Aspirin (acetylsalicylic acid)-induced asthma (AIA) consists of the clinical triad of asthma, chronic rhinosinusitis with nasal polyps, and precipitation of asthma and rhinitis attacks in response to aspirin and other NSAIDs. The prevalence of the syndrome in the adult asthmatic populations is approximately 4-10%. Respiratory disease in these patients may be aggressive and refractory to treatment. The aetiology of AIA is complex and not fully understood, but most evidence points towards an abnormality of arachidonic acid (AA) metabolism. Cyclo-oxygenase (COX), the rate-limiting enzyme in AA metabolism, exists as two main isoforms. COX-1 is the constitutive enzyme responsible for synthesis of protective prostanoids, whereas COX-2 is induced under inflammatory conditions. A number of theories regarding its pathogenesis have been proposed. The shunting hypothesis proposes that inhibition of COX-1 shunts AA metabolism away from production of protective prostanoids and towards cysteinyl leukotriene (cys-LT) biosynthesis, resulting in bronchoconstriction and increased mucus production. The COX-2 hypothesis proposes that aspirin causes a structural change in COX-2 that results in the generation of products of the lipoxygenase pathway. It is speculated that this may result in the formation of mediators that cause respiratory reactions in AIA. Related studies provide evidence for abnormal regulation of the lipoxygenase pathway, demonstrating elevated levels of cys-LTs in urine, sputum and peripheral blood, before and following aspirin challenge in AIA patients. These studies suggest that cys-LTs are continually and aggressively synthesised before exposure to aspirin and, during aspirin-induced reactions, acceleration of synthesis occurs. A genetic polymorphism of the LTC4S gene has been identified consisting of an A to C transversion 444 nucleotides upstream of the first codon, conferring a relative risk of AIA of 3.89. Furthermore, carriers of the C444 allele demonstrate a dramatic rise in urinary LTE(4) following aspirin provocation, and respond better to the cys-LT antagonist pranlukast than A444 homozygotes.AIA patients have an aggressive form of disease, and treatment should include combination therapy with inhaled corticosteroids, beta(2)-adrenoceptor agonists and LT modifiers. Furthermore, recently developed inhibitors of COX-2 may be safer in patients with AIA.

In swine, the most common and severe enterotoxigenic Escherichia coli (ETEC) infections are caused by strains that express K88 (F4)(+) fimbriae, heat-labile enterotoxin (LT), heat-stable enterotoxin b (STb), and enteroaggregative E. coli heat-stable toxin 1. Previous studies based on a design that involved enterotoxin genes cloned into a nontoxigenic fimbriated strain have suggested that LT but not STb plays an important role in dehydrating diarrheal disease in piglets <1 week old and also enhances bacterial colonization of the intestine. In the present study, we compared these two toxins in terms of importance for piglets >1 week old with a study design that involved construction of isogenic single- and double-deletion mutants and inoculation of 9-day-old F4ac receptor-positive gnotobiotic piglets. Based on the postinoculation percent weight change per h and serum bicarbonate concentrations, the virulence of the STb(-) mutant (Delta estB) did not significantly differ from that of the parent. However, deletion of the LT genes (Delta eltAB) in the STb(-) mutant resulted in a complete abrogation of weight loss, dehydration, and metabolic acidosis in inoculated pigs, and LT complementation restored the virulence of this strain. These results support the hypothesis that LT is a more significant contributor than STb to the virulence of F4(+) ETEC infections in young F4ac receptor-positive pigs less than 2 weeks old. However, in contrast to previous studies with gnotobiotic piglets, there was no evidence that the expression of LT enhanced the ability of the F4(+) ETEC strain to colonize the small intestine.

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT-specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti-IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

BACKGROUND

Oxygen consumption at peak exercise (peak VO2) is the most accurate index of aerobic capacity (AC), which reflects the physical condition of an individual and is currently considered the gold standard for cardiorespiratory fitness. Evaluation of peak VO2 to identify high-risk candidates for liver transplantation (LT) may represent an interesting approach. The aims of this study were (a) to describe AC and identify factors independently associated with peak VO2; (b) to analyze the prognostic value of peak VO2 in patients referred for preliminary evaluation of LT; and (c) to provide preliminary data on the influence of peak VO2 on length of hospitalization and the need for oxygen support after LT.

