The impact of chronic fluoxetine treatment in adolescence or adulthood on context fear memory and perineuronal nets.

Selective serotonin reuptake inhibitors, such as fluoxetine (Prozac), are commonly prescribed pharmacotherapies for anxiety. Fluoxetine may be a useful adjunct because it can reduce the expression of learned fear in adult rodents. This effect is associated with altered expression of perineuronal nets (PNNs) in the amygdala and hippocampus, two brain regions that regulate fear. However, it is unknown whether fluoxetine has similar effects in adolescents. Here, we investigated the effect of fluoxetine exposure during adolescence or adulthood on context fear memory and PNNs in the basolateral amygdala (BLA), the CA1 subregion of the hippocampus, and the medial prefrontal cortex in rats. Fluoxetine impaired context fear memory in adults but not in adolescents. Further, fluoxetine increased the number of parvalbumin (PV)-expressing neurons surrounded by a PNN in the BLA and CA1, but not in the medial prefrontal cortex, at both ages. Contrary to previous reports, fluoxetine did not shift the percentage of PNNs toward non-PV cells in either the BLA or CA1 in the adults, or adolescents. These findings demonstrate that fluoxetine differentially affects fear memory in adolescent and adult rats but does not appear to have age-specific effects on PNNs.

COVID-19 Pandemic Simulation Modelling in Anaesthesia Residency Training to Predict Delays and Workforce Deficiencies: A Case Study of the Singapore Residency Training Program.

Background COVID-19 has been the worst pandemic of this century, resulting in economic, social, and educational disruptions. Residency training is no exception, with training restrictions delaying the progression and graduation of residents. We sought to utilize simulation modelling to predict the impact on future cohorts in the event of repeated and prolonged movement restrictions due to COVID-19 and future pandemics of a similar nature. Method A Delphi study was conducted to determine key Accreditation Council for Graduate Medical Education-International (ACGME-I) training variables affected by COVID-19. Quantitative resident datasets on these variables were collated and analysed from 2018 to 2021. Using the Vensim® software (Ventana Systems, Inc., Harvard, MA), historical resident data and pandemic progression delays were used to create a novel simulation model to predict future progression delay. Various durations of delay were also programmed into the software to simulate restrictions of varying severity that would impact resident progression. Results Using the model with scenarios simulating varying pandemic length, we found that the estimated average delay for residents in each accredited year ranged from an increase of one month for year 2 residents to more than three months for year 4 residents. Movement restrictions lasting a year would require up to six years before the program returned to a pre-pandemic equilibrium. Conclusion Systems dynamic modelling can be used to predict delays in residency training programs during a pandemic. The impact on the workforce can thus be projected, allowing residency programs to institute mitigating measures to avoid progression delay.

What drives low-income older adults' intention to use mobility applications?

AIM: Mobility applications have the potential to support low-income older adults in facing mobility challenges. However, there is a generally lower uptake of technology in this segment. To understand factors affecting the intention to use a mobility app, we drew upon the Protection Motivation Theory, and tested a model of low-income older adults' technology adoption. METHODS: A cross-sectional survey was conducted across seven states in Malaysia among community-dwelling low-income older adults aged ≥60 years old (n = 282). Measurement items were adapted from pre-validated scales and 7-point Likert Scales were used. Partial least squares structural equation modeling was utilized to assess the hypothesized model. RESULTS: Mobility technology awareness was found to shape an individual's threat and coping appraisals associated with their intention to use a mobility app. The decision of a low-income older adult to adopt a mobility app as a protective action is not a direct function of threat and coping appraisals but is indirect, and mediated by the underlying cost-benefit perceptions of non-adoption and adoption of the mobility app. In terms of technology perceptions, perceived usefulness is a significant predictor, but not perceived ease of use. CONCLUSIONS: This study entails a new model by uncovering the psychological factors encompassing mobility technology awareness, threat-coping appraisals, and cost-benefit perceptions on Technology Acceptance Model studies. These insights have important implications for the development and implementation of a mobility app among low-income older adults. Geriatr Gerontol Int 2024; 24: 342-350.

