Longitudinal analysis of nursing home residents' T cell responses after SARS-CoV-2 mRNA vaccinations shows influence of biological sex and SARS-CoV-2 infection history.

BACKGROUND: Vaccines and vaccine boosting have blunted excess morbidity and mortality from SARS-CoV-2 infection suffered by older nursing home residents (NHR). However, the impact of repeated vaccination on the T cell response based on biological sex and prior infection of NHR remain understudied. METHODS: We examined T cell responses to mRNA vaccines to SARS-CoV-2 in a cohort of NHR and healthcare workers (HCW) over 2 years. We used IFN-γ ELIspot and flow cytometry to assess T cell response before, two weeks and 6 months after the initial series and each of two booster vaccines. We analyzed these data longitudinally with mixed-effect modeling and also examined subsets of our cohorts for additional changes in T cell effector function. RESULTS: We show that prior SARS-CoV-2 infection and female sex contribute to higher T cell response in NHR but not HCW. When looking across time points, NHR but not HCW with prior infection had significantly higher T cell responses than infection-naive subjects. These patterns of response were maintained across multiple booster vaccinations and suggest that the age, multimorbidity, and/or frailty of the NHR cohort may accentuate sex and infection status differences in T cell response to mRNA vaccination.

The Effects of Changes in Cigarette Menthol Content on Acute Nicotine Pharmacology and Smoking Topography.

INTRODUCTION: Menthol influences the appeal and addictiveness of cigarette smoking, however the data regarding menthol's effects on nicotine pharmacokinetics (PK) and smoking topography are inconsistent. This study investigated the impact of different cigarette menthol levels on nicotine pharmacology and smoking topography in current menthol smokers. AIMS AND METHODS: The study was a double-blind, randomized, four-period, crossover study to investigate the effects of smoking cigarettes with varying menthol content (0, 3, 6, and 12 mg menthol) on nicotine PK, smoking topography, and subjective effects in current menthol smokers. Each experimental session consisted of a prescribed use session, followed by 145 min of no smoking and a 1-h ad libitum smoking session. Serial blood samples were collected; smoking topography was recorded using CReSS Lab topography device. RESULTS: There was no significant effect of menthol on nicotine PK after prescribed smoking of cigarettes with varying menthol contents. During ad libitum smoking, there was significantly smaller total puff volume and puff duration in the 12 mg menthol condition compared to other menthol conditions. Subjective and sensory measures indicated significantly higher overall positive ratings for the 3 mg and 6 mg menthol cigarettes compared to the 0 mg menthol cigarette; the 12 mg menthol cigarette was less liked and harsher than the 3 mg condition. CONCLUSIONS: These findings suggest that menthol, at concentrations reflecting the marketplace (3-6 mg), contributes to positive subjective smoking experiences among menthol smokers, but does not have a significant effect on nicotine PK or smoking topography in an acute laboratory setting. IMPLICATIONS: While our data indicate that varying menthol content does not have a significant impact on nicotine's pharmacological effects under acute exposure conditions, these data highlight the contribution of menthol's flavor and sensory effects to product preference and positive smoking experiences, which facilitate repeated experimentation, progression to regular use, and subsequent dependence.

Adjuvant AS01 activates human monocytes for costimulation and systemic inflammation.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV) is highly effective even in adults over 80 years old. The high efficacy of RZV is attributed to its highly reactogenic adjuvant, AS01, but limited studies have been done on AS01's activation of human immune cells. METHODS: We stimulated peripheral blood mononuclear cells (PBMC) with AS01 and used flow cytometry and RNA Sequencing (RNAseq) to analyze the impacts on human primary cells. RESULTS: We found that incubation of PBMC with AS01 activated monocytes to a greater extent than any other cell population, including dendritic cells. Both classical and non-classical monocytes demonstrated this activation. RNASeq showed that TNF-ɑ and IL1R pathways were highly upregulated in response to AS01 exposure, even in older adults. CONCLUSIONS: In a PBMC co-culture, AS01 strongly activates human monocytes to upregulate costimulation markers and induce cytokines that mediate systemic inflammation. Understanding AS01's impacts on human cells opens possibilities to further address the reduced vaccine response associated with aging.

Dispersed DNA variants underlie hearing loss in South Florida's minority population.

BACKGROUND: We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations. RESULTS: The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients. CONCLUSION: This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses.

Tibiotalocalcaneal Arthrodesis Using Hybrid Plate-Nail Constructs: A Novel Technique for Treatment of Unstable Ankle and Hindfoot Deformities.

