Treatment of Peritoneal Metastasis with Pressurized Intraperitoneal Aerosol Chemotherapy: Results from the Prospective PIPAC-OPC2 Study.

BACKGROUND: Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC) is a local treatment for peritoneal metastasis (PM). Prospective data are scarce and evaluation of treatment response remains difficult. This study evaluated the use of the Peritoneal Regression Grading score (PRGS) and its prognostic value. PATIENTS AND METHODS: This was a prospective, controlled phase II trial in patients with PM from gastrointestinal, gynaecological, hepatopancreatobiliary, primary peritoneal, or unknown primary cancer. Patients in performance status 0-1, with a non-obstructed gastrointestinal tract, and a maximum of one extraperitoneal metastasis were eligible. Colorectal or appendiceal PM had PIPAC with oxaliplatin, other primaries had PIPAC with cisplatin and doxorubicin. Biopsies were taken at each PIPAC and evaluated using the PRGS. Quality-of-life questionnaires were reported at baseline and after three PIPACs. RESULTS: One hundred ten patients were treated with 336 PIPACs (median 3, range 1-12). One hundred patients had prior palliative chemotherapy and 45 patients received bidirectional treatment. Complete or major histological response to treatment (PRGS 1-2) was observed in 38 patients (61%) who had three PIPACs, which was the only independent prognostic factor in a multivariate analysis. The median overall survival (mOS) from PIPAC 1 was 10 months, while patients with PM from gastric, colorectal, and pancreatic cancer had a mOS of 7.4, 16.7, and 8.2 months, respectively. Global health scores were significantly reduced, but patients were less fatigued, nauseated, constipated, and had better appetite after three PIPACs. CONCLUSIONS: PIPAC with oxaliplatin or cisplatin and doxorubicin was able to induce a major or complete histological response during three PIPACs, which may provide significant prognostic information, both at baseline and after treatment.

Cardiac chamber volumes and left ventricular mass in people living with HIV and matched uninfected controls.

OBJECTIVES: People living with HIV (PLWH) have increased risk of cardiovascular diseases compared with uninfected populations. We assessed structural cardiac abnormalities and their associated risk factors in well-treated PLWH and uninfected controls using multidetector computed tomography (MDCT). METHODS: People living with HIV and age- and sex-matched uninfected controls underwent MDCT to determine left atrial volume (LAV), left ventricular diastolic volume (LVDV), right ventricular diastolic volume (RVDV) and left ventricular mass (LVM). All outcomes were indexed to body surface area (BSA) (LAVi, LVDVi, RVDVi and LVMi). RESULTS: A total of 592 PLWH and 1184 uninfected controls were included in the study. PLWH had smaller mean (SD) LAVi [40 (8) vs. 41 (9) mL/m2 ; P = 0.002] and LVDVi [61 (13) vs. 65 (14) mL/m2 ; P < 0.001] but larger RVDVi [89 (18) vs. 86 (17) mL/m2 ; P < 0.001] than uninfected controls. HIV was independently associated with 7 mL (95% CI: -10 to -3) smaller LVDV, and with 12 mL (95% CI: 8-16) larger RVDV, and 4 g (95% CI: 1-6) larger LVM after adjustment for cardiovascular risk factors and BSA. Large RVDV in PLWH was not associated with obstructive lung function. CONCLUSIONS: HIV was independently associated with smaller LVDV and larger RVDV and LVM. Alterations in cardiac chamber volumes in PLWH were mainly minor. The clinical impact of these findings is uncertain, but it seems unlikely that alterations in cardiac chamber volumes explain the increased burden of cardiovascular disease previously observed in PLWH.

Coronary artery calcium and intima-media thickness are associated with level of cytomegalovirus immunoglobulin G in HIV-infected patients.

Coinfection with cytomegalovirus (CMV) may be involved in cardiovascular disease in HIV-infected patients. We found that higher level of CMV immunoglobulin G (IgG) was independently associated with an increased risk of coronary artery calcium and higher intima-media thickness in HIV-infected patients but not in healthy controls after adjustment for other cardiovascular risk factors and levels of herpes viridae IgG.

Prevalence of impaired renal function in virologically suppressed people living with HIV compared with controls: the Copenhagen Comorbidity in HIV Infection (COCOMO) study.

