Use of simple lymphatic drainage on truncal lymphoedema for a patient with diabetes and peripheral arterial disease.

Lymphoedema is the gradual, abnormal build-up of lymph fluid in the tissues resulting from a failure of the lymphatic system. The swelling impedes movement and is painful. Compression garments are contraindicated and not tolerated by patients with extensive peripheral arterial disease. In this case study, simple lymphatic drainage was therefore considered a safer treatment option to reduce oedema and to encourage proactive self-management for a patient with bilateral amputations, diabetes and peripheral arterial disease.

Development of a novel serological assay for the detection of mpox infection in vaccinated populations.

In 2022 the World Health Organization declared a Public Health Emergency for an outbreak of mpox, the zoonotic Orthopoxvirus (OPV) affecting at least 104 nonendemic locations worldwide. Serologic detection of mpox infection is problematic, however, due to considerable antigenic and serologic cross-reactivity among OPVs and smallpox-vaccinated individuals. In this report, we developed a high-throughput multiplex microsphere immunoassay using a combination of mpox-specific peptides and cross-reactive OPV proteins that results in the specific serologic detection of mpox infection with 93% sensitivity and 98% specificity. The New York State Non-Vaccinia Orthopoxvirus Microsphere Immunoassay is an important tool to detect subclinical mpox infection and understand the extent of mpox spread in the community through retrospective analysis.

Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study.

BACKGROUND: Monkeypox virus has recently infected more than 88 000 people, raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has fewer side-effects than previous smallpox vaccines and has shown immunogenicity against monkeypox in animal models. This study aims to elucidate human immune responses to JYNNEOS vaccination compared with mpox-induced immunity. METHODS: Peripheral blood mononuclear cells and sera were obtained from ten individuals vaccinated with one or two doses of JYNNEOS and six individuals diagnosed with monkeypox virus infection. Samples were obtained from seven individuals before vaccination to serve as a baseline. We examined the polyclonal serum (ELISA) and single B-cell (heavy chain gene and transcriptome data) antibody repertoires and T-cell responses (activation-induced marker and intracellular cytokine staining assays) induced by the JYNNEOS vaccine versus monkeypox virus infection. FINDINGS: All participants were men between the ages of 21 and 60 years, except for one woman in the group of mpox-convalescent individuals, and none had previous orthopoxvirus exposure. All mpox cases were mild. Vaccinee samples were collected 6-33 days after the first dose and 5-40 days after the second dose. Mpox-convalescent samples were collected 20-102 days after infection. In vaccine recipients, gene-level plasmablast and antibody responses were negligible and sera displayed moderate binding to recombinant orthopoxviral proteins (A29L, A35R, E8L, A30L, A27L, A33R, B18R, and L1R) and native proteins from the 2022 monkeypox outbreak strain. By contrast, recent monkeypox virus infection (within 20-102 days) induced robust serum antibody responses to monkeypox virus proteins and to native monkeypox virus proteins from a viral isolate obtained during the 2022 outbreak. JYNNEOS vaccine recipients presented robust orthopoxviral CD4+ and CD8+ T-cell responses. INTERPRETATION: Infection with monkeypox virus resulted in robust B-cell and T-cell responses, whereas immunisation with JYNNEOS elicited more robust T-cell responses. These data can help to inform vaccine design and policies for preventing mpox in humans. FUNDING: National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), and Icahn School of Medicine.

Development of a Novel Serological Assay for the Detection of Mpox Infection in Vaccinated Populations.

In 2022 the World Health Organization declared a Public Health Emergency for an outbreak of mpox, the zoonotic Orthopoxvirus (OPV) affecting at least 103 non-endemic locations world-wide. Serologic detection of mpox infection is problematic, however, due to considerable antigenic and serologic cross-reactivity among OPVs and smallpox-vaccinated individuals. In this report, we developed a high-throughput multiplex microsphere immunoassay (MIA) using a combination of mpox-specific peptides and cross-reactive OPV proteins that results in the specific serologic detection of mpox infection with 93% sensitivity and 98% specificity. The New York State Non-Vaccinia Orthopoxvirus Microsphere Immunoassay is an important diagnostic tool to detect subclinical mpox infection and understand the extent of mpox spread in the community through retrospective analysis.

Practitioners' Views on Enabling People With Dementia to Remain in Their Homes During and After Crisis.

