Serum S100A8/A9 and MMP-9 levels are elevated in systemic lupus erythematosus patients with cognitive impairment.

Objective: Cognitive impairment (CI) is one of the most common manifestations of Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). Despite its frequency, we have a limited understanding of the underlying immune mechanisms, resulting in a lack of pathways to target. This study aims to bridge this gap by investigating differences in serum analyte levels in SLE patients based on their cognitive performance, independently from the attribution to SLE, and exploring the potential for various serum analytes to differentiate between SLE patients with and without CI. Methods: Two hundred ninety individuals aged 18-65 years who met the 2019-EULAR/ACR classification criteria for SLE were included. Cognitive function was measured utilizing the adapted ACR-Neuropsychological Battery (ACR-NB). CI was defined as a z-score of ≤-1.5 in two or more domains. The serum levels of nine analytes were measured using ELISA. The data were randomly partitioned into a training (70%) and a test (30%) sets. Differences in the analyte levels between patients with and without CI were determined; and their ability to discriminate CI from non-CI was evaluated. Results: Of 290 patients, 40% (n=116) had CI. Serum levels of S100A8/A9 and MMP-9, were significantly higher in patients with CI (p=0.006 and p=0.036, respectively). For most domains of the ACR-NB, patients with CI had higher S100A8/A9 serum levels than those without. Similarly, S100A8/A9 had a negative relationship with multiple CI tests and the highest AUC (0.74, 95%CI: 0.66-0.88) to differentiate between patients with and without CI. Conclusion: In this large cohort of well-characterized SLE patients, serum S100A8/A9 and MMP-9 were elevated in patients with CI. S100A8/A9 had the greatest discriminatory ability in differentiating between patients with and without CI.

Management of acute fever in children: Consensus recommendations for community and primary healthcare providers in sub-Saharan Africa.

Fever is one of the most common reasons for unwell children presenting to pharmacists and primary healthcare practitioners. Currently there are no guidelines for assessment and management of fever specifically for community and primary healthcare workers in the sub-Saharan Africa region. This multidisciplinary consensus guide was developed to assist pharmacists and primary healthcare workers in sub-Saharan Africa to risk stratify and manage children who present with fever, decide when to refer, and how to advise parents and caregivers. Fever is defined as body temperature ≥ 37.5 °C and is a normal physiological response to illness that facilitates and accelerates recovery. Although it is often associated with self-limiting illness, it causes significant concern to both parents and attending healthcare workers. Clinical signs may be used by pharmacy staff and primary healthcare workers to determine level of distress and to distinguish between a child with fever who is at high risk of serious illness and who requires specific treatment, hospitalisation or specialist care, and those at low risk who could be managed conservatively at home. In children with warning signs, serious causes of fever that may need to be excluded include infections (including malaria), non-infective inflammatory conditions and malignancy. Simple febrile convulsions are not in themselves harmful, and are not necessarily indicative of serious infection. In the absence of illness requiring specific treatment, relief from distress is the primary indication for prescribing pharmacotherapy, and antipyretics should not be administered with the sole intention of reducing body temperature. Care must be taken not to overdose medications and clear instructions should be given to parents/caregivers on managing the child at home and when to seek further medical care.

The psychological burden of waiting for procedures and patient-centred strategies that could support the mental health of wait-listed patients and caregivers during the COVID-19 pandemic: A scoping review.