RESULTS

Peak VO2 was determined in patients referred for preliminary evaluation for LT. One hundred thirty-five candidates were included. More than half had severe alterations in peak VO2. Age, gender, model-for-end-stage liver disease (MELD) score, tobacco use, and hemoglobin were independently associated with peak VO2. Candidates with severe alterations in peak VO2 had a lower 1-year survival than others. Model-for-end-stage liver disease score and peak VO2 were independently associated with survival. In patients with a MELD above 17, those with severe alterations of peak VO2 AC had lower 1-year survival than the others. Among patients who underwent LT, those with severe impairment of peak VO2 showed a trend toward a higher mean length of hospitalization after LT and had significantly longer need for oxygen support.

CONCLUSIONS

Peak VO2 is severely impaired in candidates for LT and affects survival and post-LT course. Perioperative respiratory rehabilitation programs validated in lung and heart transplantation must be tested.

<A<em>b</em>stractText>Existing guidelines for management of type 2 dia<em>b</em>etes recommend a patient-centred approach to guide the choice of pharmacological agents. A<em>lt</em>hough glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhi<em>b</em>itors are increasingly used as second-line agents, direct comparisons <em>b</em>etween these treatments are insufficient. In the SUSTAIN 8 trial, we compared the efficacy and safety of semaglutide (a GLP-1 receptor agonist) with canagliflozin (an SGLT2 inhi<em>b</em>itor) in patients with type 2 dia<em>b</em>etes.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This was a dou<em>b</em>le-<em>b</em>lind, parallel-group, phase 3<em>b</em>, randomised controlled trial done at 111 centres in 11 countries. Eligi<em>b</em>le patients were at least 18 years old and had uncontrolled type 2 dia<em>b</em>etes (H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) 7·0-10·5% [53-91 mmol/mol]) on sta<em>b</em>le daily metformin therapy. Patients were randomly assigned (1:1) <em>b</em>y use of an interactive we<em>b</em> response system to su<em>b</em>cutaneous semaglutide 1·0 mg once weekly or oral canagliflozin 300 mg once daily. The primary endpoint was change from <em>b</em>aseline in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>), and the confirmatory secondary endpoint was change from <em>b</em>aseline in <em>b</em>odyweight, <em>b</em>oth at week 52. The primary analysis population included all randomly assigned patients, using on-treatment data collected <em>b</em>efore initiation of rescue medication. The safety analysis was done on a population that included all patients exposed to at least one dose of trial product. The trial was powered for H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) and <em>b</em>odyweight superiority under reasona<em>b</em>le assumptions. This trial is registered with ClinicalTrials.gov, NCT03136484.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between March 15, 2017, and Nov 16, 2018, 788 patients were randomly assigned to semaglutide 1·0 mg (394 patients) or canagliflozin 300 mg (394 patients). 739 patients completed the trial (367 in the semaglutide group and 372 in the canagliflozin group). From overall <em>b</em>aseline mean, patients receiving semaglutide had significantly greater reductions in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) and <em>b</em>odyweight than those receiving canagliflozin (H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) estimated treatment difference [ETD] -0·49 percentage points, 95% CI -0·65 to -0·33; -5·34 mmol/mol, 95% CI -7·10 to -3·57; p&<em>lt</em>;0·0001; and <em>b</em>odyweight ETD -1·06 kg, 95% CI -1·76 to -0·36; p=0·0029). Gastrointestinal disorders, most commonly nausea, were the most frequently reported adverse events with semaglutide, occurring in 184 (47%) of 392 patients; whereas infections and infestations (defined using the Medical Dictionary for Regulatory Activities, version 21.0), most commonly urinary tract infections, occurred more frequently with canagliflozin, in 136 (35%) of 394 patients. Premature treatment discontinuation <em>b</em>ecause of adverse events occurred in 38 (10%) of 392 patients with semaglutide and in 20 (5%) of 394 patients with canagliflozin. One fatal adverse event confirmed unlikely to <em>b</em>e caused <em>b</em>y treatment occurred in the semaglutide group.</p><p><div>(<em>b</em>)INTERPRETATION</<em>b</em>)</div>Once-weekly semaglutide 1·0 mg was superior to daily canagliflozin 300 mg in reducing H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) and <em>b</em>odyweight in patients with type 2 dia<em>b</em>etes uncontrolled on metformin therapy. These outcomes might guide treatment intensification choices.</p><A<em>b</em>stractText>Novo Nordisk.</A<em>b</em>stractText>