OBJECTIVES: While renal impairment is reported more frequently in people living with HIV (PLWH) than in the general population, the PLWH samples in previous studies have generally been dominated by those at high renal risk. METHODS: Caucasian PLWH who were virologically suppressed on antiretroviral treatment and did not have injecting drug use or hepatitis C were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Sex- and age-matched controls were recruited 1:4 from the Copenhagen General Population Study up to November 2016. We defined renal impairment as one measurement of estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 , and assessed associated factors using adjusted logistic regression models. The impact of HIV-related factors was explored in a subanalysis. RESULTS: Among 598 PLWH and 2598 controls, the prevalence of renal impairment was 3.7% [95% confidence interval (CI) 2.3-5.5%] and 1.7% (95% CI 1.2-2.2%; P = 0.0014), respectively. After adjustment, HIV status was independently associated with renal impairment [odds ratio (OR) 3.4; 95% CI 1.8-6.3]. In addition, older age [OR 5.4 (95% CI 3.9-7.5) per 10 years], female sex [OR 5.0 (95% CI 2.6-9.8)] and diabetes [OR 2.9 (95% CI 1.3-6.7)] were strongly associated with renal impairment. The association between HIV status and renal impairment became stronger with older age (P = 0.02 for interaction). Current and nadir CD4 counts, duration of HIV infection and previous AIDS-defining diagnosis were not associated with renal impairment among virologically suppressed PLWH. CONCLUSIONS: The prevalence of renal impairment is low among low-risk virologically suppressed Caucasian PLWH, but remains significantly higher than in controls. Renal impairment therefore remains a concern in all PLWH and requires ongoing attention.

Association between smoking status assessed with plasma-cotinine and inflammatory and endothelial biomarkers in HIV-positive and HIV-negative individuals.

OBJECTIVES: Smoking is a major contributor to mortality and morbidity in HIV-positive individuals. Our primary objective was to evaluate the association between smoking status determined by plasma cotinine (P-cotinine) concentration and inflammatory and endothelial biomarkers in HIV-positive versus HIV-negative individuals. METHODS: We studied eight inflammatory/endothelial biomarkers [high-sensitivity C-reactive protein (hsCRP), E-selectin, soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), matrix metallopeptidase 9 (MMP-9), myeloperoxidase (MPO), tissue type plasminogen activator inhibitor 1 (tPAI) and endothelin] in 105 HIV-positive individuals and 105 HIV-negative individuals matched on age, sex and self-reported smoking status. Smoking status was determined using P-cotinine (a concentration > 14 ng/mL was defined as demonstrating exposure to smoke). We used linear regression models to (1) examine the association between smoking status and inflammatory/endothelial biomarkers in HIV-positive compared with HIV-negative individuals, and (2) to determine whether there was evidence to suggest that the impact of smoking status on the biomarkers differed between HIV-positive and HIV-negative individuals. RESULTS: Of the eight biomarkers, smokers had increased hsCRP, sICAM-1 and MMP-9 concentrations irrespective of HIV status and increasing P-cotinine concentration was associated with increasing hsCRP concentration. We found no interaction between smoking and HIV status. HIV infection was associated with increased hsCRP, E-selectin, sVCAM-1, sICAM-1 and MMP-9 concentrations. Self-reported smoking status differed substantially from smoking status assessed with P-cotinine. CONCLUSIONS: Several biomarkers were associated with smoking status and HIV status. However, our data do not indicate that the effects of smoking on the biomarkers differ between HIV-positive and HIV-negative individuals.

Composition and adaptation of human myotendinous junction and neighboring muscle fibers to heavy resistance training.

The myotendinous junction (MTJ) is a common site of strain injury and yet understanding of its composition and ability to adapt to loading is poor. The main aims of this study were to determine the profile of selected collagens and macrophage density in human MTJ and adjoining muscle fibers, and to investigate whether heavy exercise loading would alter this profile. Fifteen individuals scheduled for anterior cruciate ligament repair surgery were randomized into three groups: control, acute or 4 weeks heavy resistance training. MTJ samples were collected from the semitendinosus and gracilis muscles and were sectioned and stained immunohistochemically for collagen types I, III, VI, XII, XIV, XXII, Tenascin-C and CD68. Macrophage density and distribution was evaluated and the amount of each collagen type in muscle and MTJ was graded. Collagen XXII was observed solely at the MTJ, while all other collagens were abundant at the MTJ and in muscle perimysium or endomysium. The endomysial content of collagen XIV, macrophages and Tenascin-C increased following 4 weeks of training. These findings illustrate the heterogeneity of collagen type composition of human MTJ. The increase in collagen XIV following 4 weeks of training may reflect a training-induced protection against strain injuries in this region.

