visits, from 1.1 to 1.2% prior to the pandemic to 17.2% in 2020, as well as a significant decrease in patients who had at least one emergency department visit during 2020. Overall prenatal care and ultrasound utilization were unchanged. The rate of SMM across this period was stable (2.3-2.8%) with a statistically significant decrease in the preterm birth rate in 2020 (7.4%) compared with previous years (8.2-8.6%; p < 0.05) and an unchanged stillbirth rate was observed. CONCLUSION: At a time when many fields of health care were reshaped during the pandemic, these observations reveal considerable resiliency in both the processes and outcomes of obstetric care. KEY POINTS: · Overall prenatal care and ultrasound were unchanged from 2018 to 2019 to 2020.. · There was a large increase in the prevalence of telehealth visits in 2020.. · There was no change in the rate of severe maternal morbidity or stillbirth in 2020 compared with 2018 to 2019..

Ustekinumab Tissue and Serum Levels in Patients With Crohn's Disease Are Closely Correlated Though Not Consistently Associated With Objective Response After Induction.

BACKGROUND: Ustekinumab (UST), which targets p40/interleukin (IL)-23 and IL-12, is an effective treatment for Crohn's disease (CD). Therapeutic drug monitoring may optimize UST posology. The aim of this study was to investigate UST and IL-23 serum and tissue concentrations in relation to mucosal inflammation and treatment response at an early time point. METHODS: CD patients starting UST between December 2016 and November 2018 were prospectively enrolled. Endoscopies were performed at baseline and week 16. UST and IL-23 serum and tissue concentrations were measured at week 16. Clinical and biochemical response were defined as decline of ≥3 points in Harvey-Bradshaw Index and reduction of ≥50% in fecal calprotectin levels. Endoscopic response was defined as a ≥50% decline in Simple Endoscopic Score or a decline of ≥1 points in Rutgeerts score. Histological remission was defined as Global Histologic Disease Activity Score ≤4. RESULTS: Of 56 included patients, 17 (30%) of 56 showed clinical response, 16 (30%) of 53 showed biochemical response, and 20 (36%) of 56 showed endoscopic response. UST, but not IL-23, concentration in biopsies was correlated to levels in corresponding sera (P < .0001). No correlation was found between UST tissue levels and treatment response. Patients achieving biochemical response showed significantly higher UST serum levels (3.12 µg/mL vs 1.41 µg/mL; P = .01). Tissue IL-23-to-UST ratio correlated with mucosal inflammation (P = .01). CONCLUSIONS: This is the first study to demonstrate a correlation between serum and tissue UST levels. While tissue IL-23-to-UST ratio correlated with mucosal inflammation, UST serum levels were more indicative for biochemical response. The role of UST levels for therapeutic drug monitoring in inflammatory bowel disease needs further research.

Ustekinumab (UST) serum levels correlate with UST tissue levels in patients with Crohn's disease. Tissue interleukin-23-to-UST ratio correlates with histological inflammation (Global Histologic Disease Activity Score). Serum UST levels correlate with biochemical response (reduction of ≥50% in fecal calprotectin levels).

Efficacy and Utilization Patterns of Anti-Epileptic Drugs in the Management of Neonatal Seizures: A Comparative Exploration.

Background: Management of neonatal seizures with available limited guidelines across different gestation can cause long-term neurological and cognitive impairment. Objectives: To compare utilization and observe the efficacy of anti-epileptic drugs in the treatment of neonatal seizures. The association of hypoxic-ischemic encephalopathy with NS and the etiology of HIE were also determined. Subjects and Methods: A retrospective cohort study was conducted at a tertiary care hospital for a period of one year. It was approved by IEC prior to initiation. Participants: Neonates admitted for seizure management and perinatal asphyxia with hypoxic-ischemic encephalopathy were included in the study. Both term and preterm 267 neonates from January 2014 to July 2018 were retrospectively analyzed. The drugs with the fastest seizure resolution, least recurrence, and readmission rates were considered efficient. Phenobarbitone, levetiracetam, and phenytoin were compared as they were commonly prescribed. Inpatient medical records and hospital databases served as sources of information. Results: Phenobarbitone was commonly utilized, followed by phenytoin and levetiracetam. The commonly prescribed combination was phenobarbitone (first-line agent) and phenytoin (second-line agent). Phenobarbitone immediately resolved seizures (97, 75.1%) and had the least cases of seizure recurrences (53, 41.1%) and readmissions (20, 15.5%), making it most efficient. The best second-line agent was phenytoin, with the least seizure recurrence (4, 8.51%), least readmissions (7, 14.8%), and fastest resolution (25, 53.1%). Levetiracetam was an efficient third-line agent. Hypoxic-ischemic encephalopathy was the most observed cause of neonatal seizures. Conclusion: Phenobarbitone was observed as the most utilized and efficient anti-epileptic drug, followed by phenytoin and levetiracetam. Owing to limitations in this study, there is an alarming need for standardized clinical trials to establish thorough guidelines.

