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The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout ( Ces1 -/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 -/- background (TgCES1). Ces1 -/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 -/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 -/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 -/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical peripheral polyarthritis in the hands and/or feet, leading to long-term disability if not treated effectively. RA is preceded by a preclinical phase, in which genetically predisposed individuals accumulate environmental risk factors, and during which autoimmunity develops, followed by the emergence of non-specific signs and symptoms before arthritis becomes manifest. Early treatment in at-risk individuals - i.e. before the disease is fully established - has the theoretical potential to delay or prevent disease onset, with a positive impact on both patients' life and society., Objectives: We aimed to understand the feasibility of preventive treatment in at-risk individuals, taking into account recently performed studies and ongoing clinical trials, as well as patient perspectives., Methods: We performed a systematic literature review (SLR) on Medline and Embase, searching articles published between 2010 and 2021 with the following key-words: "Rheumatoid arthritis", "arthralgia", "pre-treatment" or "prevent"., Results: Our SLR identified a total of 1821 articles. Articles were independently screened by two researchers. A total of 14 articles were included after screening, and an additional 8 reports were manually included. We identified ten relevant clinical trials performed in at-risk individuals, or in individuals with undifferentiated inflammatory arthritis. Although no treatment was shown to prevent RA onset, early treatment with rituximab and abatacept delayed onset of full-blown RA, and both conventional and biological disease-modifying anti-rheumatic drugs (DMARDs) decreased disease-related physical limitations and increased DAS28-defined remission, at least temporarily., Conclusions: This SLR demonstrates that early treatment of at-risk individuals may be effective in delaying RA onset, thereby decreasing disease-related limitations in individuals in the pre-clinical phase of RA. Whether this may ultimately lead to prevention of RA remains to be determined., Competing Interests: Declaration of Competing Interest SWT and NdV were involved in the PRAIRI trial and are co-authors on the publication., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems., Patients and Methods: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of C min below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments)., Results: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%)., Conclusions: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably., Competing Interests: Disclosure IMED reported funding for investigator-initiated research by Novartis. NPvE reported funding for investigator-initiated research by Janssen-Cilag, and Astellas, and a speaker fee by Bayer (outside the submitted work). RHJM reported funding for investigator-initiated research by Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi and Servier (outside the submitted work). NS reported consultation or attendance of advisory boards for AIMM Therapeutics, Boehringer-Ingelheim and Ellipses Pharma; research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, Lilly, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho and Takeda (outside the submitted work). All other authors have declared no conflicts of interest. All authors confirm that they had full access to all data in the study and accept responsibility to submit for publication. Data sharing Data from this study can be made available to other researchers in the field upon request and approval by the Dutch Pharmacology Oncology Group and subject to appropriate data transfer agreements. Requests should be directed to SLG and NS., (Copyright © 2022. Published by Elsevier Ltd.)

The aim of this study was to explore effects of a major urban reconstruction on physical activity (PA) behavior by comparing PA intensity hotspots before and after the tunneling of a highway with a new infrastructure prioritized for walking and cycling. In total, 126 individuals participated before and after the tunneling. GPS loggers and accelerometers were used to assess location and PA levels. A geographic information system (GIS) was used to perform optimized hotspot analyses on PA data, both on transport and stationary data points. The results showed several changes in PA hotspots on trip data, even if total PA levels did not change. At follow-up, PA intensity hotspots were more connected, with the new infrastructure as a central connection. This was true for higher and lower educated individuals. Therefore, if changes in the built environment do not result in changes on population-level outcomes, this does not imply that they have no impact on behavior., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Severe obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular disease. Experimental evidence suggests that this risk may be mediated by chronic sympathetic hyperactivation and systemic inflammation, but the precise mechanisms remain to be unraveled. Our aim was to evaluate whether severe OSA patients are characterized by increased sympathetic and hematopoietic activity, potentially driving atherosclerosis., Methods: Untreated patients with severe OSA (apnea-hypopnea index (AHI) > 30 per hour) were matched with mild OSA patients (AHI<15 & >5 per hour) according to age, sex, and body mass index. Study objectives were to assess baroreflex sensitivity (BRS) and heart-rate variability (HRV) using continuous finger blood pressure measurements, hematopoietic activity in the bone marrow and spleen, and arterial inflammation with 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT)., Results: A total of 34 subjects, 17 per group, were included in the analysis. Mean age was 60.7 ± 6.2 years, 24 (70.6%) were male. Mean AHI was 40.5 ± 12.6 per hour in the severe OSA group, and 10.5 ± 3.4 per hour in the mild OSA group. Participants with severe OSA were characterized by reduced BRS (5.7 [4.6-7.8] ms/mmHg in severe vs 8.2 [6.9-11.8] ms/mmHg in mild OSA, p = 0.033) and increased splenic activity (severe OSA 18 F-FDG uptake 3.56 ± 0.77 vs mild OSA 3.01 ± 0.68; p = 0.036). HRV, bone marrow activity and arterial inflammation were comparable between groups., Conclusions: Patients with severe OSA are characterized by decreased BRS and increased splenic activity. Randomized controlled trials are warranted to assess whether OSA treatment reduces sympathetic and splenic activity., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited., Methods: A prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma., Results: A total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01)., Conclusions: A high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

An liquid chromatography-mass spectrometry (LC-MS/MS) assay was developed for the combined analysis of the five poly (ADP-ribose) polymerase (PARP) inhibitors niraparib, olaparib, rucaparib talazoparib and veliparib. A simple and fast sample pre-treatment method was used by protein precipitating of plasma samples with acetonitrile and dilution of the supernatant with formic acid (0.1% v/v in water). This was followed by chromatographic separation on a reversed-phase UPLC BEH C18 column and detection with a triple quadrupole mass spectrometer operating in the positive mode. A simplified validation procedure specifically designed for bioanalytical methods for clinical therapeutic drug monitoring (TDM) purposes, was applied. This included assessment of the calibration model, accuracy and precision, lower limit of quantification (LLOQ), specificity and selectivity, carry-over and stability. The validated range was 30-3000 ng/mL for niraparib, 100-10,000 ng/mL for olaparib, 50-5000 ng/mL for rucaparib, 0.5-50 ng/mL for talazoparib and 50-5000 for veliparib. All results were within the criteria of the US Food and Drug Administration (FDA) guidance and European Medicines Agency (EMA) guidelines on method validation. The assay has been successfully implemented in our laboratory., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A liquid chromatography-mass spectrometry assay was developed and validated for simultaneous quantification of anti-hormonal compounds abiraterone, anastrozole, bicalutamide, Δ(4)-abiraterone (D4A), N-desmethyl enzalutamide, enzalutamide, Z-endoxifen, exemestane and letrozole for the purpose of therapeutic drug monitoring (TDM). Plasma samples were prepared with protein precipitation. Analyses were performed with a triple quadrupole mass spectrometer operating in the positive and negative ion-mode. The validated assay ranges from 2 to 200 ng/mL for abiraterone, 0.2-20 ng/mL for D4A, 10-200 ng/mL for anastrozole and letrozole, 1-20 ng/mL for Z-endoxifen, 1.88-37.5 ng/mL for exemestane and 1500-30,000 ng/mL for enzalutamide, N-desmethyl enzalutamide and bicalutamide. Due to low sensitivity for exemestane, the final extract of exemestane patient samples should be concentrated prior to injection and a larger sample volume should be prepared for exemestane patient samples and QC samples to obtain adequate sensitivity. Furthermore, we observed a batch-dependent stability for abiraterone in plasma at room temperature and therefore samples should be shipped on ice. This newly validated method has been successfully applied for routine TDM of anti-hormonal drugs in cancer patients., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

