Identifying and reducing risks of neurological complications associated with vaccination.

Vaccines protect against many infectious diseases, including some that can directly or indirectly cause nervous system damage. Serious neurological consequences of immunization are typically extremely rare, although they have the potential to jeopardize vaccination programmes, as demonstrated most recently during the COVID-19 pandemic. Neurologists have an important role in identifying safety signals at population and individual patient levels, as well as providing advice on the benefit-risk profile of vaccination in cohorts of patients with diverse neurological conditions. This article reviews the links between vaccination and neurological disease and considers how emerging signals can be evaluated and their mechanistic basis identified. We review examples of neurotropic infections with live attenuated vaccines, as well as neuroimmunological and neurovascular sequelae of other types of vaccines. We emphasize that such risks are typically dwarfed by neurological complications associated with natural infection and discuss how the risks can be further mitigated. The COVID-19 pandemic has highlighted the need to rapidly identify and minimize neurological risks of vaccination, and we review the structures that need to be developed to protect public health against these risks in the future.

Review of the Patient Burden and Therapeutic Landscape of Irritable Bowel Syndrome with Constipation in the United States.

Irritable bowel syndrome (IBS) is a common disorder of the gut-brain axis. IBS with constipation (IBS-C) accounts for approximately one-third of IBS cases and is associated with substantial burden of illness and decreased quality of life. This narrative review provides an overview of the current and upcoming treatment options and disease management for IBS-C from a US perspective and discusses the importance of the relationship between patient and health care provider in diagnosis and treatment. A positive diagnostic strategy for IBS-C is recommended, based on clinical history, physical examination, and minimal laboratory tests. An effective communication strategy between patients and health care professionals is essential to ensure early diagnosis and reduce both health care costs and overall disease burden. Treatment typically begins with lifestyle interventions and nonpharmacologic options, such as dietary interventions, fiber supplements, and osmotic laxatives. In patients with inadequate response to these therapies, 4 currently available therapies (lubiprostone, linaclotide, plecanatide, and tenapanor) approved by the US Food and Drug Administration may relieve IBS-C symptoms. These agents are generally well tolerated and efficacious in improving IBS-C symptoms, including constipation and abdominal pain. In patients with persistent abdominal pain and/or psychological symptoms, brain-gut behavioral therapy or neuromodulator therapy may be beneficial.

Collagen VI: Role in synaptic transmission and seizure-related excitability.

Collagen VI (Col-VI) is an extracellular matrix protein primarily known for its bridging role in connective tissues that has been suggested to play a neuroprotective role. In the present study we report increased mRNA and protein expression of Col-VI in the hippocampus and cortex at a late stage of epileptogenesis in a post-status epilepticus (SE) model of epilepsy and in brain tissue from patients with epilepsy. We further present a novel finding that exposure of mouse hippocampal slices to Col-VI augments paired-pulse facilitation in Schaffer collateral-CA1 excitatory synapses indicating decreased release probability of glutamate. In line with this finding, lack of Col-VI expression in the knock-out mice show paired-pulse depression in these synapses, suggesting increased release probability of glutamate. In addition, we observed dynamic changes in Col-VI blood plasma levels in rats after Kainate-induced SE, and increased levels of Col-VI mRNA and protein in autopsy or postmortem brain of humans suffering from epilepsy. Thus, our data indicate that elevated levels of ColVI following seizures leads to attenuated glutamatergic transmission, ultimately resulting in less overall network excitability. Presumably, increased Col-VI may act as part of endogenous compensatory mechanism against enhanced excitability during epileptogenic processes in the hippocampus, and could be further investigated as a potential functional biomarker of epileptogenesis, and/or a novel target for therapeutic intervention.

Applications of Flow Cytometry in Diagnosis and Evaluation of Red Blood Cell Disorders.

Clinical flow cytometry plays a vital role in the diagnosis and monitoring of various red blood cell disorders. The high throughput, precision, and automation potential of this technique allows for cost-effective and timely analysis compared to older and more manual test methods. Flow cytometric analysis serves as the gold standard diagnostic method for multiple hematological disorders, especially in clinical scenarios where an assay needs to have high sensitivity, high specificity, and a short turnaround time. In this review, we discuss the role of flow cytometric analysis in paroxysmal nocturnal hemoglobinuria, fetal-maternal hemorrhage, and hereditary spherocytosis.