Soluble urokinase plasminogen activator receptor (suPAR) is a novel, independent predictive marker of myocardial infarction in HIV-1-infected patients: a nested case-control study.

OBJECTIVES: Patients infected with HIV are at increased risk of myocardial infarction (MI). Increased plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased risk of cardiovascular diseases (CVD), including MI in the general population. We tested suPAR as a predictive biomarker of MI in HIV-1-infected individuals. METHODS: suPAR levels were investigated in a nested case-control study of 55 HIV-1-infected cases with verified first-time MI and 182 HIV-1-infected controls with no known CVD. Controls were matched for age, gender, duration of antiretroviral therapy (ART), smoking and no known CVD. suPAR was measured in the four plasma samples available for each patient at different time-points; 1, Before initiation of ART; 2, 3 months after initiation of ART; 3, 1 year before the case's MI; and 4, The last sample available before the case's MI. RESULTS: In unadjusted conditional regression analysis, higher levels of suPAR were associated with a significant increase in risk of MI at all time-points. Patients in the third and fourth suPAR quartiles had a three- to 10-fold higher risk of MI compared to patients in the lowest suPAR quartile at all time-points. suPAR remained a strong significant predictor of MI, when adjusting for HIV-1 RNA, total cholesterol, triglycerides and high-density lipoprotein. CONCLUSION: Elevated suPAR levels were associated with increased risk of MI in HIV-infected patients, suggesting that suPAR could be a useful biomarker for prediction of first-time MI in this patient group, even years before the event.

The human myotendinous junction: an ultrastructural and 3D analysis study.

The myotendinous junction (MTJ) is a specialized structure in the musculotendinous system, where force is transmitted from muscle to tendon. Animal models have shown that the MTJ takes form of tendon finger-like processes merging with muscle tissue. The human MTJ is largely unknown and has never been described in three dimensions (3D). The aim of this study was to describe the ultrastructure of the human MTJ and render 3D reconstructions. Fourteen subjects (age 25 ± 3 years) with isolated injury of the anterior cruciate ligament (ACL), scheduled for reconstruction with a semitendinosus/gracilis graft were included. Semitendinosus and gracilis tendons were stripped as grafts for the ACL reconstruction. The MTJ was isolated from the grafts and prepared for transmission electron microscopy (TEM) and focused ion beam/scanning electron microscopy. It was possible to isolate recognizable MTJ tissue from all 14 patients. TEM images displayed similarities to observations in animals: Sarcolemmal evaginations observed as finger-like processes from the tendon and endomysium surrounding the muscle fibers, with myofilaments extending from the final Z-line of the muscle fiber merging with the tendon tissue. The 3D reconstruction revealed that tendon made ridge-like protrusions, which interdigitiated with groove-like indentations in the muscle cell.

Common mental disorders and long-term sickness absence in a general working population. The Hordaland Health Study.

OBJECTIVE: To examine and compare the prospective effect of the common mental disorders (CMD) anxiety and depression on duration and recurrence of sickness absence (SA), and to investigate whether the effect of CMD on SA is detectable over time. METHOD: Information from a large epidemiological health study (N = 13 436) was linked with official records of SA episodes lasting ≥16 days up to 6 years after participation. Common mental disorders were assessed with the Hospital Anxiety and Depression Scale (HADS). Associations were analysed with Cox regression and multinomial logistic regression models controlling for potential covariates. RESULTS: Comorbid anxiety and depression, and anxiety only were significant risk factors for SA after adjusting for covariates, whilst depression only was not. Anxiety and depression were stronger predictors for longer duration of SA episodes compared with shorter duration and associated with more frequent recurrence of SA. There was a general trend toward the effect of CMD on SA becoming weaker over time; however, the effect of anxiety only on SA remained stable throughout the follow-up. CONCLUSION: Common mental disorders are long-lasting predictors of onset, duration and recurrence of SA. Anxiety appears to be a more important contributor to long-term SA than previously described in the literature.

Quantitative proteomic analysis of ibuprofen-degrading Patulibacter sp. strain I11.