This systematic review examined the effect of built environment infrastructural changes (BEICs) on physical activity (PA), active transportation (AT) and sedentary behavior (SB). A literature search resulted in nineteen eligible articles. On- and off-road bicycling and/or walking trails resulted in inconsistent effects on overall PA and walking, and in predominantly positive effects on bicycling. More extensive BEICs led to mixed results, with mainly non-significant effects. However, positive effects on bicycling were found for people living closer to BEICs. None of the studies assessed SB. Improved understanding of the potential of BEICs to increase PA levels and decrease SB at population level asks for more high-quality, in-depth research, that takes into account the broader system., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: One third of bariatric surgery patients have an apnea-hypopnea index (AHI)>15/hr, representing moderate and severe forms of obstructive sleep apnea (OSA). Treating these forms of OSA is recommended to reduce the risk of perioperative complications. The AHI derived from poly(somno)graphy [P(S)G] is the gold standard for OSA diagnosis. However, performing P(S)G in all patients scheduled for bariatric surgery is time consuming and expensive. An accurate and simple screening tool able to rule out moderate to severe OSA would reduce the number of patients needing mandatory P(S)Gs., Objectives: To assess the validity of a simple sleep monitor (Checkme Health Monitor) as a screening tool for OSA in bariatric surgery patients., Setting: Obesity Center Amsterdam, OLVG-West, Amsterdam, the Netherlands METHODS: Patients scheduled for bariatric surgery were prospectively enrolled in this study. All patients underwent preoperative P(S)G and simultaneously used the Checkme to assess the oxygen desaturation index. The diagnostic performance of the Checkme for AHI ≥15/hr was assessed using receiver operating characteristic curve analysis., Results: A total of 50 patients were analyzed. Sensitivity and negative predictive value were 100% and 100%, respectively, specificity and positive predictive value were 69% and 64%, respectively, for the optimal cutoff value of Checkme-3% oxygen desaturation index ≥9/hr for P(S)G-AHI ≥15. The area under the curve value expressed by the receiver operating characteristic curve was .95., Conclusion: The Checkme is valid for exclusion of moderate and severe OSA in bariatric surgery patients. The Checkme enables bariatric clinics not to perform P(S)G in all patients scheduled for bariatric surgery., (Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Stress and anxiety levels are elevated among university and college students. Although high stress levels can lead to an increase in adiposity, it is not clear whether stress and anxiety experienced when in university or college have an influence on students' weight., Objective: The aim of this systemic review was to investigate whether stress and anxiety levels encountered during university and college enrollment were associated with higher adiposity or weight changes among students., Method: A search strategy was used to identify peer-reviewed studies published between 1985 and March 2017 using the following databases: Medline using Ovid; PubMed, CINAHL using EBSCO, Embase using Ovid, PSYCHINFO, and Open Access Theses and Dissertation. Two reviewers independently assessed the title, abstract, and then the full article of the studies that met the inclusion criteria. Data were extracted and quality assessment was conducted for the included studies., Results: Twenty-five observational studies were identified in this review (23 cross-sectional and two longitudinal); 11 found that there was no association between stress and body mass index or weight change. In addition, five studies did not find a significant association between anxiety and body mass index. A few studies revealed stress and anxiety might be associated with higher or lower weight status, thus there is a possibility that stress can increase or decrease weight, demonstrating that a bidirectional influence on body mass index may exist., Conclusions: The current data in this review are inadequate to draw firm conclusions about the role of stress on weight change in university and college students. The inconsistency of results in the literature reviewed for this article suggest that a focus on longitudinal studies with adequate sample size would better evaluate the relationship between stress or anxiety and its influence on weight status or weight change among college and university students., (Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: Obstructive sleep apnea (OSA) affects two third of morbidly obese individuals undergoing bariatric surgery. Perioperative usage of continuous positive airway pressure (CPAP) is advised for moderately and severe OSA to avoid respiratory failure and cardiac events. CPAP increases the air pressure in the upper airway, but also may elevate the air pressure in the esophagus and stomach. Concern exists that this predisposes to mechanical stress resulting in suture or staple line disruption (further referred to as suture line disruption)., Objectives: To evaluate whether perioperative CPAP usage is associated with an increased risk of suture line disruption after bariatric surgery., Setting: Obesity Center Amsterdam, OLVG-west, Amsterdam, the Netherlands., Methods: All patients who underwent bariatric surgery including a suture line were eligible for inclusion. Only patients with information regarding OSA severity as defined by the apnea-hypopnea-index and postoperative CPAP usage were included., Results: From November 2007 to August 2016, postoperative CPAP status was documented