BACKGROUND: Waiting for procedures delayed by COVID-19 may cause anxiety and related adverse consequences. OBJECTIVE: To synthesize research on the mental health impact of waiting and patient-centred mitigation strategies that could be applied in the COVID-19 context. METHODS: Using a scoping review approach, we searched 9 databases for studies on waiting lists and mental health and reported study characteristics, impacts and intervention attributes and outcomes. RESULTS: We included 51 studies that focussed on organ transplant (60.8%), surgery (21.6%) or cancer management (13.7%). Most patients and caregivers reported anxiety, depression and poor quality of life, which deteriorated with increasing wait time. The impact of waiting on mental health was greater among women and new immigrants, and those of younger age, lower socio-economic status, or with less-positive coping ability. Six studies evaluated educational strategies to develop coping skills: 2 reduced depression (2 did not), 1 reduced anxiety (2 did not) and 2 improved quality of life (2 did not). In contrast, patients desired acknowledgement of concerns, peer support, and periodic communication about wait-list position, prioritization criteria and anticipated procedure date. CONCLUSIONS: Findings revealed patient-centred strategies to alleviate the mental health impact of waiting for procedures. Ongoing research should explore how to optimize the impact of those strategies for diverse patients and caregivers, particularly in the COVID-19 context. PATIENT OR PUBLIC CONTRIBUTION: Six patients and four caregivers waiting for COVID-19-delayed procedures helped to establish eligibility criteria, plan data extraction and review a draft and final report.

The impact of cytokine levels in young South African children with and without HIV-associated acute lower respiratory infections.

Altered host immune responses are considered to play a key role in the pathogenesis of acute lower respiratory infections (ALRI). The existing literature on cytokine responses in ALRI is largely focussed on adults from developed countries and there are few reports describing the role of cytokines in childhood ALRI, particularly in African or human immunodeficiency virus (HIV)-infected populations. To measure systemic cytokine levels in blood plasma from young South African children with and without ALRI and with and without HIV to determine associations between cytokine responses and disease status and respiratory viral identification. Blood plasma samples were collected from 106 hospitalized ALRI cases and 54 non-ALRI controls less than 2 years of age. HIV status was determined. Blood plasma concentrations of 19 cytokines, 7 chemokines, and 4 growth factors (epidermal growth factor, fibroblast growth factor-basic, hepatocyte growth factor, and vascular endothelial) were measured using The Human Cytokine 30-Plex Panel. Common respiratory viruses were identified by PCR. Mean cytokine concentrations for G-CSF, interferon (IFN)-γ, interleukin (IL)-5, and MCP-1 were significantly higher in ALRI cases than in nonrespiratory controls. Within the ALRI cases, several cytokines were higher in children with a virus compared with children without a virus. Mean cytokine concentrations for IFN-α, IFN-γ, IL-4, IL-5, IL-13, tumour necrosis factor-α, and MIP-1α were significantly lower in HIV-infected cases than in HIV-uninfected cases, while IP-10 and monokine induced by interferon-γ were significantly higher in HIV-infected cases than in HIV-uninfected cases. Certain cytokines are likely to play an important role in the host immune response to ALRI. HIV-infected children have impaired inflammatory responses to respiratory infections compared with HIV-uninfected children.

Vasomotor Symptoms Across the Menopause Transition: Differences Among Women.

Vasomotor symptoms (VMS) are the primary menopausal symptoms, occurring in up 80% of women and peaking around the final menstrual period. The average duration is 10 years, longer in women with an earlier onset. Compared with non-Hispanic white women, black and Hispanic women are more likely and Asian women are less likely to report VMS. Risk factors include greater body composition (in the early stage of menopausal transition), smoking, anxiety, depression, sensitivity to symptoms, premenstrual syndrome, lower education, and medical treatments, such as hysterectomy, oophorectomy, and breast cancer-related therapies. VMS patterns over time and within higher-risk subgroups are heterogeneous across women.

The lung microbiome in children with HIV-bronchiectasis: a cross-sectional pilot study.

