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Out of hospital cardiac arrest is the leading cause of death in industrialized countries. Recovery of hemodynamics does not necessarily lead to recovery of cerebral perfusion. The neurological injury induced by a circulatory arrest mainly determines the prognosis of patients after cardiac arrest and rates of survival with a favourable neurological outcome are low. This review focuses on the temporal course of cerebral perfusion and changes in cerebral autoregulation after out of hospital cardiac arrest. In the early phase after cardiac arrest, patients have a low cerebral blood flow that gradually restores towards normal values during the first 72 hours after cardiac arrest. Whether modification of the cerebral blood flow after return of spontaneous circulation impacts patient outcome remains to be determined.

Objective. To determine if increasing variability of blood pressure influences determination of cerebral autoregulation. Methods. A prospective observational study was performed at the ICU of a university hospital in the Netherlands. 13 comatose patients after cardiac arrest underwent baseline and intervention (tilting of bed) measurements. Mean flow velocity (MFV) in the middle cerebral artery and mean arterial pressure (MAP) were measured. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, coherence, gain, and phase were calculated in the very low and low frequency bands. Results. The CV of MAP was significantly higher during intervention compared to baseline. On individual level, coherence in the VLF band changed in 5 of 21 measurements from unreliable to reliable and in 6 of 21 measurements from reliable to unreliable. In the LF band 1 of 21 measurements changed from unreliable to reliable and 3 of 21 measurements from reliable to unreliable. Gain in the VLF and LF band was lower during intervention compared to baseline. Conclusions. For the ICU setting, more attention should be paid to the exact experimental protocol, since changes in experimental settings strongly influence results of estimation of cerebral autoregulation.

We followed 353 women referred with abnormal cervical cytology in a non-intervention cohort study. In 91 pregnant women we compared high-risk human papilloma virus rates in the subsequent trimesters and postpartum in comparison to 262 non-pregnant women. High-risk human papilloma virus clearance was compared with 179 high-risk human papilloma virus positive non-pregnant women. Our main questions were: (1) do high-risk human papilloma virus rates change during pregnancy?; and (2) is there any difference between high-risk human papilloma virus clearance in pregnant and non-pregnant women? Women were monitored 3–4 monthly by cytology, colposcopy, and high-risk human papilloma virus testing. The median follow-up time was 33 months (range 3–74). Non-pregnant women showed prevalence rates of high-risk human papilloma virus of 64, 57, 53, and 50%, respectively, in four subsequent 3-months periods since the start of the study. These high-risk human papilloma virus rates were higher than in the three trimesters of pregnancy, and during the first 3 months postpartum, i.e. 50, 44, 45, and 31%, respectively. Postpartum only, this difference was statistically significant ( P =0.004). Paired comparisons of high-risk human papilloma virus prevalence rates of the different trimesters with the postpartum rate showed (McNemar test) decreased rates: first trimester: 18% ( P =0.02), second trimester: 13% ( P =0.02) and third trimester: 23% ( P <0.005). Such a phenomenon was not found in non-pregnant women. Pregnant women showed a trend for increased high-risk human papilloma virus clearance during the third trimester and postpartum compared to non-pregnant women (hazard ratios 3.3 (0.8–13.7) and 4.6 (1.6–12.8), respectively). These results suggest a lowered immune-response against human papilloma virus during the first two trimesters of pregnancy with a catch-up postpartum.

Background: Five-year survival after resection of colorectal cancer liver metastasis (CRLCM) is <30%. We recently found that aurora kinase A (AURKA) drives 20q gain-associated tumour progression and is associated with disease recurrence. This study evaluates the prognostic value of AURKA expression in CRCLM of patients who underwent liver resection. Methods: Tissue microarrays (TMAs) were generated using formalin-fixed paraffin-embedded CRCLM and matched primary tumour from a multi-institutional cohort of patients with CRCLM who underwent liver resection between 1990 and 2010. Tissue microarrays were stained for AURKA using immunohistochemistry, and a hazard rate ratio (HRR) for the association between overall survival (OS) and nuclear AURKA expression in CRCLM was calculated. Results were validated by 500-fold cross-validation. Results: The expression of AURKA was evaluated in CRCLM of 343 patients. High AURKA expression was associated with poor OS (HRR 1.55, P <0.01), with a cross-validated average HRR of 1.57 ( P =0.02). Average HRR was adjusted for the established prognostic clinicopathological variables in a multivariate analysis (average HRR 1.66; P =0.02). The expression of AURKA in CRCLM was correlated to its expression in corresponding primary tumour ( P <0.01). Conclusion: The expression of AURKA protein is a molecular biomarker with prognostic value for patients with CRCLM, independent of established clinicopathological variables.

We studied the natural course of high-risk human papillomavirus (HPV) infection and cytological regression in women referred for colposcopy because of abnormal cervical smears. We found that high-risk HPV clearance preceded regression of cervical lesions by an average of 3 months. The cumulative 1-year rate of cytological regression was similar in women with mild and moderate dyskaryotic cervical smears. Thus, retesting of high-risk HPV after 6 months in women with mild to moderate dyskaryosis predicts cytological regression.

