Single-cell Analysis of Subcutaneous Fat Reveals Pro-fibrotic Cells that Correlate with Visceral Adiposity in HIV.

CONTEXT: Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH. OBJECTIVE: We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART. METHODS: We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using HOMA2-IR. RESULTS: VAT volume was associated with HOMA2-IR (p < 0.001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC + fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (ρ=0.34-0.49, p < 0.05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)- and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism-associated genes. CONCLUSIONS: In PWH, greater VAT volume is associated with higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms.

Immunophenotypic predictors of influenza vaccine immunogenicity in pediatric hematopoietic cell transplant recipients.

ABSTRACT: Pediatric hematopoietic cell transplant (HCT) recipients exhibit poor serologic responses to influenza vaccination early after transplant. To facilitate the optimization of influenza vaccination timing, we sought to identify B- and T-cell subpopulations associated with influenza vaccine immunogenicity in this population. We used mass cytometry to phenotype peripheral blood mononuclear cells collected from pediatric HCT recipients enrolled in a multicenter influenza vaccine trial comparing high- and standard-dose formulations over 3 influenza seasons (2016-2019). We fit linear regression models to estimate relationships between immune cell subpopulation numbers before vaccination and prevaccination to postvaccination geometric mean fold rises in antigen-specific (A/H3N2, A/H1N1, and B/Victoria) serum hemagglutination inhibition antibody titers (28-42 days, and ∼6 months after 2 doses). For cell subpopulations identified as predictive of a response to all 3 antigens, we conducted a sensitivity analysis including time after transplant as an additional covariate. Among 156 HCT recipients, we identified 33 distinct immune cell subpopulations; 7 significantly predicted responses to all 3 antigens 28 to 42 days after a 2-dose vaccine series, irrespective of vaccine dose. We also found evidence that baseline absolute numbers of naïve B cells, naïve CD4+ T cells, and circulating T follicular helper cells predicted peak and sustained vaccine-induced titers irrespective of dose or timing of posttransplant vaccine administration. In conclusion, several B- and T-cell subpopulations predicted influenza vaccine immunogenicity in pediatric HCT recipients. This study provides insights into the immune determinants of vaccine responses and may help guide the development of tailored vaccination strategies for this vulnerable population.

Changes in subcutaneous white adipose tissue cellular composition and molecular programs underlie glucose intolerance in persons with HIV.

Introduction: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. Methods: We generated a comprehensive single-cell multi-omic SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH across a spectrum of metabolic health. Results: Glucose intolerance was associated with increased lipid-associated macrophages, CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue-resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Intercellular communication analysis demonstrated enhanced pro-inflammatory and pro-fibrotic signaling between immune cells and stromal cells in PWH with glucose intolerance compared with non-diabetic PWH. Lastly, while cell type-specific gene expression among PWH with diabetes was globally similar to HIV-negative individuals with diabetes, we observed substantially divergent intercellular communication pathways. Discussion: These findings suggest a central role of tissue-resident immune cells in regulating SAT inflammation among PWH with metabolic disease, and underscore unique mechanisms that may converge to promote metabolic disease.

Exploring maturity of electronic medical record use among allied health professionals.

BACKGROUND: Electronic medical records (EMRs) have the potential to improve and streamline the quality and safety of patient care. Harnessing the full benefits of EMR implementation depends on the utilisation of advanced features, defined as "mature usage." At present, little is known about the maturity of EMR usage by allied health professionals (AHPs). OBJECTIVE: To examine current maturity of EMR use by AHPs and explore perceived barriers to mature EMR utilisation and optimisation. METHOD: AHPs were recruited from three health services. Participants completed a 27-question electronic questionnaire based on the EMR Adoption Framework, which measures clinician EMR utilisation (0 = paper chart, 5 = theoretical maximum) across 10 EMR feature categories. Interviews were conducted with both clinicians and managers to explore the nature of current EMR utilisation and perceived facilitators and barriers to mature usage. RESULTS: Questionnaire responses were obtained from 192 AHPs. The majority of questions (74%) showed a mean score of <3, indicating a lack of mature EMR use. Pockets of mature usage were identified in the categories of health information, referrals and administration processes. Interviews with 18 clinicians and managers revealed barriers to optimisation across three themes: (1) limited understanding of EMR opportunities; (2) complexity of the EMR change process and (3) end-user and environmental factors. CONCLUSION: Mature usage across EMR feature categories of the EMR Adoption Framework was low. However, questionnaire and qualitative interview data suggested pockets of mature utilisation. IMPLICATIONS: Achieving mature allied health EMR use will require strategies implemented at the clinician, EMR support, and service levels.

