Suboptimal factors in maternal and newborn care for refugees: Lessons learned from perinatal audits in the Netherlands.

INTRODUCTION: Refugees and their healthcare providers face numerous challenges in receiving and providing maternal and newborn care. Research exploring how these challenges are related to adverse perinatal and maternal outcomes is scarce. Therefore, this study aims to identify suboptimal factors in maternal and newborn care for asylum-seeking and refugee women and assess to what extent these factors may contribute to adverse pregnancy outcomes in the Netherlands. METHODS: We conducted a retrospective analysis of national perinatal audit data from 2017 to 2019. Our analysis encompassed cases with adverse perinatal and maternal outcomes in women with a refugee background (n = 53). Suboptimal factors in care were identified and categorized according to Binder et al.'s Three Delays Model, and the extent to which they contributed to the adverse outcome was evaluated. RESULTS: We identified 29 suboptimal factors, of which seven were related to care-seeking, six to the accessibility of services, and 16 to the quality of care. All 53 cases contained suboptimal factors, and in 67.9% of cases, at least one of these factors most likely or probably contributed to the adverse perinatal or maternal outcome. CONCLUSION: The number of suboptimal factors identified in this study and the extent to which they contributed to adverse perinatal and maternal outcomes among refugee women is alarming. The wide range of suboptimal factors identified provides considerable scope for improvement of maternal and newborn care for refugee populations. These findings also highlight the importance of including refugee women in perinatal audits as it is essential for healthcare providers to better understand the factors associated with adverse outcomes to improve the quality of care. Adjustments to improve care for refugees could include culturally sensitive education for healthcare providers, increased workforce diversity, minimizing the relocation of asylum seekers, and permanent reimbursement of professional interpreter costs.

Central-line-associated bloodstream infection burden among Dutch neonatal intensive care units.

BACKGROUND: The establishment of an epidemiological overview provides valuable insights needed for the (future) dissemination of infection-prevention initiatives. AIM: To describe the nationwide epidemiology of central-line-associated bloodstream infections (CLABSI) among Dutch Neonatal Intensive Care Units (NICUs). METHODS: Data from 2935 neonates born at <32 weeks' gestation and/or with a birth weight <1500 g admitted to all nine Dutch NICUs over a two-year surveillance period (2019-2020) were analysed. Variations in baseline characteristics, CLABSI incidence per 1000 central-line days, pathogen distribution and CLABSI care bundles were evaluated. Multi-variable logistic mixed-modelling was used to identify significant predictors for CLABSI. RESULTS: A total of 1699 (58%) neonates received a central line, in which 160 CLABSI episodes were recorded. Coagulase-negative staphylococci were the most common infecting organisms of all CLABSI episodes (N=100, 63%). An almost six-fold difference in the CLABSI incidence between participating units was found (2.91-16.14 per 1000 line-days). Logistic mixed-modelling revealed longer central line dwell-time (adjusted odds ratio (aOR):1.08, P<0.001), umbilical lines (aOR:1.85, P=0.03) and single rooms (aOR:3.63, P=0.02) to be significant predictors of CLABSI. Variations in bundle elements included intravenous tubing care and antibiotic prophylaxis. CONCLUSIONS: CLABSI remains a common problem in preterm infants in The Netherlands, with substantial variation in incidence between centres. Being the largest collection of data on the burden of neonatal CLABSI in The Netherlands, this epidemiological overview provides a solid foundation for the development of a collaborative platform for continuous surveillance, ideally leading to refinement of national evidence-based guidelines. Future efforts should focus on ensuring availability and extraction of routine patient data in aggregated formats.

Gametic differentiation in Chlamydomonas reinhardtii. II. Flagellar membranes and the agglutination reaction.

A structural and biochemical study is presented concerning the agglutination of gametic flagella, the initial step in the mating reaction of Chlamydomonas reinhardtii. An alteration in the distribution of the intramembranous particles revealed by freeze-fracturing of flagella membranes is shown to accompany gametic differentiation in both mating types. The isolation and electrophoretic analysis of flagellar membranes and mastigonemes are reported; no electrophoretic differences can be detected when the membrane or mastigoneme glycoproteins from vegative and gametic cells are compared, nor when glycoproteins from the two mating types are compared, and no novel polypeptides are present in gametic preparations. The membrane vesicles, after they are freed of mastigonemes by sedimentation through a discontinuous sucrose gradient, are extremely active as an isoagglutinin, indicating a direct involvement of the membrane in the mating reaction.

Quality of child-parent attachment moderates the impact of antenatal stress on child fearfulness.