in 2135 patients: 497 (23.3%) used CPAP postoperatively, whereas 1638 (76.7%) used no CPAP. Mean body mass index was 44.1 kg/m 2 (standard deviation 6.6). Suture line disruption occurred in 25 patients (1.2%). The leakage rate was not associated with CPAP usage (8 [1.6%] in CPAP group versus 17 [1%] in non-CPAP group, P = .300). CPAP was no risk factor for suture line disruption in multivariable analysis as well., Conclusion: Postoperative CPAP does not appear to increase the risk of suture line disruption in bariatric surgery. CPAP is recommended in all patients with moderate or severe OSA who undergo bariatric surgery., (Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The frequency of metabolic and bariatric surgery (MBS) is increasing worldwide, with over 500,000 cases performed every year. Obstructive sleep apnea (OSA) is present in 35%-94% of MBS patients. Nevertheless, consensus regarding the perioperative management of OSA in MBS patients is not established., Objectives: To provide consensus based guidelines utilizing current literature and, when in the absence of supporting clinical data, expert opinion by organizing a consensus meeting of experts from relevant specialties., Setting: The meeting was held in Amsterdam, the Netherlands., Methods: A panel of 15 international experts identified 75 questions covering preoperative screening, treatment, postoperative monitoring, anesthetic care and follow-up. Six researchers reviewed the literature systematically. During this meeting, the "Amsterdam Delphi Method" was utilized including controlled acquisition of feedback, aggregation of responses and iteration., Results: Recommendations or statements were provided for 58 questions. In the judgment of the experts, 17 questions provided no additional useful information and it was agreed to exclude them. With the exception of 3 recommendations (64%, 66%, and 66% respectively), consensus (>70%) was reached for 55 statements and recommendations. Several highlights: polysomnography is the gold standard for diagnosing OSA; continuous positive airway pressure is recommended for all patients with moderate and severe OSA; OSA patients should be continuously monitored with pulse oximetry in the early postoperative period; perioperative usage of sedatives and opioids should be minimized., Conclusion: This first international expert meeting provided 58 statements and recommendations for a clinical consensus guideline regarding the perioperative management of OSA patients undergoing MBS., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Patients with severe obesity and obstructive sleep apnea (OSA) might decide to undergo bariatric surgery to improve this disease or, more specifically, to become independent of continuous positive airway pressure (CPAP) therapy, which is generally indicated in case of moderate and severe OSA. Knowledge of this topic is important for patient education on expectations of surgical outcome., Objectives: To evaluate the prevalence and phenotypes of patients with persistent moderate to severe OSA after bariatric surgery., Setting: Obesity Center Amsterdam, Amsterdam, the Netherlands., Methods: Patients who underwent a laparoscopic Roux-en-Y gastric bypass, had a preoperative apnea-hypopnea index (AHI)≥15/hr, and of whom a follow-up AHI/hr was available were included., Results: Out of 437 patients, 205 underwent pre- and postoperative polysomnography; 232 (53.1%) were lost to follow-up. Median AHI was 32.3/hr (range, 15-138) and mean body mass index was 46 (standard deviation 7.2) kg/m 2 . A postoperative AHI<15/hr was achieved in 152 patients (74.1%), whereas 53 (25.9%) still had moderate or severe disease 8.6 (standard deviation 4.8) months postoperatively. Predictive factors for persistent moderate to severe disease were age≥50 years, preoperative AHI≥30/hr, excess weight loss (EWL)<60%, and hypertension (area under the curve: .772)., Conclusion: After bariatric surgery, around three quarters of the moderate to severe OSA patients had no or mild OSA, whereas one quarter (25.9%) still had moderate to severe OSA. Age≥50 years, preoperative AHI≥30/hr, EWL<60%, and hypertension were predictive factors for this persistent postoperative AHI≥15/hr., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Assess the effect of intensive nutrition education by trained dedicated dietitians on osteodystrophy management among hemodialysis patients., Methods: Randomized controlled trial in 12 hospital-based hemodialysis units equally distributed over clusters 1 and 2. Cluster 1 patients were either assigned to usual care (n=96) or to individualized intensive staged-based nutrition education by a dedicated renal dietitian (n=88). Cluster 2 patients (n=210) received nutrition education from general hospital dietitians, educating their patients at their spare time from hospital duties. Main outcomes were: (1) dietary knowledge(%), (2) behavioral change, (3) serum phosphorus (mmol/L), each measured at T0 (baseline), T1 (post 6 month intervention) and T2 (post 6 month follow up)., Results: Significant improvement was found only among patients receiving intensive education from a dedicated