BACKGROUND: Data on the lung microbiome in HIV-infected children is limited. The current study sought to determine the lung microbiome in HIV-associated bronchiectasis and to assess its association with pulmonary exacerbations. METHODS: A cross-sectional pilot study of 22 children (68% male; mean age 10.8 years) with HIV-associated bronchiectasis and a control group of 5 children with cystic fibrosis (CF). Thirty-one samples were collected, with 11 during exacerbations. Sputum samples were processed with 16S rRNA pyrosequencing. RESULTS: The average number of operational taxonomy units (OTUs) was 298 ± 67 vs. 434 ± 90, for HIV-bronchiectasis and CF, respectively. The relative abundance of Proteobacteria was higher in HIV-bronchiectasis (72.3%), with only 22.2% Firmicutes. There was no correlation between lung functions (FEV1% and FEF25/75%) and bacterial community (r = 0.154; p = 0.470 and r = 0.178; p = 0.403), respectively. Bacterial assemblage of exacerbation and non-exacerbation samples in HIV-bronchiectasis was not significantly different (ANOSIM, RHIV-bronchiectasis = 0.08; p = 0.14 and RCF = 0.08, p = 0.50). Higher within-community heterogeneity and lower evenness was associated with CF (Shannon-Weiner (H') = 5.39 ± 0.38 and Pielou's evenness (J) 0.79 ± 0.10 vs. HIV-bronchiectasis (Shannon-Weiner (H') = 4.45 ± 0.49 and Pielou's (J) 0.89 ± 0.03. CONCLUSION: The microbiome in children with HIV-associated bronchiectasis seems to be less rich, diverse and heterogeneous with predominance of Proteobacteria when compared to cystic fibrosis.

Long- and Short-term Exposure to Air Pollution and Inflammatory/Hemostatic Markers in Midlife Women.

BACKGROUND: Studies have reported associations between long-term air pollution exposures and cardiovascular mortality. The biological mechanisms connecting them remain uncertain. METHODS: We examined associations of fine particles (PM2.5) and ozone with serum markers of cardiovascular disease risk in a cohort of midlife women. We obtained information from women enrolled at six sites in the multi-ethnic, longitudinal Study of Women's Health Across the Nation, including repeated measurements of high-sensitivity C-reactive protein, fibrinogen, tissue-type plasminogen activator antigen, plasminogen activator inhibitor type 1, and factor VIIc (factor VII coagulant activity). We obtained residence-proximate PM2.5 and ozone monitoring data for a maximum five annual visits, calculating prior year, 6-month, 1-month, and 1-day exposures and their relations to serum markers using longitudinal mixed models. RESULTS: For the 2,086 women studied from 1999 to 2004, PM2.5 exposures were associated with all blood markers except factor VIIc after adjusting for age, race/ethnicity, education, site, body mass index, smoking, and recent alcohol use. Adjusted associations were strongest for prior year exposures for high-sensitivity C-reactive protein (21% increase per 10 µg/m³ PM2.5, 95% confidence interval [CI]: 6.6, 37), tissue-type plasminogen activator antigen (8.6%, 95% CI: 1.8, 16), and plasminogen activator inhibitor (35%, 95% CI: 19, 53). An association was also observed between year prior ozone exposure and factor VIIc (5.7% increase per 10 ppb ozone, 95% CI: 2.9, 8.5). CONCLUSIONS: Our findings suggest that prior year exposures to PM2.5 and ozone are associated with adverse effects on inflammatory and hemostatic pathways for cardiovascular outcomes in midlife women.

Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer's disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established. Also, the prevalence of CTE among athletes with multiple concussions is unknown. METHODS: We performed a consecutive case series brain autopsy study on six retired professional football players from the Canadian Football League (CFL) with histories of multiple concussions and significant neurological decline. RESULTS: All participants had progressive neurocognitive decline prior to death; however, only 3 cases had post-mortem neuropathological findings consistent with CTE. The other 3 participants had pathological diagnoses of AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Moreover, the CTE cases showed co-morbid pathology of cancer, vascular disease, and AD. DISCUSSION: Our case studies highlight that not all athletes with history of repeated concussions and neurological symptomology present neuropathological changes of CTE. These preliminary findings support the need for further research into the link between concussion and CTE as well as the need to expand the research to other possible causes of taupathy in athletes. They point to a critical need for prospective studies with good sampling methods to allow us to understand the relationship between multiple concussions and the development of CTE.