Ibuprofen is the third most consumed pharmaceutical drug in the world. Several isolates have been shown to degrade ibuprofen, but very little is known about the biochemistry of this process. This study investigates the degradation of ibuprofen by Patulibacter sp. strain I11 by quantitative proteomics using a metabolic labelling strategy. The whole-genome of Patulibacter sp. strain I11 was sequenced to provide a species-specific protein platform for optimal protein identification. The bacterial proteomes of actively ibuprofen-degrading cells and cells grown in the absence of ibuprofen was identified and quantified by gel based shotgun-proteomics. In total 251 unique proteins were quantitated using this approach. Biological process and pathway analysis indicated a number of proteins that were up-regulated in response to active degradation of ibuprofen, some of them are known to be involved in the degradation of aromatic compounds. Data analysis revealed that several of these proteins are likely involved in ibuprofen degradation by Patulibacter sp. strain I11.

Individual hand hygiene improvements and effects on healthcare-associated infections: a long-term follow-up study using an electronic hand hygiene monitoring system.

BACKGROUND: Obtaining detailed insights into people's unique hand hygiene behaviour could play an important role in developing the most effective long-term hand hygiene compliance (HHC) interventions. AIM: To investigate the effect of two feedback interventions provided by an electronic hand hygiene monitoring system (EHHMS) on sustained HHC improvement, individual responsiveness, and prevention of hospital-acquired bloodstream infections (HABSIs) and urinary tract infections (HAUTIs). METHODS: The study included two 2-year cohorts (exposed and unexposed to EHHMS) observed over 4 years in an internal medicine department with 142 caregivers and 39 doctors. Healthcare workers (HCWs) were stratified into four groups based on their baseline performance to assess predicted responsiveness to the interventions. FINDINGS: All HCWs increased their HHC independently from their performance at baseline, except for a few in the low-performance groups with constantly low HHC. The two low-performance groups at baseline were most responsive to group feedback (weekly change in HHC of 4.4% and 3.1%) compared with individual feedback (weekly change in HHC of 1.0% and 2.2%). The number of cases of HABSI reduced significantly during the intervention period (P=0.01), with the greatest effect on Staphylococcus aureus. No significant change in HAUTIs was observed. CONCLUSION: The EHHMS interventions sustained the HHC improvements successfully and reduced the number of cases of HABSI. Nearly all HCWs responded to the interventions. The two low-performance groups at baseline never reached the same HHC levels as those in the high-performance groups, indicating the potential for further improvement and the need for intensified individualized interventions.

Personality disorders, common mental disorders and receipt of disability benefits: evidence from the British National Survey of Psychiatric Morbidity.

BACKGROUND: Common mental disorders (CMDs) are associated with occupational impairment and the receipt of disability benefits (DBs). Little is known about the relationship between personality disorders (PDs) and work disability, and whether the association between CMDs and work disability is affected by the presence of co-morbid PDs. The aim of this study was to examine the association between DB and individual categories of PDs, with special attention to the effect of co-morbid CMDs on this association. METHOD: The association between DB and PD was examined using data from the 2000 British National Survey of Psychiatric Morbidity. Probable PD caseness was identified using the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) screening questionnaire. The impact of CMDs, assessed with the revised version of the Clinical Interview Schedule (CIS-R), was examined as a covariate and in a stratified analysis of co-morbidity. Other covariates included sociodemographic factors, long-standing illnesses and substance use. RESULTS: Probable PD was associated with DB, with the strongest associations found for borderline, dependent and schizotypal PD. Antisocial PD was not associated with DB. The relationship between PD and DB was strongly modified by CMD, reducing the association from an odds ratio (OR) of 2.84 to 1.34 [95% confidence interval (CI) 1.00-1.79)]. In the stratified analysis, co-morbid PD and CMD showed a stronger association with DB than PD without CMD but, when fully adjusted, this effect was not significantly different from the association between CMD without PD. CONCLUSIONS: Individuals screening positive for PD are more likely to experience severe occupational outcomes, especially in the presence of co-morbid CMD.

Sensitivity of immunochemical faecal occult blood testing for detecting left- vs right-sided colorectal neoplasia.