CHARACTERIZATION OF VAULT WITH TWO MODELS OF POSTERIOR CHAMBER PHAKIC INTRAOCULAR LENSES.

PURPOSE: To evaluate and compare the dynamic vault range (DVR) as well as the asymmetry of the vault during a 3-month follow-up after the implantation of two posterior chamber phakic intraocular lenses (pIOLs). SETTING: Aver Clinic, Madrid, Spain. DESIGN: Prospective comparative study. METHODS: One hundred and nineteen eyes (65 patients) that underwent refractive surgical correction with implantation of one of two distinct pIOLs were enrolled: Eyecryl Phakic from Biotech Vision Care (Eyecryl group, 72 eyes) and Evo Visian Implantable Contact Lens from Staar Surgical (ICL group, 47 eyes). Besides evaluation of visual acuity, refraction, and ocular integrity, the pIOL vault was measured centrally and at 2 mm nasally and temporally as well as the DVR from photopic (50 lux) to mesopic (10 lux) illuminations conditions. RESULTS: No significant differences were found between pIOL groups in visual and refractive outcomes (p≥0.454). No significant differences between groups were found in central (523.72±168.4 vs. 494.16±156.7 µm, p=0.248) and temporal vault (499.43±155.8 vs. 431.28±150.5 µm, p=0.067). However, nasal vault was significantly lower in ICL group (465.6±149.1 vs. 375.4±144.0 µm, p=0.045). A trend to a larger DVR was observed in the ICL group, although differences between groups did not reach statistical significance (54.00±36.39 vs. 86.5±57.9 µm p=0.070). The pIOL diameter only correlated significantly with vault measurements in ICL group (r≥0.650, p<0.001). CONCLUSIONS: The Eyecryl pIOL shows more symmetric vaults and a trend to fewer light-induced changes in the central vault compared to the ICL pIOL. The clinical relevance of this finding should be investigated further.

Transcriptional regulation of the postnatal cardiac conduction system heterogeneity.

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity.

Programmable acoustic modular microrobots.

The field of microrobotics has emerged as a promising area of research with significant applications in biomedicine, both in vitro and in vivo, such as targeted cargo delivery, microsurgery, and cellular manipulation. Microrobots actuated with multiple modalities have the potential for greater adaptability, robustness, and capability to perform various tasks. Modular units that can reconfigure into various shapes, create structures that may be difficult to fabricate as one whole unit, and be assembled on-site, could provide more versatility by assembly and disassembly of units on demand. Such multi-modal modular microrobots have the potential to address challenging applications. Here, we present a biocompatible cylindrical microrobot with a dome-shaped cavity. The microrobot is actuated by both magnetic and acoustic fields and forms modular microstructures of various shapes. We demonstrate the use of these microrobots for cellular manipulation by creating patterns on a surface. Supplementary Information: The online version contains supplementary material available at 10.1007/s12213-024-00175-y.

Magnetometry in a diamond anvil cell using nitrogen vacancy centers in a nanodiamond ensemble.

The emerging field of optical magnetometry utilizing negative-charged nitrogen vacancy (NV-) centers provides a highly sensitive lab bench technique for spatially resolved physical property measurements. Their implementation in high pressure diamond anvil cell (DAC) environments will become common as other techniques are often limited due to the spatial constraints of the sample chamber. Apparatus and techniques are described here permitting for more general use of magnetic field measurements inside a DAC using continuous wave optical detected magnetic resonance in NV- centers in a layer of nanodiamonds. A microstrip antenna delivers a uniform microwave field to the DAC and is compatible with simple metal gaskets, and the sensor layer of deposited nanodiamonds allows for simple determination of the magnetic field magnitude for B in the 1-100 G range. The ferromagnetic transition in iron at 18 GPa is measured with the apparatus, along with its hysteretic response.

'It's a job to be done'. Managing polypharmacy at home: A qualitative interview study exploring the experiences of older people living with frailty.