dietitian at T1; the change regressed at T2 without statistical significance: knowledge (T0: 40.3; T1: 64; T2: 63) and serum phosphorus (T0: 1.79; T1: 1.65; T2: 1.70); behavioral stages changed significantly throughout the study (T0: Preparation, T1: Action, T2: Preparation)., Conclusion: The intensive protocol showed to be the most effective., Practice Implications: Integrating dedicated dietitians and stage-based education in hemodialysis units may improve the nutritional management of patients in Lebanon and countries with similar health care systems., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: With the increasing burden of noncommunicable disease, adolescence is viewed as an opportune time to prevent the onset of certain behaviors and promote healthy states. Although adolescents comprise a considerable portion of Saudi Arabia's population, they have received insufficient attention and indicators of their health status, as a first step in a prevention cycle are unavailable. This study was carried out with the aim of identifying the health risk behaviors and health status of adolescents in Saudi Arabia., Methods: This cross-sectional, school-based study was carried out in all 13 regions of Saudi Arabia. Through multistage, cluster, random sampling, intermediate, and secondary school students were invited to participate. Data were collected by means of a self-administered questionnaire addressing health risk behaviors and health status, clinical anthropometric measurements, and laboratory investigations., Results: A total of 12,575 adolescents participated. Various health risk behaviors, including dietary and sedentary behaviors, lack of safety measures, tobacco use, bullying, and violence were highly prevalent. Twenty-eight percent of adolescents reported having a chronic health condition, 14.3% reported having symptoms suggestive of depression, 30.0% were overweight/obese, and 95.6% were vitamin D deficient., Conclusion: Behaviors and conditions known to persist into adulthood and result in morbidity and premature mortality are prevalent among adolescents in Saudi Arabia. Preventive measures and local health policies are urgently needed and can impact adolescents and future adults. Establishing adolescent health surveillance is necessary to monitor trends and impacts of such measures., (Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The placenta plays a crucial role during pregnancy and dysfunction causes long-term neurological problems. Identifying placenta-related risks for neurological problems shortly after birth may provide clues for early interventions aiming to improve neurological outcome., Objective: To determine the association between placental pathology and neurological morbidity in preterm infants during the first two weeks after birth., Study Design: Placentas of 52 singleton, preterm infants (GA: 25-31weeks, BW: 560-2250 grammes) were examined for histopathology. The infants' neurological condition shortly after birth was determined by assessing the quality of their general movements (GMs): normal, abnormal, or hypokinetic, on days 5, 8, and 15. A motor optimality score (MOS) was also assigned., Results: Examination of the placentas revealed maternal vascular underperfusion (n=29), ascending intrauterine infection (AIUI) (n=19), villitis of unknown aetiology (n=6), chronic deciduitis (n=11), foetal thrombotic vasculopathy (FTV) (n=9), and elevated nucleated red blood cells (NRBCs) as a marker for foetal hypoxia (n=7). None of the placental lesions were significantly associated with the quality of GMs or MOS., Conclusions: This study indicated that placental lesions were not associated with infants' neurological condition as measured by the quality of their general movements during the first two weeks after birth., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Despite potential clinical importance, target cells for mother-to-child transmission of HIV-1 have not yet been identified. Cord blood-derived CD4(+) T cells are largely naive and do not express CCR5, the mandatory coreceptor for transmitted HIV-1 R5 strains in infants. In the present study, we demonstrate that in the human fetal and infant gut mucosa, there is already a large subset of mucosal memory CD4(+)CCR5(+) T cells with predominantly a Th1 and Th17 phenotype. Using next-generation sequencing of the TCRβ chain, clonally expanded T cells as a hallmark for memory development predominated in the gut mucosa (30%), whereas few were found in the lymph nodes (1%) and none in cord blood (0%). The gut mucosal fetal and infant CD4(+) T cells were highly susceptible to HIV-1 without any prestimulation; pol proviral DNA levels were similar to infected phytohemagglutinin-stimulated adult PBMCs. In conclusion, in the present study, we show that extensive adaptive immunity is present before birth and the gut mucosa is the preferential site for memory CD4(+) T cells. These CD4(+)CCR5(+) T cells in the infant mucosa provide a large pool of susceptible cells for ingested HIV-1 at birth and during breastfeeding, indicating a mucosal route of mother-to-child transmission that can be targeted in prevention strategies.