Failure to decrease HbA1c levels following TB treatment is associated with elevated Th1/Th17 CD4+ responses.

Introduction: The rising global burden of metabolic disease impacts the control of endemic tuberculosis (TB) in many regions, as persons with diabetes mellitus (DM) are up to three times more likely to develop active TB than those without DM. Active TB can also promote glucose intolerance during both acute infection and over a longer term, potentially driven by aspects of the immune response. Identifying patients likely to have persistent hyperglycemia following TB treatment would enable closer monitoring and care, and an improved understanding of underlying immunometabolic dysregulation. Methods: We measured the relationship of plasma cytokine levels, T cell phenotypes and functional responses with the change in hemoglobin A1c (HbA1c) before and after treatment of pulmonary TB in a prospective observational cohort in Durban, South Africa. Participants were stratified based on stable/increased HbA1c (n = 16) versus decreased HbA1c (n = 46) levels from treatment initiation to 12 month follow-up. Results: CD62 P-selectin was up- (1.5-fold) and IL-10 downregulated (0.85-fold) in plasma among individuals whose HbA1c remained stable/increased during TB treatment. This was accompanied by increased pro-inflammatory TB-specific IL-17 production (Th17). In addition, Th1 responses were upregulated in this group, including TNF-α production and CX3CR1 expression, with decreased IL-4 and IL-13 production. Finally, the TNF-α+ IFNγ+ CD8+ T cells were associated with stable/increased HbA1c. These changes were all significantly different in the stable/increased HbA1c relative to the decreased HbA1c group. Discussion: Overall, these data suggest that patients with stable/increased HbA1c had an increased pro-inflammatory state. Persistent inflammation and elevated T cell activity in individuals with unresolved dysglycemia following TB treatment may indicate failure to fully resolve infection or may promote persistent dysglycemia in these individuals, and further studies are needed to explore potential mechanisms.

Distinct CD3 + CD14 + T Cell-Monocytes are dynamic complexes that harbor HIV and are increased with glucose intolerance.

Persistent systemic inflammation in persons with HIV (PWH) is accompanied by an increased risk of metabolic disease. Yet, changes in the innate and adaptive immune system in PWH who develop metabolic disease remain poorly defined. Using unbiased approaches, we show that PWH with prediabetes/diabetes have a significantly higher proportion of circulating CD14 + monocytes complexed to T cells. The complexed CD3 + T cells and CD14 + monocytes demonstrate functional immune synapses, increased expression of proinflammatory cytokines, and greater glucose utilization. Furthermore, these complexes harbor more latent HIV DNA compared to CD14 + monocytes or CD4 + T cells. Our results demonstrate that circulating CD3 + CD14 + T cell-monocyte pairs represent functional dynamic cellular interactions that likely contribute to inflammation and, in light of their increased proportion, may have a role in metabolic disease pathogenesis. These findings provide an incentive for future studies to investigate T cell-monocyte immune complexes as mechanistic in HIV cure and diseases of aging. Highlights: Persons with HIV and diabetes have increased circulating CD3 + CD14 + T cell-monocyte complexes. CD3 + CD14 + T cell-monocytes are a heterogenous group of functional and dynamic complexes. We can detect HIV in T cell-monocyte complexes. The proportion of CD3 + CD14 + T cell-monocyte complexes is positively associated with blood glucose levels and negatively with plasma IL-10 and CD4 + T regulatory cells.

Tracking of activated cTfh cells following sequential influenza vaccinations reveals transcriptional profile of clonotypes driving a vaccine-induced immune response.

Introduction: A vaccine against influenza is available seasonally but is not 100% effective. A predictor of successful seroconversion in adults is an increase in activated circulating T follicular helper (cTfh) cells after vaccination. However, the impact of repeated annual vaccinations on long-term protection and seasonal vaccine efficacy remains unclear. Methods: In this study, we examined the T cell receptor (TCR) repertoire and transcriptional profile of vaccine-induced expanded cTfh cells in individuals who received sequential seasonal influenza vaccines. We measured the magnitude of cTfh and plasmablast cell activation from day 0 (d0) to d7 post-vaccination as an indicator of a vaccine response. To assess TCR diversity and T cell expansion we sorted activated and resting cTfh cells at d0 and d7 post-vaccination and performed TCR sequencing. We also single cell sorted activated and resting cTfh cells for TCR analysis and transcriptome sequencing. Results and discussion: The percent of activated cTfh cells significantly increased from d0 to d7 in each of the 2016-17 (p < 0.0001) and 2017-18 (p = 0.015) vaccine seasons with the magnitude of cTfh activation increase positively correlated with the frequency of circulating plasmablast cells in the 2016-17 (p = 0.0001) and 2017-18 (p = 0.003) seasons. At d7 post-vaccination, higher magnitudes of cTfh activation were associated with increased clonality of cTfh TCR repertoire. The TCRs from vaccine-expanded clonotypes were identified and tracked longitudinally with several TCRs found to be present in both years. The transcriptomic profile of these expanded cTfh cells at the single cell level demonstrated overrepresentation of transcripts of genes involved in the type-I interferon pathway, pathways involved in gene expression, and antigen presentation and recognition. These results identify the expansion and transcriptomic profile of vaccine-induced cTfh cells important for B cell help.

CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV.

Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1+, GPR56+, and CD57+/- T cells (termed CGC+) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid ß-oxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+. Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals.

Identifying opportunities to optimise the electronic medical record for allied health professionals: a concept mapping study.

Objective To utilise a concept mapping process to identify key opportunities for electronic medical record (EMR) optimisation for allied health professionals (AHPs). Methods A total of 26 participants (allied health managers, clinicians and healthcare consumers) completed the concept mapping process, which included generating statements, and then subsequently sorting all statements into groups, and also ranking each statement for importance and changeability (0 = not important/changeable, 4 extremely important/changeable). Multivariate analysis and multidimensional scaling were then used to identify core priorities for digital optimisation. Results Participants generated 98 discrete statements that were grouped into 13 conceptual clusters. Of these, 36 statements were subsequently determined to fall within the 'green zone' on the Go-Zone plot of importance and changeability (changeability ≥2.44, importance ≥2.79), and formed the set of key optimisation priorities. Clusters with the most items in the Go-Zone plot were 'training and business rules ' and 'service statistics .' Conclusion Concept mapping facilitated identification of 36 key optimisation priorities considered both changeable and important to assist EMR optimisation for AHPs. Addressing these priorities requires action related to end-user skills and training, EMR system capacity, and streamlining of governance and collaboration for the optimisation process.

Utilising Virtual Clinics and Orthoptists to Aid COVID-19 Service Recovery in Adult Strabismus.

Background: The Sheffield Virtual Adult Strabismus service was already well established and was put to real-time trial during the COVID-19 pandemic. We describe a multi-disciplinary adaptation to offer a safe and effective service delivery. We evaluate the efficacy of a virtual strabismus service during the pandemic to meet clinical demand, streamline patient care, balance care delivery and optimise medical input. Methods: Prospective data analysis from the virtual strabismus clinics dated from January 2015 to November 2021. All information was captured at first consultation with comprehensive specialist Orthoptic assessment and imaging; then reviewed by a strabismus consultant for clinical outcome. Management was discussed virtually with patients by the consultant. Results: Pre-COVID (January 2015-March 2020), 1,068 appointments were offered. During COVID (July 2020-November 2021), 442 appointments were offered. Clinical capacity increased to meet demand. Within two months of service re-opening, first appointment mean waiting time reduced below 18 weeks. During COVID, 24.6% of patients were listed for procedures after first visit. Face-to-face medical follow up for non-surgical cases reduced from 47.7% to 16.3%. Conclusion: Virtual strabismus services offer flexible, safe and effective ways to meet fluctuating referral patterns and maximise limited time and resources. Orthoptists are uniquely essential and highly valued keyworkers to conservatively manage non-surgical strabismus. Utilising the skillsets of Allied Health Professionals (AHPs) across the NHS is crucial to sustain ongoing clinical demand and patient care.

Conservative and Surgical Management of Unilateral and Bilateral Internuclear Ophthalmoplegia (INO)-A Retrospective Analysis.