One way of supporting people living with dementia is assisting them to live in their homes (as opposed to being admitted to hospital or other facility) and providing them with a specialist service that responds to crises. This makes it important to understand how best to organize such crisis response services. This study examines practitioners' actions to reduce inpatient admissions among this population. Through interviews with healthcare practitioners, we find that practitioners negotiate a complex intersection between (1) what constitutes a crisis in relation to the patient and/or the carer, (2) the demands of building a working relationship with both the patient and their family carers, and (3) ensuring effective communications with social services responsible for long-term community support. Findings suggest that policies aimed at reducing admissions should be based on a model of care that more closely maps practitioners' relational and bio-medical work in these services.

Supervised preoperative walking on increasing early postoperative stamina and mobility in older adults with frailty traits: A pilot and feasibility study.

Background and Aims: Frail older adults are more than twice as likely to experience postoperative complications. Preoperative exercise may better prepare these patients through improved stamina and mobility experienced in the days following surgery. We measured the impact of a walking intervention using an activity tracker and coaching on postoperative stamina, and mobility in older adults with frailty traits. Methods: We included patients aged 60+ and scoring 4+ on the Edmonton Frailty Scale. We then randomized patients to intervention versus control stratified by anticipated hospital stay (1 night vs. 2+ night) and baseline stamina (i.e., 6-min walk distance [6MWD]). Intervention patients received an activity tracker and linked smart phone. An athletic trainer (AT) prescribed a daily step count goal and titrated this up after checking in with patients during weekly telephone calls. Controls received general walking recommendations. We then measured postoperative 6MWD 1-3 days after surgery. We also assessed postoperative mobility by measuring steps walked the day after surgery using a thigh-worn monitor. Because many patients could not walk postoperatively, we compared intervention-control difference in both 6MWD and steps using Wilcoxon rank testing and Tobit and ordinal logistic regression adjusting for several patient characteristics. Results: We randomized 104 eligible patients; 80 patients remained for final analysis. There was no difference in intervention versus control postoperative 6MWD (median 72 vs. 74 m Wilcoxon p = 0.54) or postoperative steps taken (median 128 vs. 51 steps Wilcoxon p = 0.76). Analysis adjusting for patient characteristics was consistent with these findings. Conclusion: Our intervention consisting of goal setting with an activity tracker and telephonic coaching by an AT did not appear to improve stamina or mobility measured in the days after surgery. Small sample size limited our ability to examine this impact in subsets defined by surgical specialty or baseline stamina.

Serological Analysis Identifies Consequential B Cell Epitopes on the Flexible Linker and C-Terminus of Decorin Binding Protein A (DbpA) from Borrelia burgdorferi.

Decorin binding protein A (DbpA) is a surface adhesin of Borrelia burgdorferi, the causative agent of Lyme disease. While DbpA is one of the most immunogenic of B. burgdorferi's nearly 100 lipoproteins, the B cell epitopes on DbpA recognized by humans following B. burgdorferi infection have not been fully elucidated. In this report we profiled ~270 B. burgdorferi-seropositive human serum samples for IgM and IgG reactivity with a tiled DbpA 18-mer peptide array derived from B. burgdorferi sensu stricto strains B31 and 297. Using enzyme-linked immunosorbent assays (ELISA) and multiplex immunoassays (MIA), we identified 12 DbpA-derived peptides whose antibody reactivities were significantly elevated (generally <10-fold) in B. burgdorferi-seropositive sera, compared to those measured in a healthy cohort. The most reactive peptide (>80-fold IgG, 10-fold IgM) corresponded to residues 64 to 81, which map to an exposed flexible loop between DbpA's α-helix 1 and α-helix 2. This loop, whose sequence is identical between strains B31 and 297, overhangs DbpA's substrate binding pocket. A second strongly reactive antibody target (>80-fold IgG, 3 to 5-fold IgM) mapped to DbpA's C-terminus, a lysine rich tail implicated in attachment to glycosaminoglycans. We postulate that antibody responses against these two targets on DbpA could limit B.burgdorferi's ability to attach to and colonize distal tissues during the early stages of infection. IMPORTANCE The bacterium, Borrelia burgdorferi, is the causative agent of Lyme disease, the most reported tick-borne illness in the United States. In humans, clinical manifestations of Lyme disease are complex and can persist for months, even in the face of a robust antibody response directed against numerous B. burgdorferi surface proteins, including decorin binding protein A (DbpA), which is involved in the early stages of infection. In this study we employed ~270 serum samples from B. burgdorferi-seropositive individuals to better understand human antibody reactivity to specific regions (called epitopes) of DbpA and how such antibodies may function in limiting B. burgdorferi dissemination and tissue colonization.