Analysis of hemisphere-dependent effects of unilateral intrastriatal injection of α-synuclein pre-formed fibrils on mitochondrial protein levels, dynamics, and function.

Genetic and neuropathological evidence strongly implicates aberrant forms of α-synuclein in neurodegeneration. Antibodies specific for α-synuclein phosphorylated at serine 129 (pS129) are selective for the pathological protein aggregates that are characteristic of Parkinson's disease (PD) and other synucleinopathies, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the etiology of most synucleinopathies remains uncertain, a large body of evidence points to mitochondrial dysfunction. The recent development of animal models based on intracranial injection of α-synuclein pre-formed fibrils (PFFs) has provided a valuable experimental system in which to study the spread and neurotoxicity of α-synuclein aggregates, yet the effects of PFF-induced protein aggregates on mitochondrial function and dynamics have not been rigorously examined in vivo. To help fill this knowledge gap, we injected the striatum of mice unilaterally with well-characterized small length (< 30 nm) PFFs or monomeric α-synuclein control and measured the distribution and extent of pS129 α-synuclein-immunoreactive aggregates, the loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra, the abundance of mitochondrial proteins, and the activity of mitochondrial respiratory chain components at 3 months and 6 months post injection. Intrastriatal injection of small length PFFs, but not monomeric α-synuclein control, induced robust pS129 α-synuclein immunoreactive inclusions in the cortex, ventral midbrain, and striatum, as well as in rarely reported brain regions, such as the hippocampus, as early as 3 months post injection. Significant loss of nigral tyrosine hydroxylase-immunoreactive neurons was observed in the PFF-injected hemisphere at 3 months and 6 months post injection. The unilateral striatal injection of small length PFFs also caused hemisphere-dependent and treatment-dependent changes in the cortical levels of mitochondrial proteins such as VDAC1, COX-IV, and DRP-1, as well as functional changes in mitochondrial complex I activity in the contralateral striatum. Together, these data demonstrate that intrastriatal injection of mice with small length PFFs induces extensive bilateral protein aggregates, significant unilateral nigral cell loss, and altered contralateral levels of mitochondrial proteins and respiratory chain activity. Our data suggest this animal model may be useful for studying the role of mitochondrial dysfunction in α-synucleinopathies, for studying the hemisphere-dependent effects of α-synuclein aggregates, and for testing neuroprotective therapies that target mitochondrial dysfunction and protein aggregation.

An Extended UTAUT Model to Explain Factors Affecting Online Learning System Amidst COVID-19 Pandemic: The Case of a Developing Economy.

From a developing country perspective, this study explains the factors affecting online learning amidst the COVID-19 pandemic. The paper empirically tests the proposed extended unified theory of acceptance and use of technology (e-UTAUT) model in the students' intention and use behavior toward the online learning system. Understanding the acceptance of online learning technology is crucial, especially among developing countries caught off-guard by the abrupt transition of face-to-face classes to pure online learning. The enjoyment, interactivity, flexibility, and quality of online learning systems were added as antecedent variables to the UTAUT model. Eight hundred eighty valid responses from selected college students in the Visayas regions, Philippines, were collected. Structural equation modeling (SEM) was employed to verify the research hypotheses. The results supported the proposed model with acceptable fit measures and substantial explanatory power. The extended constructs provide different views on online learning based on the significant cluster of antecedents to explain technology acceptance through behavioral intentions and actual system usage. The paper implies that despite the challenges of connectivity in developing countries, the variations still conform with emerging literature about the topic. Insights for higher education institutions and policy directions are recommended.

Is age just a number? A population pharmacokinetic study of gemcitabine.

PURPOSE: Pharmacokinetic exposure to gemcitabine and its metabolite, 2',2'-difluorodeoxyuridine (dFdU), might be altered in elderly compared to their younger counterparts. It is unknown if age-based dose adjustments are necessary to reduce the development of treatment-induced adverse events. The aim of this study was to assess the impact of age on the pharmacokinetics of gemcitabine and dFdU. METHODS: Pharmacokinetic sampling following a flexible limited sampling strategy was performed in patients ≥ 70 years after gemcitabine infusion. The data were supplemented with pharmacokinetic data in patients included in four previously conducted clinical trials. Nonlinear mixed effects modelling was performed on the pooled dataset to assess the impact of age on the pharmacokinetics of gemcitabine and dFdU. RESULTS: In total, pharmacokinetic data were available of 197 patients, of whom 83 patients were aged ≥ 70 years (42%). A two-compartment model for both gemcitabine and dFdU with linear clearances from the central compartments described the data best. Age, tested as continuous and categorical (< 70 years versus ≥ 70 years) covariate, did not statistically affect the pharmacokinetics of gemcitabine and dFdU. CONCLUSION: Age was not of influence on the pharmacokinetics of gemcitabine or its metabolite, dFdU. Age-related dose adjustments for gemcitabine based on pharmacokinetic considerations are not recommended. TRIAL REGISTRATION NUMBER: NL39647.048.12, registered on May 3rd 2012.