<p><div>(<em>b</em>)OBJECTIVE</<em>b</em>)</div>Gastrointestinal micro<em>b</em>iota may <em>b</em>e involved in <i>Helico<em>b</em>acter pylori-</i>associated gastric cancer development. The aim of this study was to explore the possi<em>b</em>le micro<em>b</em>ial mechanisms in gastric carcinogenesis and potential dys<em>b</em>iosis arising from <i>H. pylori</i> infection.</p><p><div>(<em>b</em>)DESIGN</<em>b</em>)</div>Deep sequencing of the micro<em>b</em>ial 16S ri<em>b</em>osomal RNA gene was used to investigate a<em>lt</em>erations in paired gastric <em>b</em>iopsies and stool samples in 58 su<em>b</em>jects with successful and 57 su<em>b</em>jects with failed anti-<i>H. pylori</i> treatment, relative to 49 <i>H</i><i>.</i><i>pylori</i> negative su<em>b</em>jects.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>In <i>H. pylori</i> positive su<em>b</em>jects, richness and Shannon indexes increased significantly (<em>b</em>oth p&<em>lt</em>;0.001) after successful eradication and showed no difference to those of negative su<em>b</em>jects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly a<em>lt</em>ered gastric genera after eradication. The com<em>b</em>ination of these genera into a Micro<em>b</em>ial Dys<em>b</em>iosis Index revealed that the dys<em>b</em>iotic micro<em>b</em>iota in <i>H. pylori</i> positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could <em>b</em>e reversed <em>b</em>y eradication. Strong coexcluding interactions <em>b</em>etween <i>Helico<em>b</em>acter</i> and <i>Fuso<em>b</em>acterium</i>, <i>Neisseria</i>, <i>Prevotella</i>, <i>Veillonella</i>, <i>Rothia</i> were found only in advanced gastric lesion patients, and were a<em>b</em>sent in normal/superficial gastritis group. Changes in faecal micro<em>b</em>iota included increased <i>Bifido<em>b</em>acterium</i> after successful <i>H. pylori</i> eradication and more upregulated drug-resistant functional orthologs after failed treatment.</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div><i>H. pylori</i> infection contri<em>b</em>utes significantly to gastric micro<em>b</em>ial dys<em>b</em>iosis that may <em>b</em>e involved in carcinogenesis. Successful <i>H. pylori</i> eradication potentially restores gastric micro<em>b</em>iota to a similar status as found in uninfected individuals, and shows <em>b</em>eneficial effects on gut micro<em>b</em>iota.</p>

The best therapy for hepatocellular carcinoma (HCC) is still debated. Hepatic resection (HR) is the treatment of choice for single HCC in Child A patients, whereas liver transplantation (LT) is usually reserved for Child B and C patients with single or multiple nodules. The aim of this study was to compare HR and LT for HCC within the Milan criteria on an intention-to-treat basis. Forty-eight patients were treated by LT and 38 by HR. The median time on the waiting list for transplantation was 118 days. The estimated overall survival was significantly higher (P = 0.005) in the LT group than in the HR one. The estimated freedom from recurrence was also significantly higher (P < 0.0001) for LT patients than for HR ones. Indeed, the probability of HCC recurrence after resection was higher than after transplantation achieving 31% and 76% for HR and 2% and 2% for LT at 3 and 5 years after surgery. Multivariate analysis confirmed that transplantation was superior to resection in terms of patient's survival and risk of HCC recurrence. We conclude that LT is superior to HR for small HCC in cirrhotic patients assuming that LT should be performed within 6-10 months after listing to reduce the dropouts for reasons of tumor progression.

