Miracle-dz/UniFAR-FTUs huggingface dataset:
Individual-specific functional connectivity of the amygdala: A substrate for precision psychiatry

Significance Disrupted functional connectivity of the amygdala may be central to mental illness. Yet, little is known about the functional connectivity of the amygdala in individuals, limiting our ability to understand and treat amygdala dysconnectivity in individual patients. Here, we divide the amygdala into three subdivisions in each of 10 individuals and define connectivity patterns using 5 h of fMRI data per person. We demonstrate that, across individuals, each of the three amygdala subdivisions occupies a roughly consistent location and exhibits consistent functional connectivity with specific cortical functional networks: One to the default mode network, another to the dorsal attention network, and a third without preferential connectivity. The amygdala is central to the pathophysiology of many psychiatric illnesses. An imprecise understanding of how the amygdala fits into the larger network organization of the human brain, however, limits our ability to create models of dysfunction in individual patients to guide personalized treatment. Therefore, we investigated the position of the amygdala and its functional subdivisions within the network organization of the brain in 10 highly sampled individuals (5 h of fMRI data per person). We characterized three functional subdivisions within the amygdala of each individual. We discovered that one subdivision is preferentially correlated with the default mode network; a second is preferentially correlated with the dorsal attention and fronto-parietal networks; and third subdivision does not have any networks to which it is preferentially correlated relative to the other two subdivisions. All three subdivisions are positively correlated with ventral attention and somatomotor networks and negatively correlated with salience and cingulo-opercular networks. These observations were replicated in an independent group dataset of 120 individuals. We also found substantial across-subject variation in the distribution and magnitude of amygdala functional connectivity with the cerebral cortex that related to individual differences in the stereotactic locations both of amygdala subdivisions and of cortical functional brain networks. Finally, using lag analyses, we found consistent temporal ordering of fMRI signals in the cortex relative to amygdala subdivisions. Altogether, this work provides a detailed framework of amygdala–cortical interactions that can be used as a foundation for models relating aberrations in amygdala connectivity to psychiatric symptoms in individual patients.
Activation of mosquito immunity blocks the development of transmission-stage filarial nematodes

Significance Infections with filarial nematodes, resulting from the bite of an infected mosquito, have a huge health impact worldwide. Sequencing mosquito transcripts revealed that a strain of Aedes aegypti that is refractory to infection with heartworm robustly activates immune genes, compared to a susceptible strain. These differences were detected early in infection and in the tissue important for larval development. Using a new assay, we found that bolstering mosquito immune activation through knockdown of a negative regulator resulted in a strong block in the emergence of transmission-stage filarial larvae, including those that cause human lymphatic filariasis. This work provides opportunities to block pathogen transmission by targeting filarial nematodes in the mosquito vector. Mosquito-borne helminth infections are responsible for a significant worldwide disease burden in both humans and animals. Accordingly, development of novel strategies to reduce disease transmission by targeting these pathogens in the vector are of paramount importance. We found that a strain of Aedes aegypti that is refractory to infection by Dirofilaria immitis, the agent of canine heartworm disease, mounts a stronger immune response during infection than does a susceptible strain. Moreover, activation of the Toll immune signaling pathway in the susceptible strain arrests larval development of the parasite, thereby decreasing the number of transmission-stage larvae. Notably, this strategy also blocks transmission-stage Brugia malayi, an agent of human lymphatic filariasis. Our data show that mosquito immunity can play a pivotal role in restricting filarial nematode development and suggest that genetically engineering mosquitoes with enhanced immunity will help reduce pathogen transmission.
The potential role of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) single‐tablet regimen in the expanding spectrum of fixed‐dose combination therapy for HIV

Single‐tablet regimens (STRs) of highly safe and effective combination antiretroviral therapy (cART) have had a significant beneficial impact on the clinical outcomes and lives of people living with HIV (PLHIV). As a consequence, healthcare professionals caring for PLHIV in high‐income countries have increasingly focused on issues beyond those related to HIV itself, i.e. HIV‐related neurological disease, or associated opportunistic infections, which include co‐infections, and primarily age‐ and lifestyle‐related comorbidities such as cardiovascular disease, diabetes mellitus, renal impairment, osteoporosis and frailty. This review considers drug side effects and comorbidities seen in PLHIV and evaluates the role of a recently licensed STR – bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) – in mitigating some of those challenges. Factors that need to be evaluated for initial cART regimens include: pretreatment CD4 cell count; plasma HIV RNA; HIV drug resistance; hepatitis B co‐infection; HLA‐B*5701 status; drug‐drug interactions; pregnancy and pregnancy potential; psychiatric and physical comorbidities such as renal or bone disease, as well as simplicity and adherence‐friendliness, all of which need to be considered in all lines of therapy. BIC/FTC/TAF constitutes a new STR that includes an unboosted integrase strand transfer inhibitor with a high barrier against resistance with TAF and FTC. Its virological efficacy was non‐inferior to dolutegravir‐based regimens previously recommended by most guidelines for treatment initiation in large double‐blind, randomised clinical trials in treatment‐naïve or switch patients over 96 weeks. Tolerability and pharmacological properties of the regimen make it a useful tool to address several of the clinical management issues raised above.
RPGR-Associated Dystrophies: Clinical, Genetic, and Histopathological Features