Positron emission tomography in the prediction of inflammation in children with human immunodeficiency virus related bronchiectasis.

There is a lack of objective tools to reliably diagnose exacerbations in bronchiectasis. The primary aim of this study was to assess the ability of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (¹8F-FDG PET/CT) to detect sites of active inflammation in children with human immunodeficiency virus (HIV)-related bronchiectasis with or without exacerbations. The secondary aim was to assess whether ¹8F-FDG-PET/CT results are in agreement with local and systemic inflammatory markers and markers of HIV disease activity. Forty-one children with HIV-related bronchiectasis underwent ¹8F-FDG PET/CT. Data on the presence of a clinical exacerbation were recorded. Serum was collected for CD4 count, HIV viral load, C-reactive protein (CRP) and cytokines IL-8, INF-γ and TNF-α. Induced sputum samples were processed for microbiological culture and for IL-8, INF-γ and TNF-α.Mean age of all children was 8.2 ± 2.2 years. Twelve subjects showed F-FDG lung uptake while six of them had an exacerbation. There was no difference in the ¹8F-FDG uptake in participants with or without an exacerbation (P=0.613). Fluorine- 18-FDG-PET had a good correlation with the presence of consolidation (P=0.01, OR=6.67). The mean CRP was higher in the subjects with (18)F-FDG uptake when compared to those without uptake (51.96 ± 95.12 vs. 13.26 ± 19.87), although this difference was not significant (P=0.09). In conclusion, the ¹8F-FDG-PET lung uptake technique could not reliably predict the presence of an exacerbation in children with HIV and bronchiectasis, and its diagnostic value was limited to identifying disease activity on the scan in acute pneumonia cases. Fluorine-18-FDG-PET had no significant correlation with CRP or with other inflammatory biomarkers and markers of HIV disease activity.

Early benefit of preserved cognitive function is not sustained at one-year after cardiac surgery: a longitudinal follow-up of the randomized controlled trial.

PURPOSE: Recently, we showed that processing of shed blood with a continuous-flow cell saver during cardiopulmonary bypass resulted in a clinically significant reduction in postoperative cognitive decline (POCD) six weeks after coronary artery bypass graft (CABG) surgery. The current study examined if the early benefit of reduced POCD was sustained in the same patient population at one-year follow-up. METHODS: One hundred seventy patients (cell saver group, n = 84; controls, n = 86) underwent neuropsychological testing at baseline and one year after surgery. The raw scores for each test were converted to Z-scores, and a combined Z-score of ten main variables was then calculated for each study group. RESULTS: Postoperative cognitive decline was present in 16 of 84 (19%) patients in the cell saver group (95% confidence interval [CI], 10.8 to 27.2) vs 15 of 86 (17.4%) patients in the control group (95% CI, 9.6 to 25.2) (P = 0.786). Six of the 15 patients in the control group with POCD at six weeks had the impairment at one year and five did not; four were lost to follow-up. Three of the six cell saver patients with POCD at six weeks still had impairment at one year, two did not, and one was not tested. Thirteen (15.4%) and nine (10.5%) patients in the cell saver and control groups, respectively, developed new POCD which was not evident at the six-week follow-up. CONCLUSIONS: The short-term preservation of cognitive function in elderly patients using the cell saver management strategy did not translate into a long-term benefit one year after CABG surgery. The presence of progressing cerebrovascular disease may be responsible for the long-term cognitive decline.

Intraperitoneal drug delivery for ovarian cancer: why, how, who, what, and when?