Aim: To report the outcomes of the natural progression and ophthalmic treatment of patients reviewed in a tertiary hospital trust with unilateral or bilateral internuclear ophthalmoplegia. Method: A retrospective case note analysis was performed and 33 patients diagnosed with unilateral or bilateral internuclear ophthalmoplegia (INO) were identified. The diagnosis, aetiology, presence of diplopia, ophthalmic management options and progression were recorded and analysed. This included both conservative and surgical management. Results: The most common aetiologies of INO within this cohort were stroke/ischaemic (69.7%) and multiple sclerosis (MS) (30.3%). Unilateral INO was more prevalent than bilateral INO, with 20 cases (60.6%) compared to 13 cases (39.4%), respectively. A higher proportion of unilateral INO were attributed to stroke (90%) whilst a higher proportion of bilateral INO were attributed to MS (61.5%). The most prescribed management at primary assessment was occlusion (45.5%) and prisms (24.2%). Some patients required no orthoptic intervention (30.3%). Two patients had surgical management of strabismus secondary to bilateral INO. Conclusion: Occlusion was the most common form of management for symptomatic relief of diplopia. Patients who presented at the first visit with no symptoms were unlikely to need any orthoptic intervention. Of the two patients who went on to require surgical intervention, restoration of binocular single vision (BSV) was achieved post-operatively with the use of a Fresnel prism. However, the differences in both surgical technique and number of surgeries required make this difficult to generalise. Additional research is needed to further explore the surgical management of INO.

Humoral and cellular immune responses to the SARS-CoV-2 BNT162b2 vaccine among a cohort of solid organ transplant recipients and healthy controls.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased morbidity and mortality in solid organ transplant (SOT) recipients. Despite exclusion from SARS-CoV-2 vaccine clinical trials, these individuals were identified as high-risk and prioritized for vaccination in public health guidelines. METHODS: We prospectively evaluated humoral and cellular immune responses to two doses of the SARS-CoV-2 mRNA vaccine, BNT162b2, in 56 SOT recipients and 26 healthy controls (HCs). Blood specimens collected from participants prior to each dose and following the second dose were tested for SARS-CoV-2-specific antibodies, as well as CD4+ and CD8+ T-cell responses. RESULTS: SOT recipients demonstrated lower mean anti-SARS-CoV-2 antibody levels compared to HCs after each dose, and only 21.6% achieved an antibody response after the second dose within the range of HC responses. Similarly, the percentage of responsive CD4+ and CD8+ T cells in SOT recipients was lower than in HCs. While most HCs showed notable humoral and cellular responses, responses were less concordant in SOT recipients, with some showing evidence of either humoral or cellular response, but not both. CONCLUSION: Humoral and cellular immune responses to the BNT162b2 vaccine are markedly reduced in SOT recipients as compared to HCs, suggesting that SOT recipients may benefit from more tailored regimens such as higher dose and/or additional vaccinations.

The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells.

Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.

Single-cell analysis shows that adipose tissue of persons with both HIV and diabetes is enriched for clonal, cytotoxic, and CMV-specific CD4+ T cells.

Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69+ CD4+ T cells. Adipose tissue CD69+ and C-G-C+ CD4+ T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C+ CD4+ T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C+ CD4+ T cells in adipose tissue of persons with HIV.

Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV.

While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4+ T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m2, is positively correlated with greater CD4+ T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4+ T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4+ T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4+ T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4+ T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4+ T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4+ T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4+ T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4+ T reconstitution in PLWH initiating ART.

Long-term labeling of microelectrode tracks with fluorescent latex microspheres.

BACKGROUND: After physiological recordings are performed in behaving animals, it is valuable to identify microelectrode tracks in histological sections so that neuronal responses can be correlated with brain anatomy. However, no good method currently exists for long-term labeling, so that microelectrode tracks can be recovered months or even years after recording sessions. NEW METHOD: Penetrations were made into the brains of mice with microelectrodes coated with fluorescent dyes packaged into 0.2 µm polystyrene microspheres, followed by survival periods of 3 days, 2, 4, or 6 months. Sections were examined by fluorescence microscopy before and after cytochrome oxidase histochemistry to identify microelectrode tracks. RESULTS: After all 4 survival periods, 0.2 µm fluorescent microspheres clearly marked the tracks of microelectrode penetrations. COMPARISON WITH EXISTING METHODS: Fluorescent microspheres label microelectrode penetrations for longer than do fluorescent lipophilic dyes, such as FM 1-43FX. The label appears punctate, and resistant to degradation, because it is protected by the barrier of the polystyrene micro-container. CONCLUSIONS: Coating of microelectrodes with fluorescent microspheres allows one to identify the penetration track in histological sections half a year later. This technique may be useful when electrophysiological recording sessions are being carried out in behaving animals, with plans to identify electrode tracks in histological sections many months later.

Vertical Optokinetic Stimulation Induces Diagonal Eye Movements in Patients with Idiopathic Infantile Nystagmus.