This study describes the clinical, genetic, and histopathological features in patients with RPGR-associated retinal dystrophies. Nine male patients from eight unrelated families underwent a comprehensive ophthalmic examination. Additionally, the histopathology of the right eye from a patient with an end-stage cone-rod-dystrophy (CRD)/sector retinitis pigmentosa (RP) phenotype was examined. All RPGR mutations causing a CRD phenotype were situated in exon ORF15. The mean best-corrected visual acuity (BCVA, decimals) was 0.58 (standard deviation (SD)): 0.34; range: 0.05–1.13); and the mean spherical refractive error was −4.1 D (SD: 2.11; range: −1.38 to −8.19). Hyperautofluorescent rings were observed in six patients. Full-field electroretinography responses were absent in all patients. The visual field defects ranged from peripheral constriction to central islands. The mean macular sensitivity on microperimetry was 11.6 dB (SD: 7.8; range: 1.6–24.4) and correlated significantly with BCVA (r = 0.907; p = 0.001). A histological examination of the donor eye showed disruption of retinal topology and stratification, with a more severe loss found in the peripheral regions. Reactive gliosis was seen in the inner layers of all regions. Our study demonstrates the highly variable phenotype found in RPGR-associated retinal dystrophies. Therapies should be applied at the earliest signs of photoreceptor degeneration, prior to the remodeling of the inner retina.
Investigation of the Occurrence of Nighttime Topside Ionospheric Irregularities in Low-Latitude and Equatorial Regions Using CYGNSS Satellites

By using multi-satellite observations of the L1 signal-to-noise ratio (SNR) from the Cyclone Global Navigation Satellite System (CYGNSS) taken in 2017, we present the occurrence of nighttime topside ionospheric irregularities in low-latitude and equatorial regions. The most significant finding of this study is the existence of longitudinal structures with a wavenumber 4 pattern in the topside irregularities. This suggests that lower atmospheric waves, especially a daytime diurnal eastward-propagating zonal wave number-3 nonmigrating tide (DE3), might play an important role in the generation of topside plasma bubbles during the low solar minimum. Observations of scintillation events indicate that the maximum occurrence of nighttime topside ionospheric irregularities occurs on the magnetic equator during the equinoxes. The current work, which could be regarded as an important update of the previous investigations, would be readily for the further global analysis of the topside ionospheric irregularities.
Promoting Evidence Based Nutrition Education Across the World in a Competitive Space: Delivering a Massive Open Online Course

The internet is the fastest growing source of nutrition information for consumers. Massive Open Online Courses (MOOCs) provide and avenue for nutrition professionals’ urgent need to respond to consumer demand for low-cost, accessible and engaging information. This research aimed to evaluate learner participation and perceptions in an evidence-based nutrition MOOC and provide recommendations for engaging international online lay audiences. Learners completed pre and post course surveys including quantitative and open-ended questions. Pre-course surveys collected demographic data, prior nutrition knowledge and motivations for doing the course. Post-course surveys evaluated their preferred learning modes and learners’ opinions of the course. Quantitative were analyzed using descriptive statistics. Conventional content analysis was conducted on learners’ responses to open-ended survey questions using an inductive approach. Learners represented 158 countries from a range of educational backgrounds. There were 3799 qualitative comments related to learners’ learning and course content preferences. Qualitative analysis identified key themes related to (1) online interaction, the (2) value of the evidence presented by nutrition experts and (3) the course structure and practical aspects. Divergent opinions were expressed within these themes. Satisfying the needs of large international audiences with diverse backgrounds is challenging in promoting sound evidence-based nutrition messages. MOOCs provide a means for delivering evidence based global nutrition education in the online space crowded with food advertising and nutrition conjecture. Recommendations are made as to how to construct and engage diverse on-line audiences.
Identification of the plasma total cfDNA level before and after chemotherapy as an indicator of the neoadjuvant chemotherapy response in locally advanced breast cancer