SUMMARY: Tibiotalocalcaneal (TTC) arthrodesis is a treatment option for several pathologies of the ankle and hindfoot, including acute trauma, posttraumatic arthritis, and Charcot neuroarthropathy. Traditional fixation options for TTC arthrodesis include intramedullary hindfoot nailing or internal fixation with plates and/or screws. In certain patients, either due to poor bone quality, impaired sensation, or concern for noncompliance, more robust fixation may be desired. In such patients, we have used a hybrid plate-nail construct with promising results. This article and the accompanying video demonstrate our technique for TTC arthrodesis using a plate-nail construct and review treatment decisions involved with management of these complex cases.

Survey of Premium Versus Large Manufactured Cigars Use in U.S. Consumers.

INTRODUCTION: An Internet questionnaire was used to determine smoking behavior, purchasing behavior, and risk perceptions among exclusive or nearly exclusive current users of either large manufactured (LMC) or premium cigars (PC). AIMS AND METHODS: Respondents (n = 250) were recruited from a nationally representative market research panel. An a priori designation of PC users was adapted from criteria in published literature and the recent National Academy of Science report. RESULTS: Examination of responses revealed a (n = 19) disagreement between cigar users' self-classifications and the a priori classification. After eliminating ineligible respondents 188 participants were classified as PC (n = 92; 55 male) or LMC (n = 96; 49 male) users. There were no significant differences in age or gender between groups. Respondents were all over 21 years old. The largest age groups were 30-39 years and 60-69 years. PC users were significantly more likely to have higher annual incomes and to buy cigars online or through tobacco specialty shops, whereas LMC users purchased from convenience stores. Most participants had used other combustible tobacco products (88%) but few had used ENDS (24%) or oral tobacco (7.5%). There was no significant difference in the frequency of smoke inhalation or perceptions of risk for health. There was marked uncertainty in self-characterization of cigar type; our sample had higher female representation than expected (n = 84, 45%), and inhalation was frequently endorsed in both groups (52%, overall). CONCLUSIONS: The results support the need for standardized classifications and suggest current trends may indicate shifts in gender and use behavior but provide no evidence supporting less restrictive regulation of PC. IMPLICATIONS: An Internet questionnaire was used to determine smoking behavior, purchasing behavior, and risk perceptions among current users of LMC or PC. There was uncertainty about cigar classification even in this sample of regular users. Our results demonstrated more than expected inhalation of cigar smoke, considerable use by females, and under appreciation of health risks. No results supported less restrictive regulations for premium cigars.

Humoral and Cellular Immunity Induced by Adjuvanted and Standard Trivalent Influenza Vaccine in Older Nursing Home Residents.

BACKGROUND: Despite wide use of adjuvanted influenza vaccine in nursing home residents (NHR), little immunogenicity data exist for this population. METHODS: We collected blood from NHR (n = 85) living in nursing homes participating in a cluster randomized clinical trial comparing MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) with nonadjuvanted vaccine (TIV) (parent trial, NCT02882100). NHR received either vaccine during the 2016-2017 influenza season. We assessed cellular and humoral immunity using flow cytometry and hemagglutinin inhibition, antineuraminidase (enzyme-linked lectin assay), and microneutralization assays. RESULTS: Both vaccines were similarly immunogenic and induced antigen-specific antibodies and T cells, but aTIV specifically induced significantly larger 28 days after vaccination (D28) titers against A/H3N2 neuraminidase than TIV. CONCLUSIONS: NHRs respond immunologically to TIV and aTIV. From these data, the larger aTIV-induced antineuraminidase response at D28 may help explain the increased clinical protection observed in the parent clinical trial for aTIV over TIV in NHR during the A/H3N2-dominant 2016-2017 influenza season. Additionally, a decline back to prevaccination titers at 6 months after vaccination emphasizes the importance of annual vaccination against influenza. CLINICAL TRIALS REGISTRATION: NCT02882100.

A Method to Amend Cigarettes With Menthol for Use in Research.