Purpose: In patients with early ocular misalignment and nystagmus, vertical optokinetic stimulation reportedly increases the horizontal component of the nystagmus present during fixation, resulting in diagonal eye movements. We tested patients with infantile nystagmus syndrome but normal ocular alignment to determine if this crosstalk depends on strabismus. Methods: Eye movements were recorded in seven patients with infantile nystagmus. All but one patient had normal ocular alignment with high-grade stereopsis. Nystagmus during interleaved trials of right, left, up, and down optokinetic stimulation was compared with waveforms recorded during fixation. Six patients with strabismus but no nystagmus were also tested. Results: In infantile nystagmus syndrome, horizontal motion evoked a mostly jerk nystagmus with virtually no vertical component. A vertical optokinetic pattern produced nystagmus with a diagonal trajectory. It was not simply a combination of a vertical component from optokinetic stimulation and a horizontal component from the subject's congenital nystagmus, rather in six of seven patients, the slow-phase velocity of the horizontal component during vertical optokinetic stimulation differed from that recorded during fixation. In the six strabismus patients without nystagmus, responses to vertical optokinetic stimulation were normal. Conclusions: In patients with congenital motor nystagmus, a vertical noise pattern drives a diagonal nystagmus. This appears to arise because of crosstalk between the vertical and horizontal components of the optokinetic system. This abnormal response to vertical stimulation is not caused by strabismus because it occurs in patients with infantile nystagmus without strabismus. Moreover, it is absent in patients with strabismus and no spontaneous nystagmus.

Blind testing of shoreline evolution models.

Beaches around the world continuously adjust to daily and seasonal changes in wave and tide conditions, which are themselves changing over longer time-scales. Different approaches to predict multi-year shoreline evolution have been implemented; however, robust and reliable predictions of shoreline evolution are still problematic even in short-term scenarios (shorter than decadal). Here we show results of a modelling competition, where 19 numerical models (a mix of established shoreline models and machine learning techniques) were tested using data collected for Tairua beach, New Zealand with 18 years of daily averaged alongshore shoreline position and beach rotation (orientation) data obtained from a camera system. In general, traditional shoreline models and machine learning techniques were able to reproduce shoreline changes during the calibration period (1999-2014) for normal conditions but some of the model struggled to predict extreme and fast oscillations. During the forecast period (unseen data, 2014-2017), both approaches showed a decrease in models' capability to predict the shoreline position. This was more evident for some of the machine learning algorithms. A model ensemble performed better than individual models and enables assessment of uncertainties in model architecture. Research-coordinated approaches (e.g., modelling competitions) can fuel advances in predictive capabilities and provide a forum for the discussion about the advantages/disadvantages of available models.

Postcolonoscopy Appendicitis: A Review of 57 Cases.

The purpose of this study is to review the cases of postcolonoscopy appendicitis (PCA) reported in the literature. A comprehensive search using PubMed, EMBASE, Scopus, and Google Scholar identified 57 cases. The median age at presentations of PCA was 55 years. PCAs typically occurred during the first 24 hours after colonoscopy, and the majority developed after diagnostic colonoscopy. Clinical presentations were similar to those with common acute appendicitis, though with a high perforation rate. Most patients were correctly diagnosed using ultrasound or computed tomography scan. Treatment included open appendicectomy, laparoscopic appendicectomy or cecotomy, radiologic drainage of the abscess, nonoperative treatment with antibiotics. In addition to barotrauma, fecalith impaction into the appendiceal lumen, direct trauma to the appendiceal orifice, and underlying ulcerative colitis, a pre-existing subclinical disease of the appendix seems to play an important role in the pathogenesis. For PCA, timely diagnosis and management are crucial to attain a satisfactory outcome.

Adipose Tissue in Persons With HIV Is Enriched for CD4+ T Effector Memory and T Effector Memory RA+ Cells, Which Show Higher CD69 Expression and CD57, CX3CR1, GPR56 Co-expression With Increasing Glucose Intolerance.

Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4+ and CD8+ T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic (n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic (n = 8; FBG = 100-125 mg/dL) and diabetic (n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls (n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (TNai) CD45RO-CCR7+, effector memory (TEM) CD45RO+CCR7-, central memory (TCM) CD45RO+CCR7+, and effector memory revertant RA+(TEMRA) CD45RO-CCR7- CD4+ and CD8+ T cells were measured by flow cytometry. CD4+ and CD8+ TEM and TEMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4+ and CD8+ memory subsets were similar across metabolic status categories in the PLWH, but CD4+ T cell expression of the CD69 early-activation and tissue residence marker, particularly on TEM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69lo TEM and TEMRA cells co-expressing CD57, CX3CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX3CR1 and GPR56 markers indicate these TEM and TEMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4+ and CD8+ memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.