Factors influencing technology use among low-income older adults: A systematic review.

As the world's aging population increases, leveraging technology to support aging is proving advantageous. Notably, technology adoption studies among older adults have received increasing scholarly attention, but findings from these studies do not reflect the context of low-income older adults. Studies focusing on low-income older adults were relatively few and it remains unclear which factors influence this group's technology use. This systematic review aims to synthesize findings on factors influencing technology use among low-income older adults to provide directions and opportunities for future research in information systems. Observing the literature through the lens of Social Cognitive Theory, we identified avenues for future research and further integrated the framework with Maslow's hierarchy of needs to elucidate the phenomenon. Findings from this systematic review suggest that both personal and environmental factors, such as cognitions, affects, sociodemographic characteristics, technological and social environment are significant predictors of technology use among low-income older adults. Specifically, factors related to accessibility and affordability, such as income, perceived cost, and accessibility to technology are salient in a resource-limited setting. More importantly, the technology usage behavior elucidate the embeddedness of fundamental human needs which plays a central role underlying technology use among this segment. However, more research is needed to understand the interaction between person, environment and behavior determinant shaping technology use among low-income older adults from diverse economic and cultural setting. This study also sheds light on disciplinary gaps and the lack of investigations anchored on theoretical foundations, and suggests avenues for future research and implications for practice.

Neurostimulation for Chronic Pain: A Systematic Review of High-Quality Randomized Controlled Trials With Long-Term Follow-Up.

OBJECTIVE: This study aimed to review the best evidence on the long-term efficacy of neurostimulation for chronic pain. MATERIALS AND METHODS: We systematically reviewed PubMed, CENTRAL, and WikiStim for studies published between the inception of the data bases and July 21, 2022. Randomized controlled trials (RCTs) with a minimum of one-year follow-up that were of high methodologic quality as ascertained using the Delphi list criteria were included in the evidence synthesis. The primary outcome was long-term reduction in pain intensity, and the secondary outcomes were all other reported outcomes. Level of recommendation was graded from I to III, with level I being the highest level of recommendation. RESULTS: Of the 7119 records screened, 24 RCTs were included in the evidence synthesis. Therapies with recommendations for their usage include pulsed radiofrequency (PRF) for postherpetic neuralgia, transcutaneous electrical nerve stimulation for trigeminal neuralgia, motor cortex stimulation for neuropathic pain and poststroke pain, deep brain stimulation for cluster headache, sphenopalatine ganglion stimulation for cluster headache, occipital nerve stimulation for migraine, peripheral nerve field stimulation for back pain, and spinal cord stimulation (SCS) for back and leg pain, nonsurgical back pain, persistent spinal pain syndrome, and painful diabetic neuropathy. Closed-loop SCS is recommended over open-loop SCS for back and leg pain. SCS is recommended over PRF for postherpetic neuralgia. Dorsal root ganglion stimulation is recommended over SCS for complex regional pain syndrome. CONCLUSIONS: Neurostimulation is generally effective in the long term as an adjunctive treatment for chronic pain. Future studies should evaluate whether the multidisciplinary management of the physical perception of pain, affect, and social stressors is superior to their management alone.

Pericapsular nerve group (PENG) block for early pain management of elderly patients with hip fracture: a single-center double-blind randomized controlled trial.