Durable Immunity to Ricin Toxin Elicited by Intranasally Administered Monoclonal Antibody-Based Immune Complexes.

Inhalation of ricin toxin (RT) elicits profuse inflammation and cell death within the upper and lower airways, ultimately culminating in acute respiratory distress syndrome. We previously reported that the effects of pulmonary RT exposure in mice are nullified by intranasal administration of an mAb mixture consisting of PB10, directed against ricin's enzymatic subunit (RTA), and SylH3, directed against ricin's binding subunit (RTB). We now report that delivery of PB10 and SylH3 as an RT-mAb immune complex (RIC) to mice by the intranasal or i.p. routes stimulates the rapid onset of RT-specific serum IgG that persists for months. RIC administration also induced high-titer, toxin-neutralizing Abs. Moreover, RIC-treated mice were immune to a subsequent 5 × LD50 RT challenge on days 30 or 90. Intranasal RIC administration was more effective than i.p. delivery at rendering mice immune to intranasal RT exposure. Finally, we found that the onset of RT-specific serum IgG following RIC delivery was independent of FcγR engagement, as revealed through FcγR knockout mice and RICs generated with PB10/SylH3 LALA (leucine to alanine) derivatives. In conclusion, a single dose of RICs given intranasally to mice was sufficient to stimulate durable protective immunity to RT by an FcγR-independent pathway.

Harmonization of Multiple SARS-CoV-2 Reference Materials Using the WHO IS (NIBSC 20/136): Results and Implications.

Background: There is an urgent need for harmonization between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology platforms and assays prior to defining appropriate correlates of protection and as well inform the development of new rapid diagnostic tests that can be used for serosurveillance as new variants of concern (VOC) emerge. We compared multiple SARS-CoV-2 serology reference materials to the WHO International Standard (WHO IS) to determine their utility as secondary standards, using an international network of laboratories with high-throughput quantitative serology assays. This enabled the comparison of quantitative results between multiple serology platforms. Methods: Between April and December 2020, 13 well-characterized and validated SARS-CoV-2 serology reference materials were recruited from six different providers to qualify as secondary standards to the WHO IS. All the samples were tested in parallel with the National Institute for Biological Standards and Control (NIBSC) 20/136 and parallel-line assays were used to calculate the relevant potency and binding antibody units. Results: All the samples saw varying levels of concordance between diagnostic methods at specific antigen-antibody combinations. Seven of the 12 candidate materials had high concordance for the spike-immunoglobulin G (IgG) analyte [percent coefficient of variation (%CV) between 5 and 44%]. Conclusion: Despite some concordance between laboratories, qualification of secondary materials to the WHO IS using arbitrary international units or binding antibody units per milliliter (BAU/ml) does not provide any benefit to the reference materials overall, due to the lack of consistent agreeable international unit (IU) or BAU/ml conversions between laboratories. Secondary standards should be qualified to well-characterized reference materials, such as the WHO IS, using serology assays that are similar to the ones used for the original characterization of the WHO IS.

Risk of conversion from mild cognitive impairment to dementia in low- and middle-income countries: A systematic review and meta-analysis.

Introduction: With no treatment for dementia, there is a need to identify high risk cases to focus preventive strategies, particularly in low- and middle-income countries (LMICs) where the burden of dementia is greatest. We evaluated the risk of conversion from mild cognitive ompairment (MCI) to dementia in LMICs. Methods: Medline, Embase, PsycINFO, and Scopus were searched from inception until June 30, 2020. The search was restricted to observational studies, conducted in population-based samples, with at least 1 year follow-up. There was no restriction on the definition of MCI used as long as it was clearly defined. PROSPERO registration: CRD42019130958. Results: Ten thousand six hundred forty-seven articles were screened; n = 11 retained. Of the 11 studies, most were conducted in China (n = 7 studies), with only two studies from countries classified as low income. A qualitative analysis of n = 11 studies showed that similar to high-income countries the conversion rate to dementia from MCI was variable (range 6 . 0%-44 . 8%; average follow-up 3 . 7 years [standard deviation = 1 . 2]). A meta-analysis of studies using Petersen criteria (n = 6 studies), found a pooled conversion rate to Alzheimer's disease (AD) of 23 . 8% (95% confidence interval = 15 . 4%-33.4%); approximately one in four people with MCI were at risk of AD in LMICs (over 3 . 0-5 . 8 years follow-up). Risk factors for conversion from MCI to dementia included demographic (e.g., age) and health (e.g., cardio-metabolic disease) variables. Conclusions: MCI is associated with high, but variable, conversion to dementia in LMICs and may be influenced by demographic and health factors. There is a notable absence of data from low-income settings and countries outside of China. This highlights the urgent need for research investment into aging and dementia in LMIC settings. Being able to identify those individuals with cognitive impairment who are at highest risk of dementia in LMICs is necessary for the development of risk reduction strategies that are contextualized to these unique settings.