INTRODUCTION: Studies have evaluated the role of menthol cigarettes on various addiction-related outcomes; however, the effect of varying menthol content on these outcomes has not been evaluated. We developed a method to amend non-menthol SPECTRUM Research Cigarettes to contain menthol at four different levels. AIMS AND METHODS: SPECTRUM Research Cigarettes, NRC 600 (0.8 mg nicotine; 10 mg tar), were modified to contain target menthol amounts at 3, 6, and 12 mg/cigarette by injecting 25 µL ethanol/triacetin/menthol solutions of varying concentrations (120 mg menthol/mL, 240 mg/mL, and 480 mg/mL) into four distinct locations in the filter and tobacco rod. Menthol content was tested in triplicate in the whole cigarette and in the tobacco rod and filter at 1, 24, 48, and 72 hours for each target menthol level using an extraction solution of quinoline in methyl-tert-butyl ether and measured using gas chromatography with flame ionization detection. RESULTS: Injections into the filter and tobacco rod (12.5 µL each) yielded equal menthol distribution up to 72 hours. However, total menthol content decreased from an average of 90.3% of the target menthol concentration at 1 hour to 80.7% at 72 hours in cigarettes stored individually in glass tubes at room temperature. Analysis of urinary menthol glucuronide confirmed that amended cigarettes used within 24 hours of injection delivered dose-related menthol levels to participants in a clinical laboratory setting. CONCLUSION: This method can be used to modify cigarettes with a range of reliable menthol levels in both filter and tobacco rod for use in laboratory and clinical research. IMPLICATIONS: This study presents a technique for modifying cigarettes with different levels of menthol that can reliably deliver dose-related menthol levels to participants when smoked in a clinical study. The technique can be used to quickly amend cigarettes to examine the independent effects of varying flavor and additive levels on smoking behavior, nicotine pharmacokinetics, mainstream smoke emissions, and other laboratory or clinical research outcomes.

Effect of very low nicotine content cigarettes on alcohol drinking and smoking among adult smokers who are at-risk alcohol drinkers.

Alcohol and tobacco use are interrelated. This study examined response to very low nicotine content (VLNC) and moderate nicotine content (MNC) cigarettes by problematic drinking. We utilized a double-blind, randomized, within-subjects crossover design of VLNC and MNC cigarettes in two groups of adult cigarette smokers: with at-risk drinking (ARD; n = 23) and without ARD (n = 24). Participants smoked only their assigned experimental cigarette in their home environment for 7 days, and completed laboratory visits, including ad libitum smoking of the assigned experimental cigarette, at the beginning and end of each experimental week. Participants smoked their usual cigarettes for 7 days between conditions. Participants provided daily reports of alcohol and cigarette consumption. Current Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) alcohol use disorder (AUD) was assessed at baseline and the end of each experimental week. Compliance with smoking of experimental cigarettes was good. Adjusting for baseline drinking, there was no significant effect of experimental cigarette or ARD group on drinks per day or alcohol urges. There was no effect of experimental cigarette or ARD group on cigarettes per day, or on any puff topography outcome or postsmoking exhaled carbon monoxide during laboratory smoking. No participant had a change in AUD status or AUD severity. After 7 days of exposure to VLNC cigarettes, adult cigarette smokers with ARD did not show compensatory drinking or compensatory smoking behavior. A future policy change in the United States to reduce nicotine content in cigarettes may not produce unintended compensatory drinking or smoking among this vulnerable and prevalent population of smokers. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Research outside the laboratory: Longitudinal at-home neurostimulation.

The use of noninvasive transcranial electrical stimulation (tES) has rapidly increased over the past two decades. Yet, tES continues to be largely implemented in laboratory and rehabilitation settings, thereby limiting accessibility to the broader population. We have previously demonstrated that transcranial alternating current stimulation (tACS) in the theta (4-7 Hz) band improves cognitive control, such as multitasking, in younger adults following a single tACS session, as well as in older adults following three tACS sessions. Here, the goal was to extend our in-lab results by (1) assessing the feasibility for at-home tACS and (2) evaluating whether five tACS sessions may yield continuing improvements in multitasking ability in young adults. Participants (aged 18 - 34 years) received bilateral prefrontal tACS while engaged in an adaptive multitasking training over five consecutive days in their home settings. Participants were randomly assigned to receive either 20-minutes of theta or delta tACS during daily multitasking training. Prior to and on the day immediately following five days of tACS, we assessed performance on single task, multitask, and sustained attention ability with analyses of variance statistics. 92.1% of participants were able to self-administer tACS at home without researcher assistance. However, we observed that both theta and delta tACS groups exhibited improvements in both single and multitask performance. Compared to previously collected data, five days of theta tACS was comparable to one day of theta tACS. However, theta tACS has continued benefits in older, but not younger adults as evidenced by previous research. Both groups similarly improved in sustained attention. These results demonstrate that laboratory paradigms utilizing neurostimulation can be effectively deployed in a home environment without direct support from research personnel. Moreover, these results suggest that while theta tACS may facilitate multitasking improvements over one session, multiple sessions of theta tACS results in diminishing returns in young adults. Additional research will be required to confirm if delta activity plays an important role in multitasking ability.

