Utilizing Clinical and Non-clinical Patient Factors in Predicting Cardiovascular Events in Patients on JAK Inhibitor Therapy: A Retrospective Cohort Study.

BACKGROUND: Patients with autoimmune rheumatic diseases (ARDs) taking JAK inhibitors may have an increased risk of cardiovascular events, especially if they have other health conditions. Identifying high-risk patients can inform targeted preventive care. This study assessed the value of age and deprivation decile in predicting cardiovascular events in patients on JAK inhibitors for ARDs. OBJECTIVE: To assess the predictive value of age and deprivation decile in identifying patients at risk of cardiovascular events while on JAK inhibitor therapy for ARDs. METHODS: This cross-sectional cohort study enrolled 309 patients with ARDs (mean age 59.3 years, 77% female) treated with JAK inhibitors at a UK teaching hospital. Baseline characteristics, including age, gender, ethnicity, and comorbidities, were collected. Cardiovascular events (myocardial infarctions, strokes, and cardiovascular-related deaths) that occurred while on JAK inhibitor therapy were identified retrospectively. Deprivation indices were calculated using socioeconomic factors. RESULTS: Multivariate logistic regression analysis, adjusting for potential confounders, showed that a model combining age and deprivation decile was statistically significant (p = 0.031) in predicting cardiovascular events. Neither age nor deprivation decile alone was statistically significant. Older patients had an odds ratio of 1.06 (95% CI: 1.00-1.13) for increased risk of cardiovascular events. The logistic regression model as a whole was statistically significant (Chi2(14) = 24.04, p = 0.031, n = 309). The AUC of the ROC curve was 0.837. CONCLUSION: Age and deprivation decile can effectively predict cardiovascular events in patients on JAK inhibitor therapy for ARDs. Incorporating these predictive tools into routine clinical practice can help identify patients who warrant intensified cardiovascular risk management.

Safety and feasibility of intranasal heroin-assisted treatment: 4-week preliminary findings from a Swiss multicentre observational study.

BACKGROUND: Heroin-assisted treatment (HAT) is effective for individuals with severe opioid use disorder (OUD) who do not respond sufficiently to other opioid agonist treatments. It is mostly offered with injectable diacetylmorphine (DAM) or DAM tablets creating a barrier for individuals who need the rapid onset of action but are either unable or unwilling to inject, or primarily snort opioids. To explore another route of administration, we evaluated the safety and feasibility of intranasal (IN) DAM. METHODS: This is a multicentre observational cohort study among patients in Swiss HAT. All patients planning to receive IN DAM within the treatment centres were eligible to participate. Participants were either completely switched to IN DAM or received IN DAM in addition to other DAM formulations or opioid agonists. Patients were followed up for four weeks. Sociodemographic characteristics, current HAT regimen, reasons for starting IN DAM, IN DAM doses, number of injection events in the sample, IN DAM continuation rate, and appearance of adverse events and nose-related problems were evaluated. RESULTS: Participants (n = 52) reported vein damage, preference for nasal route of administration, and desire of a stronger effect or for a less harmful route of administration as primary reasons for switching to IN DAM. After four weeks, 90.4% of participants (n = 47) still received IN DAM. Weekly average realised injection events decreased by 44.4% from the month before IN DAM initiation to the month following. No severe adverse events were reported. CONCLUSIONS: After four weeks, IN DAM was a feasible and safe alternative to other routes of administration for patients with severe OUD in HAT. It addressed the needs of individuals with OUD and reduced injection behaviour. More long-term research efforts are needed to systematically assess efficacy of and patient satisfaction with IN DAM.

Risk of Malignancy in Breast FNAB Categories, Classified According to the Newly Proposed International Academy of Cytology (IAC) Yokohama System.

Background: A new category system comprising five classes (C1-insufficient material, C2-benign, C3-atypical, C4-suspicious, and C5-malignant) has been proposed by the International Academy of Cytology (IAC) for fine needle aspiration biopsy cytology (FNAB) for proper diagnosis of breast cancer. Aims and Objectives: This study is designed to categorize institutional FNAB data according to the new system and calculation of the absolute risk of malignancy (ROM), sensitivity, specificity, positive predictive values, false negative and false-positive rate. Study Design: We conducted a retrospective cross-sectional study involving 2133 cases collected between June, 2008 and August, 2019, at Foundation University Medical College's Department of Histopathology and the Surgery and Oncology Department at the Fauji Foundation Hospital. All cases fulfilling the inclusion and exclusion criteria were retrieved from the archives and reviewed by two expert pathologists. Matching histopathology was compared with the cytology reports for concordance or discordance of results. Findings: We found 6.9% (n = 147) insufficient, 65.8% (n = 1403) benign, 7.2% (n = 153) atypical, 7.5% (n = 160) suspicious and 12.6% (n = 270) malignant cases. Cyto-histological correlation was found in 421 cases from the year 2014 to 2019 with 370 concordant and 51 discordant cases. The maximum number of concordant cases was 151 in the C5 category and discordant cases had a diagnosis of C3 and C4 on cytology with 16 cases in each category. The calculated values of ROM were 45.45%, 10.3%, 30.6%, 82.79% and 99.34% from C1 to C5, respectively. We calculated 83.42% absolute sensitivity and 85.24% specificity. The positive predictive value for category 3, 4 and 5 was 67.34%, 82.7% and 99.34%, respectively, while false-negative rate was 7.9% and false-positive rate was 0.66%. Conclusion: The ROM for C1 category calculated from this study is quite high (45.45%) compared to previous studies; therefore, it is recommended to perform core needle biopsy in all these cases. The higher sensitivity and specificity of this method of diagnosing malignant lesions supports its use.