COVID-19 Serology Control Panel Using the Dried-Tube Specimen Method.

The dried-tube specimen (DTS) procedure was used to develop the COVID-19 serology control panel (CSCP). The DTS offers the benefit of shipping materials without a cold chain, allowing for greater access without deterioration of material integrity. Samples in the panel were sourced from COVID-19 convalescent persons from March to May 2020. The immunoglobulin subtypes (total Ig, IgM, and IgG) and their respective reactivity to severe acute respiratory syndrome coronavirus 2 nucleocapsid, spike, and receptor-binding domain antigens of the samples were delineated and compared with the WHO International Standard to elucidate the exact binding antibody units of each CSCP sample and ensure the CSCP provides adequate reactivity for different types of serological test platforms. We distribute the CSCP as a kit with five coded tubes to laboratories around the world to be used to compare test kits for external quality assurance, for harmonizing laboratory testing, and for use as training materials for laboratory workers.

The Role of Cognitive Self-Report Measure Type in Predicting Cognitive Decline Among Older Adults: A Systematic Review.

Many types of items are used to measure self-reported cognition, resulting in heterogeneity across studies. Certain cognitive self-report measure types may be more predictive of future decline. Therefore, the purpose of this systematic review was to compare whether specific types of cognitive self-report measures better predict risk for cognitive decline over time when measures are directly compared within the same study. The PRISMA criteria guided the review. Eligibility criteria included: longitudinal studies, outcome of cognitive decline, at least 2 different cognitive self-report measures, and no cognitive impairment at baseline. Nineteen studies were included in the final review. A narrative synthesis of results was completed, resulting in 3 thematic groups of comparisons across self-reported measure types. Self-reported memory decline with worry and peer perceptions of memory were associated with the highest risk for cognitive decline. Future longitudinal investigations of self-reported cognitive problems should focus on using measures that may be most sensitive to predicting cognitive decline risk.

Pharmacokinetics of convalescent plasma therapy in a COVID-19 patient with X-linked Agammaglobulinemia.

Convalescent plasma (CP) has been the first line of defense against numerous infectious diseases throughout history. The COVID-19 pandemic created a need for a quick, easily accessible, and effective treatment for severe disease and CP was able to meet that immediate need. The utility of CP warrants a better understanding of the pharmacokinetics of CP treatment. Here we present the case of a COVID-19 patient with a genetic deficiency in antibody production who received CP as a part of the treatment regimen. In depth serological analysis revealed a surprising lack of SARS-CoV-2 specific antibodies and reduced serum IgG following CP infusion. Our study highlights plasma dilution and accelerated antibody clearance as potential mechanisms for the variable efficacy of CP therapy.

"He Just Doesn't Want to Get Out of the Chair and Do It": The Impact of Apathy in People with Dementia on Their Carers.

Apathy, defined as a lack of motivation, is a prevalent and persistent behavioural and psychological symptom of dementia. Limited research suggests that apathy is associated with increased carer burden, but there are no studies investigating carers' subjective experiences of apathy. This study aimed to fill this gap and explore the lived experience of apathy in dementia from the perspectives of the people with dementia and their carers. This article reports on the carers' perspectives. Six dyads of people with dementia and carers participated in semi-structured interviews, which were analysed using interpretative phenomenological analysis. Three superordinate themes were identified: (1) achieving a balance of conflicting emotions-the challenges of apathy led to feelings of guilt, acceptance, and frustration; (2) new roles imposed by caring, which involved taking on new responsibilities and promoting remaining interests of person with dementia; and (3) having a life of one's own-coping with apathy by talking to others, and spending time away from the caring role. This study highlighted that carers are caught in a struggle between wanting to involve the person with dementia in decisions and finding that they cannot if they want to overcome the hurdle of apathy. Implications of this study suggest that a wider understanding of apathy at a societal level could lead to the provision of a helpful forum for carers to share their experiences.

Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity.

Coronavirus disease 2019 (COVID-19) is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, including virus-neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveals that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by immunoglobulin G (IgG), with an IgG subclass ratio skewed toward elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2-specific antibody binding to the inflammatory receptor FcÉ£RIIIa. Based on these correlational studies, we propose that spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy.