BACKGROUND: The pericapsular nerve group block (PENG) is a novel technique that blocks the articular branches of the hip joint. This study aimed to compare its effectiveness to a sham block in elderly patients with hip fractures. METHOD: A randomized double-blind controlled trial was conducted in elderly patients with intertrochanteric and neck of femur fractures. Patients were randomized to receive either PENG block or a sham block. Postblock, systemic analgesia was titrated using a standardized protocol of acetaminophen, oral morphine or patient-controlled analgesia. The primary outcome was the dynamic pain score (Numerical Rating Scale 0-10) at 30 min postblock. Secondary outcomes included pain scores at multiple other time points and 24-hour opioid consumption. RESULTS: 60 patients were randomized and 57 completed the trial (PENG n=28, control n=29). Patients in PENG group had significantly lower dynamic pain scores at 30 min compared with control group (median (IQR) 3 (0.5-5) vs 5 (3-10), p<0.01). For the secondary outcomes, dynamic pain scores were lower in PENG group at 1 hour (median (IQR) 2 (1-3.25) vs 5 (3-8), p<0.01) and 3 hours postblock (median (IQR) 2 (0-5) vs 5 (2-8), p<0.05). Patients in PENG group had lower 24-hour opioid consumption (median (IQR) oral morphine equivalent dose 10 (0-15) vs 15 (10-30) mg, p<0.05). CONCLUSION: PENG block provided effective analgesia for acute traumatic pain following hip fracture. Further studies are required to validate the superiority of PENG blocks over other regional techniques. TRIAL REGISTRATION NUMBER: NCT04996979.

Incidence of neonatal sepsis after universal antenatal culture-based screening of group B streptococcus and intrapartum antibiotics: A multicentre retrospective cohort study.

OBJECTIVE: To compare the incidences of early and late-onset neonatal sepsis, including group B streptococcus (GBS) and Escherichia coli (E. coli) before and after implementation of universal screening and intrapartum antibiotics prophylaxis (IAP). DESIGN: Retrospective cohort study. SETTING: Eight public hospitals and 31 Maternal and Child Health Centres (in Hong Kong. POPULATION: 460 552 women attending routine antenatal service from 2009 to 2020. METHODS: Universal culture-based GBS screening has been offered to eligible women since 2012. Total births, GBS screening tests, maternal GBS colonisation and neonatal sepsis with positive blood or cerebrospinal fluid were retrieved from clinical and laboratory database. MAIN OUTCOME MEASURES: Maternal GBS colonisation rate, early- and late-onset neonatal sepsis (including GBS and E. coli). RESULTS: Of 318 740 women with universal culture-based screening, 63 767 women (20.0%) screened positive. After implementation of GBS screening and IAP, the incidence of early-onset neonatal sepsis decreased (3.25 versus 2.26 per 1000 live births, p < 0.05), including those caused by GBS (1.03 versus 0.26 per 1000 live births, p < 0.05). Segmented regression showed that change in early-onse GBS sepsis incidence after screening was the only significant variable in the outcome trend. There was no significant evidence of increase in incidence of late-onset neonatal sepsis including those caused by GBS. CONCLUSIONS: Universal culture-based GBS screening and IAP were associated with reduction in early-onset neonatal sepsis including GBS disease. Although an increase in incidence of late-onset neonatal sepsis including those caused by GBS cannot be totally ruled out, we did not identify significant evidence that this occurred.

Effects of regional anaesthesia on mortality in patients undergoing lower extremity amputation: A retrospective pooled analysis.

Background and Aims: Lower extremity amputation (LEA) is a commonly performed surgery and is associated with significant mortality and morbidity. This review compares the impact of anaesthetic technique on 30-day mortality and other perioperative outcomes in patients undergoing LEA. Methods: A systematic search of databases including PubMed, Embase, Scopus and Cochrane Central Register of Controlled Trials, from January 2010 to March 2021, was performed. Studies were eligible if they compared 30-day mortality following either general anaesthesia (GA) or regional anaesthesia (RA), in adult patients undergoing LEA. Results: Ten retrospective observational studies were identified. Four of these studies utilised a propensity-score matching technique. Based on these four studies, RA when compared to GA, is not associated with a reduction in the 30-day mortality (Odds ratio 0.83, 95% confidence interval (CI): 0.65, 1.05, I2 20%, P = 0.12). Also there is a very low level of evidence that RA may result in a decrease in the hospital length-of-stay and intensive care unit admissions of patients undergoing LEA. Conclusion: RA does not decrease the 30-day postoperative mortality in patients undergoing LEA when compared to GA.