This study aimed to retrospectively evaluate the circulating free DNA (cfDNA) level in patients with locally advanced breast cancer (LABC) having different neoadjuvant chemotherapy (NCT) responses and to investigate whether dynamic changes in cfDNA level could predict the effectiveness of NCT in patients with LABC. Data on 61 patients with LABC were included. NCT responses were evaluated using the response evaluation criteria. Blood samples were collected for cfDNA detection before treatment and after the first and eighth courses of chemotherapy. The Alu 111‐bp and 260‐bp fragment levels were evaluated by polymerase chain reaction, and the predictive value of the cfDNA level in the NCT response was determined. In vitro, the MCF‐7 and MCF‐7/ADR cell lines were applied to simulate the phenomenon of drug resistance and explain the underlying mechanism. The Alu 111‐bp level increased after the first NCT course (P = .014) and then remained high after NCT in the high‐R group (P = .047), but it remained steady in the low‐R group during NCT. A similar tendency in the Alu 260‐bp level was revealed in different groups. The ∆∆Ct value of Alu 260‐bp had good diagnostic efficiency in assessing predictive ability. The area under the curve for the ∆∆Ct1 and ∆∆Ct2 of Alu 260‐bp was 0.697 and 0.647, respectively. The cfDNA level was closely related to epirubicin‐induced apoptosis and changes in the Ki‐67 index in vitro. The elevation of cfDNA after one chemotherapy cycle was mediated by the apoptosis of tumor cells and related to the improved chemotherapy response.
Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F‐18]FEPPA

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)–seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high‐dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C‐11](R)‐PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second‐generation TSPO radioligand, [F‐18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (VT) of [F‐18]FEPPA was estimated with a two‐tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM‐ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F‐18]FEPPA VT (P = .81). No significant correlations between [F‐18]FEPPA VT and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self‐reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F‐18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.
Pediatric Pulmonology

Department of Pediatrics, General Paediatrics Service, KK Women's and Children's Hospital, Singapore Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore Department of Nutrition and Dietetics, KK Women's and Children's Hospital, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Department of Pediatric Subspecialties, Children's Intensive Care Unit, KK Women's and Children's Hospital, Singapore Department of Pediatrics, Respiratory Medicine Service, KK Women's and Children's Hospital, Singapore Centre for Quantitative Medicine, Duke‐NUS Medical School, Singapore
Drug utilization review of tramadol hydrochloride in a regional hospital in South Africa; findings and implications

ABSTRACT Background Drug utilization reviews (DURs) can be used to promote rational prescribing and ensure compliance with standard treatment guidelines. In recent years, the use of tramadol hydrochloride (HCl) for pain has increased significantly across countries. We sought to determine prescribing patterns and the use of tramadol in a regional hospital in South Africa to provide future guidance in view of increasing concerns with the prescribing of tramadol. Method A prospective, quantitative and descriptive study was conducted over two months. Outpatient and inpatient prescriptions and ward requisitions where tramadol HCl was prescribed or ordered were identified, which included outpatients collecting antiretroviral treatment. Prescriptions were reviewed and evaluated to determine the level of compliance to the Standard Treatment Guidelines and Essential Medicines List (STGs/EML) for South Africa as a measure of rational prescribing. Quantities issued to the inpatient wards and expenditure incurred by the pharmacy departments were assessed to determine overall usage and total costs. Results In total, 415 tramadol HCl prescriptions were collected over a 2-month period. Compliance was 70.1% to the STGs/EML. The outpatient pharmacy department had the highest compliance at 76.4% while the antiretroviral pharmacy compliance was 29.1%. Most prescriptions dispensed at the outpatient pharmacy were from the Surgical Outpatient Department (140; 33.7%) and the Orthopedic Outpatient Department (108; 26.0%). The outpatient pharmacy had the highest tramadol HCl consumption and expenditure at $4,874.13 (R72,054.28), while the inpatient pharmacy’s expenditure was $2,526.63 (R37,351.20), and the antiretroviral pharmacy $590.13 (R8,722.75). The hospital’s tramadol HCl expenditure increased when compared to previous financial years, from $10,576.04 (R156,326.00) in 2014–2015 to $39,584.00 (R585,088.80) in 2016–2017. Conclusion This study highlights the need for the implementation of monitoring and evaluation tools to enhance rational prescribing and use of tramadol HCl. These are being implemented and will be evaluated in future projects.
Pharmacological and genetic characterisation of the canine P2X4 receptor

P2X4 receptors are emerging therapeutic targets for treating chronic pain and cardiovascular disease. Dogs are well‐recognised natural models of human disease, but information regarding P2X4 receptors in dogs is lacking. To aid the development and validation of P2X4 receptor ligands, we have characterised and compared canine and human P2X4 receptors.
Fantastic Four: Age, Spinal Cord Stimulator Waveform, Pain Localization and History of Spine Surgery Influence the Odds of Successful Spinal Cord Stimulator Trial.