Differential CD4+ T-Cell Cytokine and Cytotoxic Responses Between Reactivation and Latent Phases of Herpes Zoster Infection.

Background: CD4+ T cells are a critical component of effective immune responses to varicella zoster virus (VZV), but their functional properties during the reactivation acute vs latent phase of infection remain poorly defined. Methods: Here we assessed the functional and transcriptomic properties of peripheral blood CD4+ T cells in persons with acute herpes zoster (HZ) compared to those with a prior history of HZ infection using multicolor flow cytometry and RNA sequencing. Results: We found significant differences between the polyfunctionality of VZV-specific total memory, effector memory, and central memory CD4+ T cells in acute vs prior HZ. VZV-specific CD4+ memory T-cell responses in acute HZ reactivation had higher frequencies of IFN-γ and IL-2 producing cells compared to those with prior HZ. In addition, cytotoxic markers were higher in VZV-specific CD4+ T cells than non-VZV-specific cells. Transcriptomic analysis of ex vivo total memory CD4+ T cells from these individuals showed differential regulation of T-cell survival and differentiation pathways, including TCR, cytotoxic T lymphocytes (CTL), T helper, inflammation, and MTOR signaling pathways. These gene signatures correlated with the frequency of IFN-γ and IL-2 producing cells responding to VZV. Conclusions: In summary, VZV-specific CD4+ T cells from acute HZ individuals had unique functional and transcriptomic features, and VZV-specific CD4+ T cells as a group had a higher expression of cytotoxic molecules including Perforin, Granzyme-B, and CD107a.

Adjuvant effect of type I interferon induced by many but not all commercial influenza vaccines.

BACKGROUND: Seasonal influenza vaccines approved and offered in the United States have varying reported degrees of effectiveness year over year and between manufacturers. Influenza vaccines produced from live virus may include single stranded RNA (ssRNA) that is a potent activator of the innate Toll-like receptor 7 (TLR-7) ligand. Plasmacytoid dendritic cells (pDC) can be activated by ssRNA to produce type I interferons such as IFN-α, which has been shown to have an adjuvant-like effect. OBJECTIVE: Our aim was to determine if IFN-α induction in peripheral blood mononuclear cells (PBMCs) exposed to eight different commercial influenza vaccines is a pDC-dependent process mediated through TLR-7 signaling. RESULTS: We demonstrate the ability of multiple vaccines to induce IFN-α in a TLR-7-dependent fashion. A number of vaccines however lacked IFN-α induction. The significance of these differences between vaccines is unclear, since all the approved vaccine formulations offer some degree of protection.

Impact of smoked cannabis on tobacco cigarette smoking intensity and subjective effects: A placebo-controlled, double-blind, within-subjects human laboratory study.

Co-users of cannabis and tobacco frequently use cannabis, then tobacco cigarettes, in a sequential pattern within an occasion, that is, they "chase" smoked cannabis with a tobacco cigarette. The objective of this placebo-controlled, double-blind, within-subjects human laboratory study was to gather preliminary data on how smoking active versus placebo cannabis impacts tobacco cigarette smoking behavior, craving, and subjective effects. Adult daily cannabis and tobacco co-users (N = 9) were randomly assigned to two experimental visit orders (i.e., active cannabis (5.2% THC) first visit and placebo cannabis second visit, or vice versa). Participants smoked one cannabis cigarette, and approximately 30 min later were given a 5-min ad libitum period to smoke one of their own brand of tobacco cigarette. As expected, boost in plasma THC levels and cannabis-related subjective effects differed between active and placebo cannabis conditions. Tobacco cigarette puff topography measures and tobacco craving did not differ between cannabis conditions, but there appeared to be between-participants heterogeneity in cumulative total puff volume. After smoking active versus placebo cannabis, the changes in subjective effects of tobacco smoking after adjusting for pretobacco smoking levels were not significant. Results do not support the notion that immediate effects of smoked cannabis change the behavior of tobacco smoking. The strong overlap between cannabis and tobacco smoking may not be explained by primarily pharmacological factors, but may be driven by more nuanced and complex mechanisms involving pharmacological processes as well as learning factors. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The spectrum of lupus myocarditis: from asymptomatic forms to cardiogenic shock.

Lupus myocarditis is a serious, potentially deadly disease. When it presents as an acute or fulminant myocarditis in a patient without an established diagnosis of lupus, lupus as an etiology of the condition is not commonly suspected. Meanwhile, it has a distinct treatment which may be lifesaving. Review of the literature can shed more light as current management is mostly based on clinical experience and case reports rather than randomized control trials. In this review we are discussing this diagnostic entity, focusing on cardiogenic shock as a manifestation of lupus myocarditis, and discussing management including aggressive immunosuppression, mechanical circulatory support, and cardiac transplantation.