Background Although life-saving in selected patients, ECMO treatment still has high mortality which for a large part is due to treatment-related complications. A feared complication is ischemic stroke for which heparin is routinely administered for which the dosage is usually guided by activated partial thromboplastin time (aPTT). However, there is no relation between aPTT and the rare occurrence of ischemic stroke (1.2%), but there is a relation with the much more frequent occurrence of bleeding complications (55%) and blood transfusion. Both are strongly related to outcome. Methods We will conduct a three-arm non-inferiority randomized controlled trial, in adult patients treated with ECMO. Participants will be randomized between heparin administration with a target of 2–2.5 times baseline aPTT, 1.5–2 times baseline aPTT, or low molecular weight heparin guided by weight and renal function. Apart from anticoagulation targets, treatment will be according to standard care. The primary outcome parameter is a combined endpoint consisting of major bleeding including hemorrhagic stroke, severe thromboembolic complications including ischemic stroke, and mortality at 6 months. Discussion We hypothesize that with lower anticoagulation targets or anticoagulation with LMWH during ECMO therapy, patients will have fewer hemorrhagic complications without an increase in thromboembolic complication or a negative effect on their outcome. If our hypothesis is confirmed, this study could lead to a change in anticoagulation protocols and a better outcome for patients treated with ECMO. Trial registration ClinicalTrials.gov NCT04536272 . Registered on 2 September 2020. Netherlands Trial Register NL7969

For a nationwide real-word data study on the application of predictive mutation testing of patients with colorectal cancer (CRC) for anti-epidermal growth factor receptor (EGFR) therapy stratification, pathology data were collected from the Dutch Pathology Registry from October 2017 until June 2019 (N=4060) and linked with the Netherlands Cancer Registry. Mutation testing rates increased from 24% at diagnosis of stage IV disease to 60% after 20–23 months of follow-up (p<0.001). Application of anti-EGFR therapy in KRAS/NRAS wild-type patients was mainly observed from the third treatment line onwards (65% vs 17% in first/second treatment line (p<0.001)). The national average KRAS/NRAS/BRAF mutation rate was 63.9%, being similar for next-generation sequencing (NGS)-based approaches and single gene tests (64.4% vs 61.2%, p=ns). NGS-based approaches detected more additional potential biomarkers, for example, ERBB2 amplifications (p<0.05). Therefore, single gene tests are suitable to stratify patients with mCRC for anti-EGFR therapy, but NGS is superior enabling upfront identification of therapy resistance or facilitate enrolment into clinical trials.

Background: Preparing for HPV vaccine programs, studies are needed of HPV infection in different populations. Goal: The goal was to evaluate HPV prevalence and determinants in Concordia, Argentina. Study Design: A stratified random sample of 1786 households was obtained. Consenting women aged ≥15 years were interviewed and underwent examination, including colposcopy. Cells were collected for a Papanicolaou smear and HPV DNA testing with GP5+/6+ primermediated PCR-EIA. Results: PCR was performed on specimens from 987 women. Prevalence among women reporting no previous sexual activity was 3%, and among sexually active women it was 17.7%, peaking at <25 years of age and decreasing to a minimum at ≥65 years of age. However, low-risk types had similar prevalence (~5%) in all age groups. HPV16 (4.0%), HPV35 (2.6%), and other high-risk types were the most common. Almost half of infections were multiple. Younger women initiated sexual activity earlier and had more partners. The main determinants of HPV detection were lifetime number of sex partners and vaginal discharge. Conclusion: A clear pattern of decreasing prevalence of HPV with age was observed. This could be explained by development of immunity against specific types over time or related to a cohort effect associated with a recent spread of HPV in this population after recent changes in sexual behavior.

Background Glatiramer acetate (GA) and interferon-beta (IFN-β) are disease-modifying therapies (DMTs) for multiple sclerosis that are administered through subcutaneous (SC) or intramuscular (IM) injections. Skin reactions associated with DMTs are common and may influence patient’s health-related quality of life (QoL). We aimed to determine the prevalence of cutaneous adverse events associated with long-term DMT use, and to assess the impact of cutaneous adverse events on QoL. Methods A cross-sectional study among patients with multiple sclerosis who had been treated with their first DMT for at least 2 years. Cutaneous events were assessed from photographs of injection-sites by dermatologists blinded for DMT. Generic and dermatology-specific health-related QoL were assessed using validated patient-reported questionnaires. Results A total of 229 patients were enrolled, of whom 156 (68%) had at least one skin reaction. The prevalence of cutaneous adverse events was higher for SC DMTs (75-82%) compared to IM DMT (41%) (P < 0.001). Erythema and lipoatrophy were the most common skin reactions, observed in 156 (68%) and 45 (20%) patients, respectively. Dermatology-specific, but not generic, QoL was significantly lower among patients with skin reactions compared to those without. Conclusions The prevalence of cutaneous adverse events was high in long-term DMT-treatment. Patients with cutaneous adverse events had a lower perceived dermatology-specific QoL.

Seroreactivity to human papillomavirus type 16 (HPV-16) virus-like particles (VLPs) in men attending clinics for sexually transmitted diseases (STDs) in Denmark (n = 219) and Greenland (n = 88) was compared with seroreactivity in women attending the same clinics and was furthermore related to epidemiologic variables and concurrent HPV DNA detection. Risk factors for male seropositivity in Denmark were lifetime number of sex partners, a history of STDs, and sexual preference and in Greenland were ever having had syphilis and years at school. Although men reported significantly more sex partners, the mean seroreactivity was significantly lower in men than in women: 0.50 and 0.75, respectively, in Denmark and 0.53 and 0.86 in Greenland (P = .0001). Male seropositivity was not correlated with concurrent HPV DNA detection, but only 15 Danish and 6 Greenlandic men had HPV-16 DNA. Presence of HPV-16 VLP antibodies appears to be a biomarker for exposure to genital HPVs in men but is less sensitive than in women.