BACKGROUND: Faecal occult blood tests (FOBTs) are used for colorectal cancer (CRC) screening. We aimed to assess the sensitivity of an immunochemical FOBT for detecting advanced colorectal neoplasia in the left vs the right colon and to explore reasons for potential differences in site-specific test performance. METHODS: We prospectively measured faecal occult blood levels by a quantitative immunochemical FOBT (RIDASCREEN) in 2310 average-risk subjects undergoing screening colonoscopy. We compared diagnostic performance for subjects with left- vs right-sided advanced neoplasia, as well as patient characteristics and adenoma characteristics that have been suggested to impact faecal haemoglobin levels. RESULTS: Sensitivities for subjects with left- vs right-sided advanced neoplasia were 33% (95% confidence interval (CI), 26-41%) and 20% (CI, 11-31%) (P=0.04) at a specificity of 95% (overall sensitivity: 29%) and the areas under the receiver-operating characteristics curve were 0.71 (CI, 0.69-0.72) and 0.60 (CI, 0.58-0.63), respectively. Pedunculated shape was strikingly more common in participants with left- vs right-sided advanced neoplasia (47% vs 14%). In logistic regression analyses adjusted for site, pedunculated shape was statistically significantly associated with test sensitivity (P=0.04). CONCLUSIONS: The immunochemical FOBT in our study was more sensitive for detecting subjects with left- vs right-sided advanced colorectal neoplasia. Our findings may stimulate further diagnostic research in the field as well as modelling analyses to estimate the potential effect of site-specific test performance on the effectiveness of annual or biennial FOBT-based screening programmes, in particular with respect to protection from right-sided CRC.

Effectiveness of an electronic hand hygiene monitoring system in increasing compliance and reducing healthcare-associated infections.

During an interventional study in a nephrology department, we investigated the effect of an electronic hand hygiene monitoring system on the hand hygiene compliance of healthcare workers (N = 99) and hospital-acquired bloodstream infections. The hand hygiene compliance of the doctors and nurses improved significantly during the intervention phase when they received group and individual feedback based on actionable insights from the electronic hand hygiene monitoring system. The improvements in hand hygiene compliance were associated with a significant reduction in the number of hospital-acquired bloodstream infections.

Attenuated familial adenomatous polyposis: results from an international collaborative study.

AIM: The study aimed to describe genetical and clinical features of attenuated familial adenomatous polyposis (AFAP) and to propose clinical criteria and guidelines for treatment and surveillance. METHOD: A questionnaire study was carried out of polyposis registries with data on patients with presumed AFAP, defined as having ≤ 100 colorectal adenomas at age ≥ 25. RESULTS: One hundred and ninety-six patients were included. The median number of adenomas was 25 (0-100) with a uniform distribution of colorectal adenomas and carcinomas (CRC). Age at CRC diagnosis was delayed by 15 years compared with classic FAP. Eighty-two patients had a colectomy and an ileorectal anastomosis and 5/82 (6%) had a secondary proctectomy. The location of the mutation in the APC gene was known in 69/171 (40%) tested patients. Only 15/29 (52%) of mutations in APC were found in parts of the gene usually associated with AFAP (the 5' end, exon 9 and 3' end). CONCLUSIONS: A subset of FAP patients with a milder phenotype does exist and treatment and surveillance had to be modified accordingly. The mutation detection rate is lower than in classic FAP and mutations in AFAP patients are located throughout the APC gene. We propose the following clinical diagnostic criteria for AFAP: a dominant mode of inheritance of colorectal adenomatosis and <100 colorectal adenomas at age 25 or older. Colonoscopy had to be preferred to sigmoidoscopy and surveillance had to be life-long. In the majority of patients, prophylactic colectomy and ileorectal anastomosis are recommended at the age of 20-25 years.

Classification of pain in cancer patients--a systematic literature review.

One of the aims of the European Palliative Care Research Collaborative (EPCRC) is to achieve consensus on a classification system for cancer pain. We performed a systematic literature review to identify existing classification systems and domains/items used to classify cancer patients with pain. In a systematic search in the databases Medline and Embase, covering 1986-2006, 692 hits were obtained. 92 papers were evaluated to address pain classification. Six standardised classification systems were identified; three of them systematically developed and partially validated. Both pain characteristics and patient characteristics relevant for cancer pain classification were included in the classification systems. All but one of the standardised systems aim at predicting treatment response or adequacy of treatment. Several domains and items used to describe cancer pain but not formally described as part of a classification system were also identified and systematized. The existing approaches to pain classification in cancer patients are different, mostly not thoroughly validated, and none is widely applied. An internationally accepted classification system for cancer pain could improve research and cancer pain management. This systematic review suggests a need for developing an international consensus on how to classify pain in cancer patients.