Impact of pain sensitisation on the quality of life of patients with knee osteoarthritis.

OBJECTIVES: We aim to evaluate the effect on different ways of classifying pain sensitisation on impact and quality of life (QoL) in knee osteoarthritis (KOA). METHODS: We used baseline data from a cohort of consecutive patients with KOA listed for arthroplasty. We collected demographics and number of painful body sites. We measured pressure pain thresholds at the right forearm (PPTarm). Pain sensitisation was classified using: (1) widespread pain, (2) lowest 10th percentile of PPTarm and (3) PainDETECT questionnaire ≥13/38. Impact and QoL were assessed using Western Ontario and McMaster Universities Osteoarthritis Index and Short Form-36. Impact and QoL scores in patients with or without pain sensitisation were compared. We evaluated the association of pain sensitisation measures with QoL scores using multivariable regression. RESULTS: 233 patients (80% female, mean age 66 years) included in the analysis; 7.3%, 11.6% and 4.7% were classified as having pain sensitisation by widespread pain, low PPTarm and PainDETECT criteria, respectively. There was minimal overlap of patients as classified as pain sensitisation phenotype by different measures. Patients with pain sensitisation had poorer QoL compared with those without. Low PPTarm identified patients with poorer general health, while widespread pain and PainDETECT identified poorer QoL in more psychological domains. There was weak correlation between number of painful body sites and PainDETECT (rho=0.23, p<0.01), but no significant correlation with PPTarm. CONCLUSION: Patients with KOA with pain sensitisation have poorer QoL compared with those without, regardless of classification method. Different criteria defined patients with different pattern of QoL impact.

Use of oral progestogen in women with threatened miscarriage in the first trimester: a randomized double-blind controlled trial.

STUDY QUESTION: Will use of oral progestogen in women with threatened miscarriage in the first trimester reduce the miscarriage rate when compared with placebo? SUMMARY ANSWER: Use of oral progestogen in women with threatened miscarriage in the first trimester did not reduce miscarriage before 20 weeks when compared with placebo. WHAT IS KNOWN ALREADY: Miscarriage is a common complication of pregnancy and occurs in 15-20% of clinically recognized pregnancies. Use of vaginal progestogens is not effective in reducing miscarriage but there is still no good evidence to support use of oral progestogen for the treatment of threatened miscarriage. STUDY DESIGN, SIZE, DURATION: This was a randomized double-blind controlled trial. A total of 406 women presenting with threatened miscarriage in the first trimester were recruited from 30 March 2016 to May 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women attending Early Pregnancy Assessment Clinics because of vaginal bleeding during the first trimester were recruited and randomly assigned to use dydrogesterone 40 mg orally, followed by 10 mg orally three times a day or placebo until 12 completed weeks of gestation or 1 week after the bleeding stopped, whichever was later. The primary outcome was the miscarriage rate before 20 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: The two groups of women had comparable age, BMI, number of previous miscarriages, gestation and ultrasound findings at presentation. The miscarriage rate before 20 weeks of gestation was similar in both groups, being 12.8% (26/203) in the progestogen group and 14.3% (29/203) in the placebo group (relative risk 0.897, 95% CI 0.548-1.467; P = 0.772). The live birth rate was 81.3% in the progestogen group versus 83.3% in the placebo group (P = 0.697). No significant differences were found between the two groups in terms of obstetric outcomes and side effects. LIMITATIONS, REASONS FOR CAUTION: The primary outcome was the miscarriage rate, rather than the live birth rate. Women were recruited from Early Pregnancy Assessment Clinics and those with heavy vaginal bleeding might be admitted into wards directly instead of attending Early Pregnancy Assessment Clinic. The severity of vaginal bleeding was subjectively graded by women themselves. The sample size was not adequate to demonstrate a smaller difference in the miscarriage rate between the progestogen and placebo groups. We did not exclude women with multiple pregnancy, which increased the risk of miscarriage although there was only one set of twin pregnancy in the placebo group. WIDER IMPLICATIONS OF THE FINDINGS: Use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov with an identifier NCT02128685. TRIAL REGISTRATION DATE: 1 May 2014. DATE OF FIRST PATIENT'S ENROLMENT: 30 March 2016.