<A<em>b</em>stractText>Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American foot<em>b</em>all. We hypothesized a dose-response relationship <em>b</em>etween duration of foot<em>b</em>all played and CTE risk and severity.</A<em>b</em>stractText><A<em>b</em>stractText>In a convenience sample of 266 deceased American foot<em>b</em>all players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of foot<em>b</em>all played with CTE pathological status and severity. We evaluated the a<em>b</em>ility of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection <em>b</em>ias.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of foot<em>b</em>all played was associated with having CTE (odds ratio [OR]=1.30 per year played, 95%CI, 1.19-1.41; P=3.8x10^-9 ) and with CTE severity (severe vs. mild; OR=1.14 per year played, 95%CI, 1.07-1.22; P=3.1x10^-4 ). Participants with CTE were 1/10^th as likely to have played &<em>lt</em>;4.5 years (negative likelihood ratio [LR]=0.102, 95%CI, 0.100-0.105) and were 10X as likely to have played >14.5 years (positive LR=10.2, 95%CI, 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were <em>b</em>oth related to <em>b</em>rain <em>b</em>ank selection across widely ranging scenarios.</p><A<em>b</em>stractText>The odds of CTE dou<em>b</em>le every 2.6 years of foot<em>b</em>all played. After accounting for <em>b</em>rain <em>b</em>ank selection, the magnitude of the relationship <em>b</em>etween years played and CTE status remained consistent. This article is protected <em>b</em>y copyright. All rights reserved.</A<em>b</em>stractText>

<p><div>(<em>b</em>)PURPOSE</<em>b</em>)</div>SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.(<em>b</em>)Experimental Design:</<em>b</em>) A discovery cohort and independent validation cohort were classified <em>b</em>y SMAD4 status. SMAD4 status and immune infi<em>lt</em>rate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infi<em>lt</em>rating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all <i>P</i> &<em>lt</em>; 0.04). SMAD4 loss was associated with worse RFS (<i>P</i> = 0.02). When stratified <em>b</em>y SMAD4 and immune infi<em>lt</em>rate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (<i>P</i> = 0.002 and <i>P</i> = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-<em>b</em>ased systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infi<em>lt</em>rate, as well as worse disease-specific survival.</p><A<em>b</em>stractText>Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infi<em>lt</em>rate, supporting its use as a prognostic marker in patients with colorectal cancer.</A<em>b</em>stractText>

The murine severe combined immunodeficiency (scid) mutation was used to assess whether the diabetogenic effects of multiple low-dose streptozocin (MD-STZ) administration required the presence of functional T-cells. An STZ dose as low as 30 mg/kg body wt for 5 days induced hyperglycemia in young NOD/Lt-+/+ male mice, whereas a dose of 50 mg/kg for 5 days was required to elicit comparable hyperglycemia in C.B.-17-+/+ male mice. The greater NOD strain sensitivity was not a function of preexisting insulitis, because insulitis- and diabetes-free NOD male mice congenic for a diabetes-resistant major histocompatibility complex haplotype were equally susceptible to MD-STZ. This was confirmed in NOD-scid/scid and C.B.-17-scid/scid males. Both were completely insulitis-free, and despite the absence of functional T- cells and B-cells, both congenic stocks were as sensitive to MD-STZ as congenic +/+ controls. Indeed, MD-STZ-induced hyperglycemia in NOD-scid/scid male mice was significantly higher than in NOD/Lt-+/+ male mice. The NOD-scid/scid mouse as a recipient of adoptively transferred splenocytes clearly delineated a distinct pathogenesis of spontaneous insulin-dependent diabetes mellitus (IDDM) versus MD-STZ-induced hyperglycemia. Splenocytes from spontaneously diabetic NOD/Lt males, but not those from donors given MD-STZ, readily transferred IDDM, even when host beta-cells were sensitized by a single injection of STZ before adoptive transfer. We conclude that IDDM induced by MD-STZ is not mediated by T-cell- or B-cell-dependent autoimmune mechanisms in a fashion analogous to the spontaneous IDDM characteristic of NOD mice.