Objective: Despite the efficacy of collagen in femoral artery pseudoaneurysm treatment, as reported in one patient study, its use has not yet gained wide acceptance in clinical practice. In this particular study, the collagen was not described in detail. To further investigate the potential of collagen preparations, we prepared and characterized highly purified injectable fibrillar type I collagen and evaluated its use for femoral artery pseudoaneurysm (PSA) treatment in vivo using a pig model., Methods: Purified fibrillar type I collagen was characterized using electron microscopy. The effect of three different sterilization procedures, ie, hydrogen peroxide gas plasma (H2O2), ethylene oxide gas (EtO), and gamma irradiation, was studied on both SDS-PAGE and platelet aggregation. Different collagen injectables were prepared (3%, 4%, and 5%) and tested using an injection force test applying a 21-gauge needle. To evaluate the network characteristics of the injectable collagen, the collagen was suspended in phosphate buffered saline (PBS) at 37°C and studied both macroscopically and electron microscopically. To determine whether the collagen induced hemostasis in vivo, a pig PSA model was used applying a 4% EtO sterilized collagen injectable, and evaluation by angiography and routine histology., Results: Electron microscopy of the purified type I collagen revealed intact fibrils with a distinct striated pattern and a length<300 μm. Both SDS-PAGE and platelet aggregation analysis of the sterilized collagen indicated no major differences between EtO and H2O2 sterilization, although gamma-irradiated collagen showed degradation products. Both 3% and 4% (w/v) collagen suspensions were acceptable with respect to the force used (<50 N). The 4% suspension was selected as the preferred injectable collagen, which formed a dense network under physiologic conditions. Testing the collagen in vivo (n=5), the angiograms revealed that the PSA partly or completely coagulated. Histology confirmed the network formation, which was surrounded by thrombus., Conclusions: Collagen injectables were prepared and EtO sterilized without major loss of structural integrity and platelet activity. In vivo, the injectable collagen formed a dense network and triggered (partial) local hemostasis. Although optimization is needed, an injectable collagen may be used as a therapeutic agent for femoral PSA treatment., (Copyright © 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: The assessment of the quality of general movements (GMs) in preterm infants early in life has been used mainly to determine temporary or permanent neurological dysfunction and not to predict outcome., Aim: Assessing the quality and evolution of GMs during the first ten days of life in preterm infants, and relating them to clinical factors and neurological outcome at 24months' post-term., Methods: Using Prechtl's method, the GM quality was assessed in 45 preterm infants on days 2, 4, 6 and 10. They were related to clinical factors and outcome. After GM assessment, an extra item was scored: chaotic features (ChF). ChF was defined as chaotic GMs or poor repertoire GMs+chaotic movements., Results: Abnormal GMs were seen mostly in early recordings. A better GM trajectory correlated with a higher birth weight, a higher gestational age and a lower Nursery Neurobiologic Risk Score (NBRS). Predictive value for normal outcome of at least one normal GM was 94%. Predictive value for abnormal outcome of only abnormal GMs was 21%. ChF were seen mostly in early recordings. Occurrence of ChF on day 2 correlated with lower serum calcium., Conclusions: Preterm infants often showed abnormal GMs during the first few days. This was related mostly to a higher NBRS. Normalization of GMs during the first ten days was associated with a lower NBRS and was a reliable predictor for neurological outcome. ChFs could be a GM quality that is associated to lower calcium, indicating hyperexcitability of the nervous system., (2010 Elsevier Ltd. All rights reserved.)