INTRODUCTION: Many older people live with both multiple long-term conditions and frailty; thus, they manage complex medicines regimens and are at heightened risk of the consequences of medicines errors. Research to enhance how people manage medicines has focused on adherence to regimens rather than on the wider skills necessary to safely manage medicines, and the older population living with frailty and managing multiple medicines at home has been under-explored. This study, therefore, examines in depth how older people with mild to moderate frailty manage their polypharmacy regimens at home. METHODS: Between June 2021 and February 2022, 32 patients aged 65 years or older with mild or moderate frailty and taking five or more medicines were recruited from 10 medical practices in the North of England, United Kingdom, and the CARE 75+ research cohort. Semi-structured interviews were conducted face to face, by telephone or online. The interviews were recorded, transcribed verbatim and analysed using reflexive thematic analysis. FINDINGS: Five themes were developed: (1) Managing many medicines is a skilled job I didn't apply for; (2) Medicines keep me going, but what happened to my life?; (3) Managing medicines in an unclear system; (4) Support with medicines that makes my work easier; and (5) My medicines are familiar to me-there is nothing else I need (or want) to know. While navigating fragmented care, patients were expected to fit new medicines routines into their lives and keep on top of their medicines supply. Sometimes, they felt let down by a system that created new obstacles instead of supporting their complex daily work. CONCLUSION: Frail older patients, who are at heightened risk of the impact of medicines errors, are expected to perform complex work to safely self-manage multiple medicines at home. Such a workload needs to be acknowledged, and more needs to be done to prepare people in order to avoid harm from medicines. PATIENT AND PUBLIC INVOLVEMENT: An older person managing multiple medicines at home was a core member of the research team. An advisory group of older patients and family members advised the study and was involved in the first stages of data analysis. This influenced how data were coded and themes shaped.

Neural Changes after Vision Therapy in Convergence Insufficiency: A Systematic Review.

Objective: To investigate if the use of vision therapy (VT) in convergence insufficiency (CI) has a significant neural impact and how it correlates with the clinical changes occurring with this option of treatment. Methods: A systematic review of the scientific literature was carried out in the PubMed and Scopus databases, where all the scientific literature on the neural impact of VT in CI was analyzed. A total of 17 articles were initially found and a detailed analysis was carried out. After full-text reading, only four studies met the defined inclusion criteria. The following data from them were extracted: CI cases and controls, clinical and neural parameters evaluated, the neural response to VT observed, type of study, and VT performed. The quality of the studies was assessed using the GRADE tool. Results: Some neural changes have been reported after VT in CI with the use of functional magnetic resonance imaging (fMRI). Specifically, a modification of the functional activity of some brain areas (especially front fields, oculomotor vermis, and cerebellum) was found. However, contradictory findings in terms of the change in functional activity (increase or decrease) were found that might be associated to differences in fMRI protocols. In the GRADE analysis, serious concerns were found in the categories of risk of bias, inconsistency, indirectness, and imprecision, so the certainty of evidence for each outcome was very low. Conclusion: The research performed to this date does not allow confirming if there are neural changes occurring after vision therapy in patients with CI because the quality of the research performed on this issue is very low, with several methodological concerns.

Varicella Zoster Virus disrupts MAIT cell polyfunctional effector responses.

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that respond to riboflavin biosynthesis and cytokines through TCR-dependent and -independent pathways, respectively. MAIT cell activation plays an immunoprotective role against several pathogens, however the functional capacity of MAIT cells following direct infection or exposure to infectious agents remains poorly defined. We investigated the impact of Varicella Zoster Virus (VZV) on blood-derived MAIT cells and report virus-mediated impairment of activation, cytokine production, and altered transcription factor expression by VZV infected (antigen+) and VZV exposed (antigen-) MAIT cells in response to TCR-dependent and -independent stimulation. Furthermore, we reveal that suppression of VZV exposed (antigen-) MAIT cells is not mediated by a soluble factor from neighbouring VZV infected (antigen+) MAIT cells. Finally, we demonstrate that VZV impairs the cytolytic potential of MAIT cells in response to riboflavin synthesising bacteria. In summary, we report a virus-mediated immune-evasion strategy that disarms MAIT cell responses.

Cl alloying improves thermal stability and increases luminescence in iodine-rich inorganic perovskites.