<A<em>b</em>stractText>The clinical efficacy of curcumin has not yet <em>b</em>een esta<em>b</em>lished for the treatment of cancer, despite a large <em>b</em>ody of evidence from numerous preclinical studies suggesting the therapeutic potential of curcumin, particularly in a synergistic com<em>b</em>ination with paclitaxel. The main o<em>b</em>stacle in using curcumin for adjunctive cancer therapy is its low <em>b</em>ioavaila<em>b</em>ility via oral administration.</A<em>b</em>stractText><A<em>b</em>stractText>We assessed the efficacy and safety of intravenous curcumin infusion in com<em>b</em>ination with paclitaxel in patients with metastatic and advanced <em>b</em>reast cancer.</A<em>b</em>stractText><A<em>b</em>stractText>A randomized, dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled, parallel-group comparative clinical study was conducted.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>A total of 150 women with advanced and metastatic <em>b</em>reast cancer were randomly assigned to receive either paclitaxel (80 mg/m²) plus place<em>b</em>o or paclitaxel plus curcumin (CUC-1®, 300 mg solution, once per week) intravenously for 12 weeks with 3 months of follow-up. The primary outcome was determined <em>b</em>ased on the o<em>b</em>jective response rate (ORR), as assessed <em>b</em>y the Response Evaluation Criteria in Solid Tumors (RECIST). The secondary outcomes were progression-free survival (PFS), time to tumor progression (TTP), time to tumor treatment failure (TTTF), safety, and quality of life.</p><A<em>b</em>stractText>The intention-to-treat (ITT) analysis revealed that the ORR of curcumin was significantly higher than that of the place<em>b</em>o (51% vs. 33%, p &<em>lt</em>; 0.01) at 4 weeks of follow-up. The difference <em>b</em>etween the groups was even greater when only patients who had completed the treatment (61% vs. 38%, odds ratio ==2.64, p &<em>lt</em>; 0.01) were included. A superior effect of curcumin vs place<em>b</em>o was o<em>b</em>served in <em>b</em>oth patients who had completed the treatment and all patients included in the ITT analysis, 3 months after termination of the treatment. No other significant differences were o<em>b</em>served <em>b</em>etween the curcumin and the place<em>b</em>o groups, except for fatigue (3 vs. 10 patients, respectively; odds ratio ==3.7, p = 0.05). However, the patients' self-assessed overall physical performance was significantly higher with curcumin than the place<em>b</em>o during the treatment and at the end of the follow-up, suggesting <em>b</em>etter tolerance in the curcumin group.</A<em>b</em>stractText><A<em>b</em>stractText>Overall, treatment with curcumin in com<em>b</em>ination with paclitaxel was superior to the paclitaxel-place<em>b</em>o com<em>b</em>ination with respect to ORR and physical performance after 12 weeks of treatment. Intravenously administered curcumin caused no major safety issues and no reduction in quality of life, and it may <em>b</em>e <em>b</em>eneficial in reducing fatigue.</A<em>b</em>stractText><A<em>b</em>stractText>This is the first clinical study to explore the efficacy and safety of administering curcumin intravenously in com<em>b</em>ination with chemotherapy in the treatment of cancer patients.</A<em>b</em>stractText>

Accumulation of mutations in somatic cells has been implicated as a cause of aging since the 1950s. However, attempts to establish a causal relationship between somatic mutations and aging have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan using a highly accurate single-cell whole-genome sequencing method. We found that the number of somatic mutations increases from &lt;500 per cell in newborns to >3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, were located at Ig genes associated with somatic hypermutation (SHM). B cell-specific mutation signatures associated with development, aging, or SHM were found. The SHM signature strongly correlated with the signature found in human B cell tumors, indicating that potential cancer-causing events are already present even in B cells of healthy individuals. We also identified multiple mutations in sequence features relevant to cellular function (i.e., transcribed genes and gene regulatory regions). Such mutations increased significantly during aging, but only at approximately one-half the rate of the genome average, indicating selection against mutations that impact B cell function. This full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.

Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β = 0.56, P &lt; 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β = 0.67, P &lt; 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β = 0.79, P &lt; 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression.

Keywords: Alzheimer’s disease; biomarker; p-tau; p-tau217; plasma.

<A<em>b</em>stractText>Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adu<em>lt</em>s. Here, we examined the importance of hypoxia in UM growth and tested the antitumor effects of arylsulfonamide 64B, an inhi<em>b</em>itor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms.</A<em>b</em>stractText><A<em>b</em>stractText>UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver, and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal-epithelial transition factor (c-Met) were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Systemic administration of 64B had potent antitumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (∼70% reduction) and spontaneous liver metastasis (∼50% reduction), and extending mice survival (<i>P</i> &<em>lt</em>; 0.001) while <em>b</em>eing well tolerated. 64B inhi<em>b</em>ited hypoxia-induced expression of CXCR4 and c-Met, 2 key drivers of tumor invasion and metastasis. 64B disrupted the HIF-1 complex <em>b</em>y interfering with HIF-1α <em>b</em>inding to p300/CBP co-factors, thus reducing p300 recruitment to the <i>MET</i> and <i>CXCR4</i> gene promoters. 64B could thermosta<em>b</em>ilize p300, supporting direct 64B <em>b</em>inding to p300.</p><A<em>b</em>stractText>Our preclinical efficacy studies support the further optimization of the 64B chemical scaffold toward a clinical candidate for the treatment of UM.</A<em>b</em>stractText>

Internet gaming and social media use are prevalent and integral to many people's lives. However, excessive engagement in either could lead to negative health impacts. This study aimed to investigate relationships between severities of internet gaming disorder (IGD) and problematic social media use (operationalized as social media addiction; SMA) with sleep quality and psychological distress among young adults. A cross-sectional study with snowball sampling was conducted among Hong Kong university students in 2019. All participants (n = 300; mean (SD) age = 20.89 (1.48); 122 males (40.67%)) responded to an online survey that included Chinese versions of the Internet Gaming Disorder Scale-Short Form (IGDS9-SF), Bergen Social Media Addiction Scale (BSMAS), Pittsburgh Sleep Quality Index (PSQI), and Depression Anxiety Stress Scales (DASS-21). Multiple linear regressions demonstrated that IGDS-SF9 scores demonstrated associations with psychological distress measures (standardized coefficient (β) = 0.295 for depression, 0.325 for anxiety, 0.339 for stress, all p &lt; 0.001). BSMAS scores showed similar albeit numerically less robust associations (β = 0.235 for depression, p &lt; 0.001; 0.219 for anxiety, p = 0.001; 0.262 for stress, p &lt; 0.001). BSMAS scores demonstrated associations with poorer sleep quality (β = 0.292; p &lt; 0.001) and IGDS9-SF scores (β = 0.157; p = 0.024) showed a significantly less robust association (p = 0.01 for comparing the two βs). These findings suggest that both severities of IGD and SMA associate with more psychological distress and poorer sleep quality, although the strengths of associations may differ.

Effects of intranasal administration of cholera toxin (CT) [or Escherichia coli heat-labile enterotoxin (LT)] B subunits supplemented with a trace amount of the holotoxin, CTB* or LTB*, on the brain were examined in BALB/c mice by comparing with those of the intracerebral injection. Intracerebral injection of CTB* at doses more than 10 microg/mouse caused significant body weight loss and dose-dependent death within 7 days, with localization of conjugates of horseradish peroxidase with CTB (HRP-CTB) in the ventricular system and in the perineural space of olfactory nerves of the nasal mucosa 3 h after injection. Intracerebral injection of CTB* at doses less than 3 microg/mouse (or LTB* at doses less than 22.7 microg/mouse) did not cause any significant body weight loss for 7 days, with localization of HRP-CTB in the brain but not in the nasal mucosa. On the other hand, intranasal administration of 10 microg of CTB* caused localization of HRP-CTB in the nasal mucosa but not in the brain 3 h after administration and caused body weight loss even after 30 administrations. Neither any histological changes of brain tissues nor marked changes in serum biochemical parameters were found in mice after the 30 administrations of CTB* or LTB*. These results suggest that 0.1 microg of CTB* or LTB*, which is known to be close to the minimal effective dose as an adjuvant for nasal influenza vaccine in mice and corresponds to 100 microg per person, can be used as a safe nasal adjuvant without adversely affecting the brain.

Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV-based all-oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years; 93% had genotype 1 HCV and 31% had biopsy-proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End-Stage Liver Disease (MELD) score was 13.0 ± 6.0, and the proportion with Child-Turcotte-Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3 × 6 log10 IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n = 77), DCV+SMV (n = 18), and DCV+SMV+SOF (n = 2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels <43 IU/mL. CTP and MELD scores significantly improved between DCV-based treatment initiation and last contact. Three virological breakthroughs and 2 relapses occurred in patients treated with DCV+SMV with or without RBV. None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy. In conclusion, DCV-based all-oral antiviral therapy was well tolerated and resulted in a high sustained virological response in LT recipients with severe recurrent HCV infection. Most treated patients experienced stabilization or improvement in their clinical status.

The aetiology of inflammatory bowel diseases (IBD) seems to be strongly connected to changes in the enteral microbiome. The dysbiosis pattern seen in Crohn's disease (CD) differs among published studies depending on patients' age, disease phenotype and microbiome research methods. The aims was to investigate microbiome in treatment-naive paediatric patients to get an insight into its structure at the early stage of the disease in comparison to healthy. Stool samples were obtained from controls and newly diagnosed patients prior to any intervention. Microbiota was analysed by 16SrRNAnext-generation-sequencing (NGS). Differences in the within-sample phylotype richness and evenness (alpha diversity) were detected between controls and patients. Statistically significant dissimilarities between samples were present for all used metrics. We also found a significant increase in the abundance of OTUs of the Enterococcus genus and reduction in, among others, Bifidobacterium (B. adolescentis), Roseburia (R.faecis), Faecalibacterium (F. prausnitzii), Gemmiger (G. formicilis), Ruminococcus (R. bromii) and Veillonellaceae (Dialister). Moreover, differences in alpha and beta diversities in respect to calprotectin and PCDAI were observed: patients with calprotectin &lt;100 µg/g and with PCDAI below 10 points vs those with calprotectin >100 µg/g and mild (10-27.7 points), moderate (27.5-40 points) or severe (>40 points) CD disease activity had higher richness and diversity of gut microbiota. The results of our study highlight reduced diversity and dysbiosis at the earliest stage of the disease. Microbial imbalance and low abundance of butyrate-producing bacteria, including Bifidobacterium adolescentis, may suggest benefits of microbial modification therapy.

BACKGROUND

Amyotrophic lateral sclerosis (ALS) is a paralytic and fatal neurodegenerative disorder caused by the gradual loss of both upper and lower motoneurons. There is compelling evidence from ALS experimental models that neuroinflammation actively contributes to motoneuron damage. We recently proposed that interferon gamma (IFNγ), a potent proinflammatory cytokine, induces motoneuron death by eliciting the activation of the lymphotoxin beta receptor (LT-βR) through its ligand LIGHT. Here, we explore the pertinence of this non-cell-autonomous mechanism in human ALS.

METHODS

The levels and expression pattern of IFNγ, LIGHT, and LT-βR were investigated by Western blot and immunohistochemical analysis in spinal cord of patients with sporadic ALS.

RESULTS

We observed significant increased levels of IFNγ in human ALS spinal cords compared to control cases. We found that large ventral horn neurons as well as glial cells were immunoreactive for IFNγ in sporadic ALS spinal cord. We further observed that LIGHT and LT-βR were expressed mainly by motoneurons in both ALS and control cases, and while LT-βR levels remained constant between ALS and control cases, LIGHT levels were increased in human ALS spinal cords.

CONCLUSIONS

These findings in sporadic ALS cases, which are consistent with the observation made in ALS experimental models, propose that the IFNγ-triggered LIGHT/LT-βR-mediated death pathway may contribute to human ALS pathogenesis.