BACKGROUND There is a dearth in our understanding of the factors that are predictive of successful spinal cord stimulator (SCS) trials and eventual conversion to permanent implants. Knowledge of these factors is important for appropriate patient selection and treatment optimization. OBJECTIVES Although previous studies have explored factors predictive of trial success, few have examined the role of waveform in trial outcomes. This study sought to establish the relationship of neuraxial waveform and related measures to trial outcomes. STUDY DESIGN This study used a retrospective chart review design. METHODS Data were retrospectively collected on 174 patients undergoing SCS trials upon institutional review board approval of the study protocol. Indications for SCS were: complex regional pain syndrome, failed back surgery syndrome with radicular symptoms, peripheral neuropathy, and axial low back pain. Descriptive statistics and logistic regression analyses were used to assess the association of demographic and clinical variables with SCS trial outcomes. RESULTS The study population comprised 56% women, had a median age of 55 (interquartile range [IQR], 44-64), and 32 of 174 (18%) patients failed SCS trials. Individuals with successful trials (>= 50% pain relief) were significantly younger and had a median age of 54 years (IQR, 42-60) compared to those who failed SCS trials (median age 66 years; IQR, 50-76; P = .005). Adjusting for age, gender, number of leads, pain category, and diagnoses: surgical history (odds ratio [OR] = 4.4; 95% confidence interval [CI], 1.3-15.8) and paresthesia-based tonic-stimulation (OR = 10.3; 95% CI, 1.7-62.0), but not burst or high frequency, were significantly associated with successful trials. Of note, the number of leads (whether dual or single), pain duration, characteristics, and category (nociceptive vs neuropathic) were not significant factors. An interaction between surgical spine history and lower extremity pain was significantly associated with a positive trial (P = .005). LIMITATIONS This study was limited by its retrospective nature and focus on a patient population at a single major academic medical center. CONCLUSIONS Paresthesia-based tonic stimulation, age, and surgical history have significant effects on SCS trials. Prospective and randomized controlled studies may provide deeper insights regarding impact on costs and overall outcomes.IRB Approval #: 2018P002216. KEY WORDS Pain duration, pain location, spinal cord stimulator trial, stimulator waveform, surgical history.
Clinicobiological features and prognostic impact of diffuse large B-cell lymphoma component in the outcome of patients with previously untreated follicular lymphoma.

BACKGROUND The co-existence at diagnosis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) components (FL/DLBCL) has been considered a transformed lymphoma and accordingly treated although clinicobiological information on these patients is scarce. The aim of this study was to analyze the initial features and outcome of FL/DLBCL patients in the rituximab era. PATIENTS AND METHODS All patients consecutively diagnosed at a single institution with FL/DLBCL (n = 40), as well as those with pure FL (n = 328) or de novo DLBCL (n = 510) as controls. RESULTS The proportion of the DLBCL component was highly variable (median 50%). In 29 FL/DLBCL cases analyzed, the cell of origin was GCB in 86%, ABC in 10% and unclassifiable in 4%. NOTCH1-2 was mutated in 10% of these cases. The proportion of DLBCL component did not impact on overall survival (OS). Regarding initial characteristics, patients with FL/DLBCL were closer to FL in terms of primary nodal origin, good performance status and advanced stage, whereas the other features were intermediate between FL and DLBCL. FL/DLBCL patients were treated as DLBCL with no further intensification. Complete response and primary refractory rates were 65% and 20%, respectively, with these figures being similar to DLBCL and worse than FL. Progression-free survival and OS were intermediate between FL and DLBCL (5-year OS: 85%, 73% and 63% for FL, FL/DLBCL and DLBCL, respectively). FL/DLBCL histology did not reach independent prognostic value for OS in the multivariate analyses. CONCLUSIONS The outcome of FL/DLBCL patients is not worse than that of de novo DLBCL. These cases should be treated with immunochemotherapy as DLBCL, but intensification with ASCT may not be necessary. The biological insights of FL/DLBCL warrants further genetic and molecular studies.