Clinical Challenges and Considerations in Management of Chronic Pain Patients During a COVID-19 Pandemic.

Since the coronavirus disease 2019 (COVID-19) was deemed a pandemic on 11 March 2020, we have seen exponential increases in the number of cases and deaths worldwide. The rapidly evolving COVID-19 situation requires revisions to clinical practice to defer non-essential clinical services to allocate scarce medical resources to the care of the COVID-19 patient and reduce risk to healthcare workers. Chronic pain patients require long-term multidisciplinary management even during a pandemic. Fear of abandonment, anxiety and depression may increase during this period of social isolation and aggravate pain conditions. Whilst physical consults for chronic pain patients were reduced, considerations including continuity of support and analgesia, telemedicine, allied health support and prioritising necessary pain services and interventions, were also taken to ensure biopsychosocial care for them. Chronic pain patients are mostly elderly with multiple comorbidities, and are more susceptible to morbidity and mortality from COVID-19. It is imperative to review pain management practices during the COVID-19 era with respect to infection control measures, re-allocation of healthcare resources, community collaborations, and analgesic use and pain interventions. The chronic pain patient faces a potential risk of functional and emotional decline during a pandemic, increasing healthcare burden in the long term. Clinical decisions on pain management strategies should be based on balancing the risks and benefits to the individual patient. In this commentary, we aim to discuss the basis behind some of the decisions and safeguards that were made at our tertiary pain centre over the last 6 months during the COVID-19 outbreak.

Collaboration between a tertiary pain centre and community teams during the pandemic.

People with chronic pain faced potential treatment disruption during the COVID-19 pandemic in Singapore, as the focus of healthcare shifted. A model of rapid integration of a pain centre with community healthcare teams was implemented to care for vulnerable older patients with chronic pain and multiple comorbidities. Telemedicine and home visits by community nurses were used, with risk-mitigation measures, ensuring comprehensive assessment and treatment compliance. Medications from pain physicians were delivered at home through a hospital pharmacy. A secure national electronic health records system used by all teams ensured seamless access and documentation. Potential emergency department visits, admissions and delayed discharges were thus avoided. Integration of community teams with chronic pain management services can be recommended to ensure pandemic preparedness.

Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism.

Differences between female and male immunity may contribute to variations in response to infections and predisposition to autoimmunity. We previously reported that neutrophils from reproductive-age males are more immature and less activated than their female counterparts. To further characterize the mechanisms that drive differential neutrophil phenotypes, we performed RNA sequencing on circulating neutrophils from healthy adult females and males. Female neutrophils displayed significant up-regulation of type I IFN (IFN)-stimulated genes (ISGs). Single-cell RNA-sequencing analysis indicated that these differences are neutrophil specific, driven by a distinct neutrophil subset and related to maturation status. Neutrophil hyperresponsiveness to type I IFNs promoted enhanced responses to Toll-like receptor agonists. Neutrophils from young adult males had significantly increased mitochondrial metabolism compared to those from females and this was modulated by estradiol. Assessment of ISGs and neutrophil maturation genes in Klinefelter syndrome (47, XXY) males and in prepubescent children supported that differences in neutrophil phenotype between adult male and female neutrophils are hormonally driven and not explained by X chromosome gene dosage. Our results indicate that there are distinct sex differences in neutrophil biology related to responses to type I IFNs, immunometabolism, and maturation status that may have prominent functional and pathogenic implications.

Pandemic Uropathogenic Fluoroquinolone-resistant Escherichia coli Have Enhanced Ability to Persist in the Gut and Cause Bacteriuria in Healthy Women.

