Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal Abs generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, HA stalk-biased, response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies.

SUMMARYT cell subsets in the gut mucosa are disliiicl populations and their imbalance in HIV has specilic implications in infection. Alterations in T cell subsets in duodenal biopsies vvere investigated in 17 asymptomatic HIV patients, 24 AIDS patienis and 10 controls wilh non-ulcer dyspepsia. Immunohistochemislry and immunofluorescence using MoAbs to CD3, CD4, CDS, CD68, CD45RA, CD45RO and gp 120 were performed on frozen sections. In the lamina propria, there was a significant depletion of CD4'^ cells at all stages of HIV, bul the density of CDS lamina propria cells was increased. Iniraepithelial lymphocytes were decreased in AIDS patients. There was a signilieunl correlation between cellular density and mucosal CD3 ' lymphocytes, and between mucosal CD3' and CDS' lymphocytes. Allhotigh mucosal CD4,CD45RO* 'memory" cells were decreased, CD8,CD45RO^ 'memory cells were increased. MucosatCD4' lymphocyte depletion occurred early in HIV, and thus their role in mueosal proleciion against opportunistic infeetion should be revised. Mucosal CD8' lymphocytes initially increased, but decreased when CD4 blood counts were depicted, perhaps contributing to loss ofhost protection against infection. Intraepitheiial lymphocyte depletion may also eontHbute lo opportunisiic infeciion.

The study investigated the oral absorption of two antifungal agents, fluconazole and itraconazole, under conditions of low intragastric acidity. Twelve healthy male volunteers received each of 4 dosing regimens : 200 mg itraconazole alone, 200 mg itraconazole and famotidine, 100 mg fluconazole alone, and 100 mg fluconazole and farnotidine. Two oral doses of 40 mg famotidine were used to induce hypochlorhydria.Serum drug concentrations were measured (by high pressure liquid chromatography) for 48 h after a single dose of each anti-fungal agent. When dosed with famotidine, there was a significant 52.9 % decrease of the peak intraconazole concentration (P < 0.01 l), and a significant 5 1.1 % decrease of the 48-h integrated serum intraconazole concentration (P = 0.005). Famotidine-induced hypochlorhydria did not affect the absorption of fluconazole.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterised neurological syndromes involving the peripheral and central nervous system (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with central nervous system inflammation (encephalitis and acute disseminated encephalomyelitis) (14800pg/mL [400, 32400]), compared to those with encephalopathy (1410pg/mL [756, 1446], peripheral syndromes (GBS) (740pg/mL [507, 881]) and controls (872pg/mL [654,1200]). Serum neurofilament light levels were elevated across patients hospitalised with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.

The relationships among intestinal permeability, advancing human immunodeficiency virus (HIV) infection, and the presence of diarrhoea or weight loss were investigated in 51 HIV patients and 20 healthy controls. Ten patients with untreated coeliac disease were also investigated for comparison. Fasting subjects drank an isosmolar test solution containing D-xylose, lactulose (LL), L-rhamnose (R) and 3-O-methyl-D-glucose. Urine was collected for 5 h, test sugar content being subsequently measured by thin-layer chromatography for the dosing sugars. Intestinal permeability (LL/R excretion ratio) and recovery of D-xylose and 3-O-methyl-D-glucose in urine were abnormal in patients with HIV disease, and especially those with diarrhoea, as they were in coeliac disease. Patients with coeliac disease and HIV disease, especially when diarrhoea and/or weight loss were present, had significantly reduced 5-h excretion of L-rhamnose, D-xylose, and 3-O-methyl-D-glucose. These data indicate that abnormal permeability and reduced intestinal absorption capacity are common in HIV patients, occur at all stages of HIV disease, especially in the presence of diarrhoea, and, with the exception of lactulose permeation, are relatively similar to the alterations seen in coeliac disease.

Twenty-four patients with proven systemic sclerosis and with symptoms suggestive of malabsorption (i.e. chronic diarrhoea and weight loss) were investigated for small bowel bacterial overgrowth. Of the patients selected, six were suffering from the diffuse form of the disease. Jejunal aspiration was performed in all patients, and in nine normal volunteers. A specially designed double-lumen sterile catheter was used for this purpose and was introduced via a gastroscope. Twenty of these patients underwent a glucose hydrogen breath test. Eight patients (33%) had significant bacterial counts: > 10(5) colony forming units per ml (cfu/ml) of jejunal fluid. Less than 10(2) cfu/ml were found in the jejunal fluid from the nine control subjects. Glucose hydrogen breath testing was positive in seven patients, all of whom had significant jejunal bacterial growth. Diarrhoea rather than weight loss was shown to be the symptom which correlated best with the presence of bacterial overgrowth. Ciprofloxacin was used in six patients whose diarrhoeal symptoms ceased dramatically within 48 h of commencing the antibiotic. Trimethoprim produced a partial response despite bacterial sensitivity. A disadvantage of the hydrogen breath test is that subsequent antibacterial therapy cannot be specific, as bacterial species, antibiotic sensitivity and resistance are unknown. Systemic sclerosis involving the small intestine in the past has been said to more prevalent in patients with diffuse disease, whereas this study showed a preponderance of patients with long-standing limited cutaneous systemic sclerosis and small bowel involvement.

SummaryBackgroundRifaximin reduces the risk of overt hepatic encephalopathy (HE) and is associated with significant reductions in hospitalisations and 30‐day readmissions.AimTo examine the outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.MethodsPatient records of those listed for liver transplantation over a 2‐year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment.ResultsOf the 622 patients listed for transplantation, 101 had HE. Sixty‐six patients were treated with rifaximin and 35 were naïve at listing. The use of concurrent lactulose was not significantly different between groups. Median MELD score was similar (15 [14‐16)] rifaximin‐treated and 16 [14‐18] rifaximin‐naïve). Patients on the waiting list treated with rifaximin had reduced all‐cause admissions, episodes of spontaneous bacterial peritonitis and variceal bleeding. Mean length of stay was 9 days (95% CI 6‐12) in the rifaximin‐treated group vs 14 (95% CI 7‐21) in the rifaximin‐naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in average days to readmission (adjusted effect estimate 71, 95% CI 3‐140 days) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89‐0.93).ConclusionRifaximin prescribed for HE in patients listed for liver transplantation improved outcomes with significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and variceal bleeding.

The nature of the immunoglobulin light chain affects peripheral B cell tolerance and autoreactivity.