In 1996, intraperitoneal (IP) administration of cisplatin plus intravenous (i.v.) cyclophosphamide proved superior to both drugs given intravenously at the same doses--which, at the time, was the standard treatment in the United States. The IP 'option' was not adopted, however, because the standard treatment had shifted to i.v. cisplatin plus paclitaxel.Two additional phase III trials by the Gynecologic Oncology Group (GOG) comparing IP versus i.v. cisplatin, but including other variables, have shown similar superior effects of the IP route on outcome, but with toxicities-particularly local tolerance and neuropathy--increased. An ongoing trial by the GOG is again looking into an IP versus i.v. comparison, and introducing in one of the IP arms the substitution of IP carboplatin for IP cisplatin. All three arms of this trial contain bevacizumab (Avastin). Two other trials comparing i.v. versus IP administration of platinums or platinums and paclitaxel have just been launched, led by Japanese and Canadian investigators, respectively. While awaiting additional data on the ongoing debate over IP versus i.v. therapy, it is important that we consider issues concerning why the IP route may be relevant, how can one increase the safety of this route, and who should be treated and with what drugs, particularly when faced with a patient outside the clinical trials setting. The underlying hypothesis for use of IP therapy is based on the existence of a dose-effect relationship for platinum drugs in ovarian cancer. We review the known data on this relationship, and explore why interest in platinum drugs has become the central focus of ovarian cancer treatment.

Cardiovascular risk factor variation within a Hispanic cohort: SWAN, the Study of Women's Health Across the Nation.

OBJECTIVES: Hispanics have less favorable cardiovascular risk profiles relative to other groups, although little is known regarding variability in risk profiles according to country of origin. Our goal was to examine the association of cardiovascular risk factors with country of origin and acculturation in a cohort of middle-aged Hispanic women. SETTING: Baseline data for participants at the New Jersey Site of the Study of Women's Health Across the Nation (SWAN). PARTICIPANTS: 419 women, aged 42-52 years, comprising 142 non-Hispanic Whites and 277 Hispanic: Central American (n = 29), South American (n = 106), Puerto Rican (n = 56), Dominican (n = 42) and Cuban (n = 44). MAIN OUTCOME MEASURES: BMI, smoking, blood pressure, lipid profiles, and presence of hypertension, hyperlipidemia, diabetes and metabolic syndrome were compared using univariate and multivariable models. RESULTS: LDL and HDL varied significantly across Hispanic subgroups (overall P < or = .05). Prevalence of metabolic syndrome was greatest in Puerto Rican women (48.2% vs 40.0%, 35.0%, 13.9% and 29.3% in Central American, South American, Dominican and Cuban women, respectively, P = .016). Central American women were least likely to smoke (P < .05 vs Puerto Rican, Cuban and South American). Prevalence of hypertension and diabetes were similar across groups. Differences in lipids and metabolic syndrome were not explained by acculturation, financial strain, education, physical activity, smoking or dietary fat intake. CONCLUSIONS: There is significant heterogeneity in cardiovascular risk status among middle-aged Puerto Rican, Cuban, Dominican, Central American and South American women, not explained by acculturation or socioeconomic indicators. These differences may be important for targeting screening and preventive interventions.

Concerns of patients with allergic rhinitis: the Allergic Rhinitis Care Programme in South Africa.

BACKGROUND: The major reason for treating chronic rhinitis is to improve quality of life. Although primary symptoms cause morbidity in their own right, these symptoms are significantly aggravated by the impact of cognitive dysfunction and quality of life. OBJECTIVE: The Allergic Rhinitis Care Programme was initiated by the South African Allergic Rhinitis Working Group. An important task of this programme was to document health-related quality of life impairment amongst allergic rhinitis patients in South Africa. METHODS: A questionnaire, appropriate to South Africa, was distributed to patients. The questionnaire inquired about symptoms, quality of life, complications, trigger factors, associated allergic conditions, medication preference, medication adherence and concerns about the condition. RESULTS: 1181 people completed the questionnaire and returned the survey. Nasal congestion was identified as a common and frequent problem, while seasonality of symptoms was uncommon. Symptoms affected sleep in 76.6% of sufferers, and in at least a third this was every night. Over 1000 respondents felt miserable due to allergic rhinitis (85.2%). 63.1% indicated that they always followed instructions for taking rhinitis medication. A variety of perceived concerns around having and being treated for allergic rhinitis were identified, suggesting multiple reasons for non-adherence. CONCLUSIONS: We report symptom frequency and quality of life impairment for respondents who identify themselves as having allergic rhinitis. Since allergic rhinitis is, in the main, a doctor-diagnosed condition, this would suggest a significant problem with inappropriate, insufficient or incorrect therapy.

