Barrett's esophagus and the risk of adenocarcinoma

Barrett’s esophagus is the precursor lesion of esophageal adenocarcinoma, a tumor with increasing incidence and poor prognosis. The overall aim of the thesis was to assess risk and prognosis in patients with Barrett’s esophagus and esophageal adenocarcinoma. Four studies were conducted based on data from Swedish nationwide registers and medical records from 71 Swedish hospitals. Study I was a population-based cohort study which assessed the risk of esophageal adenocarcinoma among patients with Barrett’s esophagus. Among 7,932 study participants with Barrett’s esophagus (median age 66 years, 68% men), 89 developed esophageal adenocarcinoma. After excluding prevalent adenocarcinomas (70%), 27 adenocarcinomas developed over a period of 18,415 person-years, which corresponded to an incidence rate of 1.5 (95% CI 0.9-2.0) cases per 1,000 person-years at risk and a standardized incidence ratio of 9.4 (95% CI 6.2-13.6). Study II was a population-based, nested case-control study designed to identify a prediction model for progression from Barrett’s esophagus to adenocarcinoma or high-grade dysplasia. All adenocarcinoma and high-grade dysplasia in patients with Barrett’s esophagus in Sweden were included as cases (n=279). Four randomly selected non-progressors per case were included as controls (n=1,089). For the included patients, endoscopy and histopathology records were collected and reviewed. Older age, male sex and longer Barrett’s esophagus segment length were associated with increased risk of adenocarcinoma/high-grade dysplasia. In contrast, hiatal hernia and esophagitis were not associated with tumor progression. A model based on age, sex and segment length predicted 71% of adenocarcinoma/high-grade dysplasia. Study III was a population-based cohort study which evaluated the adherence to surveillance and treatment guidelines for Barrett’s esophagus. All patients with dysplastic Barrett’s esophagus in Study II were included and followed for median 3.9 years using nationwide registers. Among 211 participants (71% low-grade dysplasia, 29% high-grade dysplasia), 84% had a follow-up endoscopy, 17% received endoscopic therapy and 8% underwent esophagectomy. However, 60% were not managed in accordance with clinical guidelines, mainly due to under-surveillance. Risk factors for deviation from surveillance and treatment recommended in guidelines were low-grade dysplasia compared to high-grade dysplasia and longer segment length compared to shorter segment length, while treatment in surgical compared to gastroenterological departments was associated with recommended surveillance and treatment. Study IV was a population-based cohort study which assessed whether endoscopy screening improves the prognosis of esophageal adenocarcinoma. Among 6,600 study participants with adenocarcinoma (mean age 70 years, 79% male) followed for 9,138 person-years, 7% had a history of gastroesophageal reflux disease and 9% underwent endoscopy before cancer diagnosis. The 5-year mortality was decreased in patients with history of gastroesophageal reflux disease (HR 0.71, 95% CI 0.64-0.80), and this decrease was only slightly attenuated by adjustment for prior endoscopy (HR 0.79, 95% CI 0.70-0.90). The 5-year mortality was unchanged in patients with 1-2 screening endoscopies (compared to patients without screening endoscopy), while those with ≥3 endoscopies for gastroesophageal reflux disease had improved survival in esophageal adenocarcinoma (HR 0.55, 95% CI 0.36-0.85). To conclude, the overall risk of adenocarcinoma in Barrett’s esophagus is low, but it is possible to predict a clearly higher risk of tumor progression based on a few clinically available risk factors, enabling tailored endoscopy surveillance in these patients. Currently, adherence to recommended surveillance and treatment guidelines is poor, and efforts to implement these guidelines in clinical practice are needed. Use of endoscopy screening has a limited impact on survival in adenocarcinoma unless performed frequently

Anbefalinger for videreutvikling av Innbyggerundersøkelsen. Anbefalinger gjort på bakgrunn av ekspertevaluering og analyser av Innbyggerundersøkelsene 2010–2017

Statistisk sentralbyrå har, på oppdrag fra Difi (Direktoratet for forvaltning og IKT), kommet med anbefalinger for hvordan Difi kan videreutvikle Innbyggerundersøkelsen fremover. Innbyggerundersøkelsen gjennomføres av Direktoratet for forvaltning og IKT (Difi). Den gjøres hvert andre år, og ble første gang gjennomført i 2009. Utvalget er trukket fra Folkeregisteret og stratifisert etter fylke, kjønn og alder. Omleggingen til å være primært en web-undersøkelse i 2017, førte til et fall i svarprosent fra 40 til 20. Den lave svarvilligheten gjorde at Difi tok kontakt med Statistisk sentralbyrå (SSB) for å få råd om hva som kan gjøres for å øke svarprosenten. Noen av spørsmålene Difi har reist, er om spørreskjemaet kan gjøres kortere eller om det kan splittes opp i mindre bolker slik at ikke alle trenger å svare på alle spørsmålene

Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria

Background: One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated. Methods: Cerebrospinal fuid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cogni‑ tive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren’s Children’s Hospital were quantifed and used for comparison. Results: Children with CM had signifcantly higher CSF concentration of kynurenine and KYNA than Swedish children (P \u3c 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respec‑ tively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old. Conclusions: CSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of atten‑ tion and cognition

Incidence and Mortality in Upper Gastrointestinal Cancer After Negative Endoscopy for Gastroesophageal Reflux Disease