The Experience of Apathy in Dementia: A Qualitative Study.

We aimed to explore and gain an understanding into how people with dementia experience apathy, and consequently suggest effective interventions to help them and their carers. Twelve participants (6 dyads of 6 people with dementia and their family carers) were recruited from "memory cafes" (meeting groups for people with dementia and their families), social groups, seminars, and patient and public involvement (PPI) meetings. People with dementia and their carers were interviewed separately and simultaneously. Quantitative data were collected using validated scales for apathy, cognition, anxiety, and depression. The interviews were semi-structured, focusing on the subjective interpretation of apathy and impacts on behaviour, habits, hobbies, relationships, mood, and activities of daily living. Interviews were recorded and transcribed. Transcripts were analysed using interpretative phenomenological analysis (IPA), which generated codes and patterns that were collated into themes. Four major themes were identified, three of which highlighted the challenging aspects of apathy. One described the positive aspects of the individuals' efforts to overcome apathy and remain connected with the world and people around them. This study is the first to illustrate the subjective experience of apathy in dementia, portraying it as a more complex and active phenomenon than previously assumed. Apathy and its effects warrant more attention from clinicians, researchers, and others involved in dementia care.

Glycolipid-Containing Nanoparticle Vaccine Engages Invariant NKT Cells to Enhance Humoral Protection against Systemic Bacterial Infection but Abrogates T-Independent Vaccine Responses.

CD4+ T cells enable the critical B cell humoral immune protection afforded by most effective vaccines. We and others have recently identified an alternative source of help for B cells in mice, invariant NK T (iNKT) cells. iNKT cells are innate glycolipid-specific T cells restricted to the nonpolymorphic Ag-presenting molecule CD1d. As such, iNKT cells respond to glycolipids equally well in all people, making them an appealing adjuvant for universal vaccines. We tested the potential for the iNKT glycolipid agonist, α-galactosylceramide (αGC), to serve as an adjuvant for a known human protective epitope by creating a nanoparticle that delivers αGC plus antigenic polysaccharides from Streptococcus pneumoniae αGC-embedded nanoparticles activate murine iNKT cells and B cells in vitro and in vivo, facilitate significant dose sparing, and avoid iNKT anergy. Nanoparticles containing αGC plus S. pneumoniae polysaccharides elicits robust IgM and IgG in vivo and protect mice against lethal systemic S. pneumoniae However, codelivery of αGC via nanoparticles actually eliminated Ab protection elicited by a T-independent S. pneumoniae vaccine. This is consistent with previous studies demonstrating iNKT cell help for B cells following acute activation, but negative regulation of B cells during chronic inflammation. αGC-containing nanoparticles represent a viable platform for broadly efficacious vaccines against deadly human pathogens, but their potential for eliminating B cells under certain conditions suggests further clarity on iNKT cell interactions with B cells is warranted.

Stereotactic Body Radiotherapy for Palliation of Hematuria Arising From Urothelial Carcinoma of the Kidney in Unfavorable Surgical Candidates.

INTRODUCTION: Hematuria can be a distressing and debilitating complication of urothelial carcinoma (UC) of the kidney for patients who are not candidates for surgery or ureteroscopic ablation. We retrospectively assessed the efficacy, tolerability, and safety of stereotactic body radiotherapy (SBRT) for controlling gross hematuria in this patient population. MATERIALS AND METHODS: Institutional Review Board (IRB)-approved review of the records, laboratory values, pathology, and imaging of 8 consecutive patients treated with SBRT over a 5-year period for uncontrolled gross hematuria caused by UC of the renal pelvis or calyces. RESULTS: Therapy was delivered in 3 to 5 treatments over 1 to weeks. Individual treatments lasted an average of 17.2 minutes. No patient experienced treatment-related pain, vomiting, or diarrhea. All enjoyed cessation of bleeding within a week of completing therapy. Hematuria recurred in 2 patients in 4 and 22 months. Of the patients who have not re-bled, 3 expired of metastatic disease or co-morbidities, and 3 remain alive up to 6 years posttreatment. Of patients who have survived longer than a year, creatinine has changed by -0.05 to +0.35, and estimated glomerular filtration rate has fallen by an average of 22%. No patient has required dialysis. CONCLUSIONS: SBRT appears to be an effective and well-tolerated means of palliating gross hematuria secondary to UC of the renal pelvis or calyces in patients who are unfavorable candidates for nephrectomy or ureteroscopic ablation. Treatment was associated with a moderate decline in renal function.