Continuous-flow cell saver reduces cognitive decline in elderly patients after coronary bypass surgery.

BACKGROUND: Cerebral microembolization during cardiopulmonary bypass may lead to cognitive decline after cardiac surgery. Transfusion of the unprocessed shed blood (major source of lipid microparticulates) into the patient during cardiopulmonary bypass is common practice to reduce blood loss and blood transfusion. Processing of shed blood with cell saver before transfusion may limit cerebral microembolization and reduce cognitive decline after surgery. METHODS AND RESULTS: A total of 226 elderly patients were randomly allocated to either cell saver or control groups. Anesthesia and surgical management were standardized. Epiaortic scanning of the proximal thoracic aorta was performed in all patients. Transcranial Doppler was used to measure cerebral embolic rates. Standardized neuropsychological testing was conducted 1 week before and 6 weeks after surgery. The raw scores for each test were converted to Z scores, and then a combined Z score of 10 main variables was calculated for both study groups. The primary analysis was based on dichotomous composite cognitive outcome with a 1-SD rule. Cognitive dysfunction was present in 6% (95% confidence interval, 1.3% to 10.7%) of patients in the cell saver group and 15% (95% confidence interval, 8% to 22%) of patients in the control group 6 weeks after surgery (P=0.038). The severity of aortic atheroma and cerebral embolic count were similar between the 2 groups. CONCLUSIONS: The present report demonstrates that processing of shed blood with cell saver results in clinically significant reduction in postoperative cognitive dysfunction after cardiac surgery. These findings emphasize the clinical importance of lipid embolization in contributing to postoperative cognitive decline in patients exposed to cardiopulmonary bypass.

Hepatitis C virus NS2/3 processing is required for NS3 stability and viral RNA replication.

The hepatitis C virus NS2/3 protease is responsible for cleavage of the viral polyprotein between nonstructural proteins NS2 and NS3. We show here that mutation of three highly conserved residues in NS2 (His(952), Glu(972), and Cys(993)) abrogates NS2/3 protease activity and that introduction of any of these mutations into subgenomic NS2-5B replicons results in complete inactivation of NS2/3 processing and RNA replication in both stable and transient replication assays. The effect of uncleaved NS2 on the various activities of NS3 was therefore explored. Unprocessed NS2 had no significant effect on the in vitro ATPase and helicase activities of NS3, whereas immunoprecipitation experiments demonstrated a decreased affinity of NS4A for uncleaved NS2/3 as compared with NS3. This subsequently resulted in reduced kinetics in an in vitro NS3 protease assay with the unprocessed NS2/3 protein. Interestingly, NS3 was still capable of efficient processing of the polyprotein expressed from a subgenomic replicon in Huh-7 cells in the presence of uncleaved NS2. Notably, we show that fusion with NS2 leads to the rapid degradation of NS3, whose activity is essential for RNA replication. Finally, we demonstrate that uncleaved NS2/3 degradation can be prevented by the addition of a proteasome inhibitor. We therefore propose that NS2/3 processing is a critical step in the viral life cycle and is required to permit the accumulation of sufficient NS3 for RNA replication to occur. The regulation of NS2/3 cleavage could constitute a novel mechanism of switching between viral RNA replication and other processes of the hepatitis C virus life cycle.