Objective: To assess the quality of general movements (GMs) in the first fourteen days of life in relation to obstetric and postnatal risk factors and neurodevelopmental outcome in extremely low birth weight (ELBW) infants., Study Design: The GMs of nineteen infants were assessed on days 2, 4, 6, 10 and 14 with Prechtl's method. Additionally, detailed GM assessment produced optimality scores (OSs). GMs and the OSs were related to obstetric and postnatal data and to neurodevelopmental outcome at 18 months., Results: GMs and OSs fluctuated substantially during the first fourteen days of life. Most infants had abnormal GMs, especially poor repertoire (PR) GMs. No relation was found between GMs and obstetric factors. Regarding postnatal factors, septicaemia correlated to hypokinesia (H) and artificial ventilation correlated to a lower OS., Conclusions: Due to physiological disturbances the quality of GM in ELBW infants fluctuates substantially during the first fourteen days of life. Abnormal GMs, especially PR GMs, are mostly seen for the same reason. Septicaemia and artificial ventilation are associated with deterioration of the GMs (lower OSs), and in case of septicaemia also with hypokinesia.

Background: Presently there is no consensus regarding the extent of workup required in newborns who present with an isolated single umbilical artery (SUA). Because of the association with silent renal anomalies, some studies advise to perform renal ultrasonography in infants born with an isolated SUA., Aims: To decide whether screening (performing a renal ultrasound and in case of abnormalities on the ultrasound performing a micturating cystourethrogram) infants with an isolated SUA is justified by evaluating the prevalence of clinically relevant renal abnormalities., Study Design: Retrospective descriptive study., Subjects: Live-born infants with SUA detected by physical examination born between January 1st, 1997 and February 1st, 2005, in a tertiary care university hospital., Outcome Measures: Renal anomalies detected by renal ultrasonography and a micturating cystourethrogram in infants with abnormalities on renal ultrasound., Results: We included 52 live-born infants with an isolated SUA. Renal ultrasonography was performed in 92.3% of these 52 infants. In this group, abnormalities were found in 5 infants (10.4 %) on renal ultrasound. A relative subpelvine stenosis was detected in 1 infant, the other abnormalities on renal ultrasound were mild hydronephrosis without further consequences., Conclusion: Our data suggest that it is not necessary to screen for renal anomalies in infants with a single umbilical artery without other anomalies seen at physical examination.

In this paper we describe self-reported health problems and haemoglobin status among 1200 Sudanese adolescents (53.2% females, 46.8% males). Many adolescents report their general health as excellent and good (84%). A large number, however, report separate physical and psychological complaints. Report of psychological complaints is equal for both gender, and more psychological problems are reported with increasing age. Females and age groups 13-15 more often report chronic diseases. Malaria consistently has a relatively high prevalence. The overall prevalence of anaemia in our study is 32% (46.9% males, 19.2% females). The findings in our study do not sustain the traditional assumption that adolescence is a healthy period in human life. Implications for Sudanese health policies are discussed.

Many diseases that have a substantial effect on health have a complex pathogenesis. Examples are atherosclerosis, diabetes mellitus, and rheumatoid arthritis. Here, we discuss a hierarchy of goals of research in complex diseases, and introduce a stepwise approach for the development of disease models, paying specific attention to the position of genetic factors and stochastic variables in these models.

Fifty-four patients with laryngeal cancer and lung cancer were analyzed with regard to histology and localization of the lung cancer, the time interval between the detection of the two tumours and survival. It appeared that most lung tumours were squamous cell carcinomas, half of which were centrally localized and most occurred metachronously in the first 4 years after the laryngeal carcinoma. The survival rate was poor, due to the fact that the bronchial carcinoma usually was found beyond a curative stage. It appears that the present follow-up in laryngeal cancer patients--frequent ENT-examination, yearly chest X-ray examination--is often inadequate for early detection of lung cancer and curative treatment. It might be that by intensifying follow-up in laryngeal cancer patients by bronchoscopy, sputum cytology and more frequent chest X-ray examination, more bronchial carcinomas would be detected in a curative stage.