We report that fluoroquinolone-resistant Escherichia coli are found in feces of 8.8% of healthy women, with most bacteria belonging to pandemic multidrug-resistant ST131-H30R or ST1193 clonal groups. Moreover, these highly uropathogenic clonal groups demonstrate an especially prolonged gut persistence and high rate of bacteriuria without documented urinary tract infection.

Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus.

Neutrophil dysregulation is implicated in the pathogenesis of systemic lupus erythematosus (SLE). SLE is characterized by elevated levels of a pathogenic neutrophil subset known as low-density granulocytes (LDGs). The origin and phenotypic, functional, and pathogenic heterogeneity of LDGs remain to be systematically determined. Transcriptomics and epigenetic assessment of lupus LDGs, autologous normal-density neutrophils, and healthy control neutrophils was performed by bulk and single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. Functional readouts were compared among neutrophil subsets. SLE LDGs display significant transcriptional and epigenetic heterogeneity and comprise 2 subpopulations of intermediate-mature and immature neutrophils, with different degrees of chromatin accessibility and differences in transcription factor motif analysis. Differences in neutrophil extracellular trap (NET) formation, oxidized mitochondrial DNA release, chemotaxis, phagocytosis, degranulation, ability to harm the endothelium, and responses to type I interferon (IFN) stimulation are evident among LDG subsets. Compared with other immune cell subsets, LDGs display the highest expression of IFN-inducible genes. Distinct LDG subsets correlate with specific clinical features of lupus and with the presence and severity of coronary artery disease. Phenotypic, functional, and pathogenic neutrophil heterogeneity are prevalent in SLE and may promote immune dysregulation and prominent vascular damage characteristic of this disease.

Safety and Tolerability of Omalizumab: A Randomized Clinical Trial of Humanized Anti-IgE Monoclonal Antibody in Systemic Lupus Erythematosus.

OBJECTIVE: Autoreactive IgE antibodies have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesize that omalizumab, a monoclonal antibody binding IgE, may improve SLE activity by reducing type I interferon (IFN) production by hampering plasmacytoid dendritic cells and basophil activation. This study was undertaken to assess the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. METHODS: Sixteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 and elevated autoreactive IgE antibody levels were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16 weeks of open-label treatment and a 4-week washout period. The SLEDAI-2K score, British Isles Lupus Assessment Group index (BILAG 2004) score, and physician's global assessment of disease activity were recorded at each visit. The type I IFN-induced gene signature was determined using quantitative polymerase chain reaction. RESULTS: Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to those experienced with placebo treatment. SLEDAI-2K scores improved in the omalizumab group compared to the placebo group at week 16 (P = 0.038), as well as during the open-label phase in subjects initially receiving placebo (P = 0.02). No worsening in BILAG scores or the physician's global assessment was detected. There was a trend toward a reduction in IFN gene signature in subjects treated with omalizumab (P = 0.11), especially in subjects with a high baseline IFN signature (P = 0.052). CONCLUSION: Our findings indicate that omalizumab is well tolerated in SLE and is associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess the efficacy of omalizumab in patients with SLE.

A precision medicine approach to pharmacological adjuncts to extinction: a call to broaden research.

There is a pressing need to improve treatments for anxiety. Although exposure-based therapy is currently the gold-standard treatment, many people either do not respond to this therapy or experience a relapse of symptoms after treatment has ceased. In recent years, there have been many novel pharmacological agents identified in preclinical research that have potential as adjuncts for exposure therapy, yet very few of these are regularly integrated into clinical practice. Unfortunately, the robust effects observed in the laboratory animal often do not translate to a clinical population. In this review, we discuss how age, sex, genetics, stress, medications, diet, alcohol, and the microbiome can vary across a clinical population and yet are rarely considered in drug development. While not an exhaustive list, we have focused on these factors because they have been shown to influence an individual's vulnerability to anxiety and alter the neurotransmitter systems often targeted by pharmacological adjuncts to therapy. We argue that for potential adjuncts to be successfully translated from the lab to the clinic empirical research must be broadened to consider how individual difference factors will influence drug efficacy.