The inorganic perovskite CsPbI3 shows promising photophysical properties for a range of potential optoelectronic applications but is metastable at room temperature. To address this, Br can be alloyed into the X-site to create compositions such as CsPbI2Br that are stable at room temperature but have bandgaps >1.9 eV - severely limiting solar applications. Herein, in an effort to achieve phase stable films with bandgaps <1.85 eV, we investigate alloying chlorine into iodine-rich triple-halide CsPb(I0.8Br0.2-x Cl x )3 with 0 < x < 0.1. We show that partial substitution of iodine with bromine and chlorine provides a path to maintain broadband terrestrial absorption while improving upon the perovskite phase stability due to chlorine's smaller size and larger ionization potential than bromine. At moderate Cl loading up to ≈5%, X-ray diffraction reveals an increasingly smaller orthorhombic unit cell, suggesting chlorine incorporation into the lattice. Most notably, this Cl incorporation is accompanied by a significant enhancement over Cl-free controls in the duration of black-phase stability of up to 7× at elevated temperatures. Additionally, we observe up to 5× increased steady state photoluminescence intensity (PL), along with a small blue-shift. In contrast, at high loading (≈10%), Cl accumulates in a second phase that is visible at grain boundaries via synchrotron fluorescence microscopy and negatively impacts the perovskite phase stability. Thus, replacing small fractions of bromine for chlorine in the iodine-rich inorganic perovskite lattice results in distinct improvement thermal stability and optoelectronic quality while minimally impacting the bandgap.

Increasing Efficiency With Point-of-Care Ultrasound-Guided Arthrocentesis: A Case Report and Procedure Demonstration.

Patients with chief complaints of musculoskeletal pain comprise a significant portion of emergency department (ED) visits. Identifying and utilizing methods to expedite diagnosis in these cases may help reduce ED crowding, improve outcomes, and increase patient satisfaction. We present a case in which a 52-year-old man presented to the ED with complaints of unilateral right knee pain, swelling, and stiffness. An initial plain film X-ray showed a large suprapatellar effusion over the patient's arthritic right knee. Point-of-care ultrasound (POCUS) was used by an ED physician to facilitate a suprapatellar arthrocentesis. The patient tolerated the procedure well, remarking that he had no pain during or after its completion. POCUS can increase the accuracy, efficacy, and speed of procedures for which physicians have traditionally used landmarks or formal radiology consultations. While POCUS can prove helpful, barriers to its widespread implementation still remain. However, these barriers can be addressed with relative ease.

Antimicrobial susceptibility profile of ceftolozane/tazobactam, ceftazidime/avibactam and cefiderocol against carbapenem-resistant Pseudomonas aeruginosa clinical isolates from Türkiye.

PURPOSE: Carbapenem resistant Pseudomonas aeruginosa (CR-PA) is escalating worldwide and leaves clinicians few therapeutic options in recent years, ß-lactam/ß-lactamase inhibitor combinations (ceftolozane-tazobactam, ceftazidime-avibactam) and a new siderophore cephalosporin (cefiderocol) have been approved for the treatment of P. aeruginosa infection and have shown potent activity against isolates defined as carbapenem resistant. The aim of this study was to determine the phenotypic profile of these agents against CR-PA in the emerging setting of carbapenemases. METHODS: CR-PA clinical isolates were collected from three teaching hospitals in different geographical regions between January 2017-December 2021. All isolates were subjected to phenotypic carbapenemase testing using modified carbapenem inactivation method. MICs were determined by reference broth microdilution and evaluated according to EUCAST standards, while genotypic profiling was determined using PCR methods. RESULTS: 244 CR-PA sourced most frequently from the respiratory tract (32.2%), blood (20.4%) and urine (17.5%) were evaluated. Of all isolates, 32 (13.1%) were phenotypically and 38 (15.6%) were genotypically defined as carbapenemase-positive. The most common carbapenemase was GES (63.1%), followed by VIM (15.8%). The MIC50/90(S%) of ceftazidime/avibactam, ceftolozane/tazobactam and cefiderocol in all CR-PA isolates were 4 and 32 (80%), 1 and > 64 (69%) and 0.25 and 1 mg/L (96%), respectively. Cefiderocol was also the most active agent in carbapenemase-positive isolates (90%). CONSLUSION: While ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against CR-PA devoid of carbapenemases, cefiderocol provided potent in vitro activity irrespective of carbapenemase production. When considering the potential clinical utility of newer agents against CR-PA, regional variations in carbapenemase prevalence must be considered.

Effect of reboxetine and citalopram on anal opening pressure in healthy women: A randomized, double-blind, placebo-controlled crossover study.