BACKGROUND AND AIMS: Gastroesophageal reflux disease (GERD) is associated with an increased risk of cancer of the upper gastrointestinal tract. This study aimed to assess whether and to what extent a negative upper endoscopy in patients with GERD is associated with decreased incidence and mortality in upper gastrointestinal cancer (ie, esophageal, gastric, or duodenal cancer). METHODS: We conducted a population-based cohort study of all patients with newly diagnosed GERD between July 1, 1979 and December 31, 2018 in Denmark, Finland, Norway, and Sweden. The exposure, negative upper endoscopy, was examined as a time-varying exposure, where participants contributed unexposed person-time from GERD diagnosis until screened and exposed person-time from the negative upper endoscopy. The incidence and mortality in upper gastrointestinal cancer were assessed using parametric flexible models, providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 1,062,740 patients with GERD (median age 58 years; 52% were women) followed for a mean of 7.0 person-years, 5324 (0.5%) developed upper gastrointestinal cancer and 4465 (0.4%) died from such cancer. Patients who had a negative upper endoscopy had a 55% decreased risk of upper gastrointestinal cancer compared with those who did not undergo endoscopy (HR, 0.45; 95% CI, 0.43-0.48), a decrease that was more pronounced during more recent years (HR, 0.34; 95% CI, 0.30-0.38 from 2008 onward), and was otherwise stable across sex and age groups. The corresponding reduction in upper gastrointestinal mortality among patients with upper endoscopy was 61% (adjusted HR, 0.39; 95% CI, 0.37-0.42). The risk reduction after a negative upper endoscopy in incidence and mortality lasted for 5 and at least 10 years, respectively. CONCLUSIONS: Negative upper endoscopy is associated with strong and long-lasting decreases in incidence and mortality in upper gastrointestinal cancer in patients with GERD.Peer reviewe

Boosters of a therapeutic HIV-1 vaccine induce divergent T cell responses related to regulatory mechanisms

AbstractTherapeutic human immunodeficiency virus (HIV) vaccines aim to reduce disease progression by inducing HIV-specific T cells. Vacc-4x are peptides derived from conserved domains within HIV-1 p24 Gag. Previously, Vacc-4x induced T cell responses in 90% of patients which were associated with reduced viral loads. Here we evaluate the effects of Vacc-4x boosters on T cell immunity and immune regulation seven years after primary immunization. Twenty-five patients on effective antiretroviral therapy received two Vacc-4x doses four weeks apart and were followed for 16 weeks. Vacc-4x T cell responses were measured by proliferation (CFSE), INF-γ, CD107a, Granzyme B, Delayed-Type Hypersensitivity test (DTH) and cytokines and chemokines (Luminex). Functional regulation of Vacc-4x-specific T cell proliferation was estimated in vitro using anti-IL-10 and anti-TGF-ß monoclonal antibodies.Vacc-4x-specific CD8+ T cell proliferation increased in 80% after either the first (64%) or second (16%) booster. Only 40% remained responders after two boosters with permanently increased Vacc-4x-specific proliferative responses (p=0.005) and improved CD8+ T cell degranulation, IFN-γ production and DTH. At baseline, responders had higher CD8+ T cell degranulation (p=0.05) and CD4+ INF-γ production (p=0.01), whereas non-responders had higher production of proinflammatory TNF-α, IL-1α and IL-1ß (p<0.045) and regulatory IL-10 (p=0.07).Notably, IL-10 and TGF-ß mediated downregulation of Vacc-4x-specific CD8+ T cell proliferation increased only in non-responders (p<0.001). Downregulation during the study correlated to higher PD-1 expression on Vacc-4x-specific CD8+ T cells (r=0.44, p=0.037), but was inversely correlated to changes in Vacc4x-specific CD8+ T cell proliferation (r=−0.52, p=0.012).These findings show that Vacc-4x boosters can improve T cell responses in selected patients, but also induce vaccine-specific downregulation of T cell responses in others. Broad surveillance of T cell functions during immunization may help to individualize boosting, where assessment of vaccine-related immune regulation should be further explored as a potential new parameter

Absorption Characteristics of Periodically Perforated Suspended Ceilings

The sound absorption characteristics of resonant absorbers, implemented as perforated suspended inner ceilings attached with thin porous layers, are investigated. Several existing theories model the principal absorption mechanisms, but the interaction with the outer sound field influences the absorption in ways that can be modelled with new approaches. The effect of arranging the absorbing surfaces in various patterns is modelled with a variational model. Periodic effects, depending on correspondence of projected wavelength and the dimensions of the periodic cells for certain incidence angles and frequencies, is modelled with an approach that formerly has been used on periodically reinforced floors. The model presupposes reflection from absorbing points and is therefore intended for small perforations. In this way an efficient mathematical treatment is gained at the expense of generality. This model is then extended to incorporate the backing field, which makes it possible to handle lateral waves within the absorber and therefore non-locally reacting absorbers. In order to evaluate the presented theories, the static flow resistance, R, of the compound absorber (thin porous layer and rigid facing) has to be known. Since R of a compound absorber in many cases is hard to estimate from a R-value measured on separate samples of the porous layer, a new device for measurements of R. on compound absorbers was implemented. The device, which has a simple and robust construction, is intended for measurements on standard tiles of perforated plaster boards attached with a thin porous layer, but, by changing measurement interface, measurements can also be performed on the sole thin porous layer

Absorption and radiation impedance of finite absorbing patches

A variational formulation is used to calculate the sound absorption in order to incorporate the interaction between several absorbing patches of arbitrary shape. In particular, this formulation is applied to small periodic patches. The absorption characteristics are governed by the radiation impedance, Z(r), which is a function of the absorber's geometry and the incidence angle, together with the surface impedance of the absorber. The behaviour of Z(r) is evaluated numerically for a number of typical configurations, and the effect on the statistical absorption coefficient, alpha(stat) is calculated. The evaluations stress that alpha(stat) is regulated by the interaction between Z(r) and the impedance of the absorber. A comparison is made of results from measurements and calculations performed on the measurement set-up