CCR5-, DC-SIGN-dependent endocytosis and delayed reverse transcription after human immunodeficiency virus type 1 infection in human astrocytes.

We sought to determine the pathway of HIV-1 entry into human astrocytes and the fate of HIV-1 by detecting viral DNA and GFP-tagged HIV-1 in HIV-1-infected primary astrocytes. Immunochemistry and FACS analysis were used to assess the expression of DC-SIGN in human purified cultures of astrocytes. HIV-1 LTR was detected by PCR in infected cultures of human embryonic astrocytes at their third passage. GFP-Vpr-labeled R5 tropic HIV-1 was used to infect astrocytes, and was followed by confocal microscopy. Forty percent of astrocytes expressed DC-SIGN at the membrane level. Viral DNA was detected 5 days after infection in human astrocytes, but not in the presence of anti-CCR5 and anti-DC-SIGN mAbs. T20, NH4Cl, and bafilomycin had no effect on viral DNA detection. We found that 67% of the fluorescent GFP-Vpr-labeled R5 tropic HIV-1 viruses were present in the endosomes of astrocytes at 24 h, but not in the presence of anti-CCR5 or DC-SIGN mAbs. Bafilomycin and NH(4)Cl each increased the amount of fluorescent HIV-1 detected outside endosomes. Titers of p24 remained low from day 1 to day 5 postinfection, in the presence or absence of NH4Cl. Astrocytes express DC-SIGN and HIV-1 penetrates into these cells through CCR5- and/or DCSIGN- mediated endocytosis, via a pH-dependent pathway, with a delayed reverse transcription after infection without productive infection.

Effects of SDF-1alpha and gp120IIIB on apoptotic pathways in SK-N-SH neuroblastoma cells.

CXCR4, a chemokine receptor constitutively expressed in the brain, binds both ligands, the chemokine SDF-1alpha and the HIV envelope glycoprotein gp120(IIIB). There seem to be intracellular differences between the neuronal apoptosis induced by SDF-1alpha and that induced by gp120(IIIB), but the apoptotic pathways involved have not been compared in human neuronal cells. In this study, we characterized the apoptotic intracellular pathways activated by neurotoxic concentrations of SDF-1alpha and gp120(IIIB) in human neuroblastoma cells SK-N-SH. SDF-1alpha (10 nM) and gp120(IIIB) (2 nM) induced similar levels of apoptosis after 24 h of incubation (49 +/- 4% and 48 +/- 3%, respectively, of the neurons were apoptotic). SDF1alpha-induced apoptosis was completely abolished by the inhibition of Src phosphorylation by PP2. Exposure to SDF-1alpha (10 nM) triggered an increase in Src phosphorylation, with a maximum after 20 min of incubation (1.80 +/- 0.24 times higher than control, P = 0.01). NMDA calcium flux was enhanced only if cells were incubated with SDF-1alpha for 20 min before applying NMDA. By contrast, gp120(IIIB)-induced apoptosis was not affected by the inhibition of Src phosphorylation. Moreover, gp120(IIIB) enhanced NMDA calcium flux immediately, without modifying Src phosphorylation status. Finally, levels of phospho-JNK increased following exposure to gp120(IIIB) (by a factor of 1.46 +/- 0.4 at 120 min, P = 0.03), but not after exposure to SDF-1alpha. Thus, SDF-1alpha and gp120(IIIB) induced a similar level of neuronal apoptosis, but by activating different intracellular pathways. SDF-1alpha enhanced NMDA activity indirectly via Src phosphorylation, whereas gp120(IIIB) probably activated the NMDA receptor directly and phosphorylated JNK.

Fractalkine reduces N-methyl-d-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation.

Our purpose was to investigate in human neurons the neuroprotective pathways induced by Fractalkine (FKN) against glutamate receptor-induced excitotoxicity. CX(3)CR1 and FKN are expressed constitutively in the tested human embryonic primary neurons and SK-N-SH, a human neuroblastoma cell line. Microfluorometry assay demonstrated that CX(3)CR1 was functional in 44% of primary neurons and in 70% of SK-N-SH. Fractalkine induced ERK1/2 phosphorylation within 1 min and Akt phosphorylation after 10 min, and both phosphorylation decreased after 20 min. No p38 and SAPK/JNK activation was observed after FKN treatment. Application of FKN triggered a 53% reduction of the NMDA-induced neuronal calcium influx, which was insensitive to pertussis toxin and LY294002 an inhibitor of Akt pathway, but abolished by PD98059, an ERK1/2 pathway inhibitor. Moreover, FKN significantly reduced neuronal NMDA-induced apoptosis, which was pertussis toxin insensitive and abolished in presence of PD98059 and LY294002. In conclusion, FKN protected human neurons from NMDA-mediated excitotoxicity in at least two ways with different kinetics: (i) an early ERK1/2 activation which reduced NMDA-mediated calcium flux; and (ii), a late Akt activation associated with the previously induced ERK1/2 activation.