BACKGROUND: In placebo-controlled clinical trials, reboxetine, a selective noradrenaline reuptake inhibitor, increases urethral pressure and relieves stress urinary incontinence symptoms in women. Considering the close connection in neural regulation of the external urethral and anal sphincters, we hypothesized that reboxetine may also enhance anal sphincter pressure. Conversely, it is believed that selective serotonin reuptake inhibitors may contribute to fecal incontinence by reducing anal sphincter pressure. In this study, we investigated the effect of reboxetine and citalopram on anal opening pressure in healthy female volunteers. METHODS: In a double-blind, three-way crossover trial, 24 female participants received single doses of 40 mg citalopram, 8 mg reboxetine, and matching placebos, with a minimum of 8-day washout between sessions. Using anal acoustic reflectometry, we measured anal opening pressure during both resting and squeezing conditions at the estimated time of peak plasma concentration for both study drugs. KEY RESULTS: Compared with placebo, reboxetine increased anal opening pressure with 23.4 cmH2O (95% confidence interval [CI] 16.5-30.2, p < 0.001) during rest and with 22.5 cmH2O (95% CI 15.2-29.8, p < 0.001) during squeeze. Citalopram did not change anal opening pressure statistically significantly compared to placebo. CONCLUSIONS & INFERENCES: An 8-mg dose of reboxetine increased anal opening pressure substantially in healthy women, suggesting potential benefits for fecal incontinence symptoms. In contrast, a 40-mg dose of citalopram showed a marginal and statistically insignificant effect on anal opening pressure, indicating that selective serotonin reuptake inhibitors do not contribute to fecal incontinence by reducing anal sphincter tone.

Global threats of extractive industries to vertebrate biodiversity.

Mining is a key driver of land-use change and environmental degradation globally, with the variety of mineral extraction methods used impacting biodiversity across scales. We use IUCN Red List threat assessments of all vertebrates to quantify the current biodiversity threat from mineral extraction, map the global hotspots of threatened biodiversity, and investigate the links between species' habitat use and life-history traits and threat from mineral extraction. Nearly 8% (4,642) of vertebrates are assessed as threatened by mineral extraction, especially mining and quarrying, with fish at particularly high risk. The hotspots of mineral extraction-induced threat are pantropical, as well as a large proportion of regional diversity threatened in northern South America, West Africa, and the Arctic. Species using freshwater habitats are particularly at risk, while the effects of other ecological traits vary between taxa. As the industry expands, it is vital that mineral resources in vulnerable biodiversity regions are managed in accordance with sustainable development goals.

Effects of clinically relevant radionuclides on the activation of a type I interferon response by radiopharmaceuticals in syngeneic murine tumor models.

Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90 Y, 177 Lu, and 225 Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to 225 Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8 + /Treg ratios increased in tumors 7 days after 90 Y- and 177 Lu-NM600 and day 21 after 225 Ac-NM600. 225 Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models. Teaser: This study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.

Adapting to PFAS contamination of private drinking water wells near a PFAS production facility in the US Atlantic Coastal Plain of North Carolina.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are widespread groundwater contaminants and are present in over 7000 drinking water wells near a North Carolina (NC) PFAS plant (Chemours). To understand options available to affected residents, we used new and previously existing water quality data to investigate deeper aquifers as alternate drinking water supplies and compared the regulatory responses near Chemours and three other PFAS production facilities with nearby contaminated wells. Data from >100 wells show that GenX concentrations decrease with increasing depth through the four aquifers in the study area: surficial, Black Creek, Upper Cape Fear, and bedrock. This illustrates the extent of vertical PFAS penetration through the aquifer sequence following roughly 40 years of atmospheric emissions. Detailed data on 143 water quality parameters in nine deep wells (two Upper Cape Fear, seven bedrock) revealed only eight exceedances of drinking water standards (one each for arsenic, perfluorooctanoic acid [PFOA], iron, chloride, and gross alpha, and three for manganese) and nine exceedances of health advisories (all for sodium). Regulatory responses to PFAS contamination of wells in four states included mention of deeper wells as an alternate water source only for nonresidential users in NC and residential users in Vermont. The bedrock aquifer is currently used by some residents and may be a viable alternative to shallower groundwater, though arsenic treatment may be beneficial at some deep wells and long-term sustainability of the aquifer should be evaluated. PRACTITIONER POINTS: GenX concentrations decreased with increasing depth in four aquifers near a PFAS plant. A few exceedances of drinking water standards and health advisories were found in deep bedrock wells. New bedrock wells could be part of the response to PFAS issues in shallower wells. In the long term, deep bedrock wells might be a less expensive option for some residents.