ORIF of Distal Humerus Fractures with Modern Pre-contoured Implants is Still Associated with a High Rate of Complications.

BACKGROUND: The purpose of this study was to identify complications after operative treatment of distal humerus fractures with anatomic, pre-contoured, locking distal humeral plates. We hypothesized that these fractures have high complication rates despite the use of these modern implants. MATERIALS AND METHODS: Between 2010 and 2018, 43 adult patients with a distal humerus fracture underwent open reduction and internal fixation (ORIF) at a Level I trauma center. Pre-operative variables, including medical comorbidities, mechanism of injury, open or closed fracture, AO/OTA fracture classification (Type A, B, or C), and nerve palsy, were recorded. Intra-operative variables including surgical approach, ulnar nerve transposition, and plate configuration were recorded. Anatomic, pre-contoured, locking distal humeral plates were used in all patients. Various plating systems were used based on surgeon preference and fracture pattern. Post-operative complications including infection, nonunion, malunion, painful implants, nerve palsy, heterotopic ossification, stiffness, and post-traumatic arthritis were recorded. RESULTS: Most fractures were Type C (53%). The posterior olecranon osteotomy approach (51%) and parallel plate configuration (42%) were used in most cases. At a mean follow-up of 15 months, the complication rate was 61% (26/43 patients). Among all patients, 49% (21/43 patients) required a reoperation. Elbow stiffness (19%) was the most common complication followed by nerve palsy (16%). There were four fracture nonunions (9%), deep infections (9%), painful implants (9%), post-traumatic arthritis (9%), and heterotopic ossification (9%). CONCLUSIONS: Distal humerus fractures treated with ORIF utilizing anatomic, pre-contoured, locking distal humeral plates have a high complication rate, with many requiring reoperation. LEVEL OF EVIDENCE: Therapeutic Level IV.

Intramedullary Headless Screw Fixation for Metacarpal Fractures.

Multiple techniques have been proposed for metacarpal fracture fixation, including percutaneous Kirschner-wires, interfragmentary screws, plate and screw constructs, intramedullary (IM) nails, and cannulated IM headless screws. Each of these treatment options has its proposed advantages and disadvantages, and there remains no consensus on the optimal mode of treatment. We describe a technique of retrograde IM headless screw fixation for extra-articular metacarpal fractures.

A Unique Case of Systemic Lupus Erythematosus Myocarditis Complicated by Plasmapheresis-Responsive Cardiogenic Shock.

A 25-year-old woman with systemic lupus erythematosus complicated by biventricular failure with a history of multiple admissions presented with cardiogenic shock unresponsive to steroids, intravenous immunoglobulin, cyclophosphamide, and required extra-corporeal membrane oxygenation. Left ventricular function eventually recovered after plasmapheresis. (Level of Difficulty: Advanced.).

Morphometric analysis of the second through fifth metacarpal through posteroanterior X-Rays.

Over the past 10 years, metacarpal fractures have had an annual incidence of 13.6 per 10,000 individuals. Literature has not reviewed anatomical variations through radiographic imaging, which may play a role in reducing postoperative complications. The purpose of this study was to use radiographic imaging to provide a detailed anatomy of the second through fifth metacarpals. This retrospective study measured length, neck width, narrowest body width, and narrowest medullary canal width of the second through fifth metacarpals through the use of posteroanterior X-rays. Patients who were ≥18 years and received hand radiographs from January 2015 to July 2019 were included in this study. Those with acute injury or fracture of the metacarpal were excluded. Five hundred and seventy-two metacarpals were included in this study, with 143 metacarpals measured each for the second through fifth metacarpal. The second metacarpal had the largest measured length, neck width, and narrowest body width at 68.72, 12.34, and 8.74 mm, respectively. The fifth metacarpal had the greatest average medullary canal width at 4.15 mm. This is the largest study in literature to comprehensively examine the anatomical variation of the second through fifth metacarpals. The second metacarpal had greatest dimensions except for canal width, which was the fifth metacarpal. Men almost consistently had greater metacarpal size when compared to women, and age was associated with second and third metacarpal canal width. The increased knowledge of metacarpal anatomy may potentially lay the foundation of further improvement of metacarpal implants and potentially reduce postoperative complications. Clin. Anat., 33:1014-1018, 2020. © 2019 Wiley Periodicals, Inc.