BACKGROUND: Animal studies have shown that prenatal stress has persisting effects on several aspects of offspring development; more recent studies show that this effect may be eliminated by positive postnatal rearing. Human studies of prenatal anxiety/stress are now also beginning to document links between antenatal stress/anxiety and behavioural and cognitive development of the child; however, there is no human evidence as to whether the early caregiving environment moderates the effect of antenatal anxiety/stress on child outcomes. METHODS: Antenatal and postnatal measures of stress were collected on 123 women who were recruited from an antenatal clinic. Laboratory-based assessment of the children's cognitive development and fearfulness were assessed when the children were aged 17 months. In addition, child-parent attachment quality was assessed using the Strange Situation. RESULTS: Attachment classification moderated the link between antenatal stress and observed fearfulness. The effect of antenatal stress on fearfulness was most accentuated in children with an Insecure/Resistant attachment classification; the significant antenatal stress x attachment classification interaction held after controlling for postnatal stress and obstetric, social and demographic factors. Attachment did not moderate the effects of antenatal anxiety on cognitive development. DISCUSSION: These findings provide the first human evidence that postnatal parenting may moderate the adverse effects of antenatal stress. These results raise developmental questions about the timing and effect of interventions to reduce the adverse effects of antenatal stress exposure.

[Neonatal infection with Listeria monocytogenes: rare, but serious]. / Neonatale infectie met listeria monocytogenes: zeldzaam, maar ernstig.

Between 1993 and 2003, three infants, two girls and a boy, were found to have an invasive infection with Listeria monocytogenes. They received intensive care including respiratory and circulatory support, antibiotics, and treatment of the neurological complications when possible. One of the girls survived without sequelae but the other two infants died in the neonatal period. In one of these two cases there was a clear clue to the source of the infection in the dietary history of the mother: she had consumed unpasteurised cow's milk. The mothers ofthe infants that died had developed fever shortly before parturition. In The Netherlands, the incidence of neonatal invasive infection with Listeria is estimated at 1.3 per 100,000 live-born children per year. This figure seems not to have changed in the last 20 years. Because of the risk of this rare but serious infection, dietary advice to pregnant women to avoid possibly contaminated food is still relevant.

[Primary cytomegalovirus infection in the postnatal period]. / Primaire cytomegalovirus-infectie in de postnatale periode.

A male infant born vaginally after a gestation period of 25 4/7 weeks with a birth weight of 875 g underwent surgical correction for oesophageal atresia with a distal tracheo-oesophageal fistula. Postoperative complications included seam leakage, mediastinitis with sepsis, transient elevated diaphragm, recurrent fistula and seam stenosis. Persistent ductus arteriosus was closed surgically. The further course of disease was characterised by periventricular haemorrhage, recurrent infections, bronchopulmonary dysplasia and retinopathy. Anaemia caused by the premature birth and frequent blood sampling necessitated multiple transfusions of filtered, Cytomegalovirus(CMV)-free erythrocyte concentrate. At the age of 3 months, the patient developed cholestatic jaundice that was attributed to a CMV infection contracted through breast milk. The patient recovered spontaneously. At the age of 2 years, the patient had mildly impaired psychomotor development. Reactivation of CMV during lactation is common in CMV-seropositive women. This carries a high risk of transmission of the virus through breast milk, especially for extremely premature neonates. In these infants, an early acquired postnatal CMV infection may lead to serious disorders.

Autoradiographic distribution of 14C-labeled 3H-imidazo[4,5-f]quinoline-2-amines in mice.

The highly mutagenic heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), are formed during heating of protein-rich foods. In order to gain information about the distribution and fate of IQ and MeIQ in vivo, a whole-body autoradiographic study of i.v.-injected 14C-labeled IQ and MeIQ has been performed in male NMRI, pregnant NMRI, and female C3H mice. IQ and MeIQ showed similar distribution patterns. At short survival times, the autoradiograms were characterized by an accumulation of radioactivity in metabolic and excretory organs (liver, kidney, bile, urine, gastric and intestinal contents, salivary glands, nasal mucosa, and Harder's gland), as well as in lymphomyeloid tissues (bone marrow, thymus, spleen and lymph nodes) and in endocrine and reproductive tissues (adrenal medulla, pancreatic islets, thyroid, hypophysis, testis, epididymis, seminal vesicles, ampulla, and prostate). The liver and kidney cortex were identified as sites of retention of nonextractable radioactivity. IQ and MeIQ showed a strong affinity for melanin. IQ and MeIQ passed the placenta, but no radioactivity was retained in fetal tissues. The results pinpoint the liver as a site of IQ- and MeIQ-mediated toxicity. Future studies of IQ and MeIQ may be guided by and clarify the role of other tissue localizations in the toxicity of IQ and MeIQ.

Physical training in Syndrome X: physical training counteracts deconditioning and pain in Syndrome X.

OBJECTIVES: The aim of this study was to evaluate the effects of exercise training and body-awareness training in female patients with Syndrome X. BACKGROUND: Patients with Syndrome X, defined as effort-induced angina pectoris, a positive exercise test and a normal coronary angiogram, suffer from a chronic pain disorder. We hypothesized that this disorder results in physical deconditioning with decreased exertional pain threshold. METHODS: Twenty-six patients were randomly assigned to two training groups (A, B) and a control group (C). Group A (n = 8) started, after baseline measurements, with eight weeks of body-awareness training followed by eight weeks of exercise training on a bicycle ergometer three times a week for 30 min at an intensity of 50% of peak work rate. Group B (n = 8) performed only eight weeks of exercise training. Group C (n = 10) acted as controls without any intervention whatsoever. The effects on exercise performance, hormonal secretion, vascular function, adenosine sensitivity and quality of life were evaluated. RESULTS: Body-awareness training did not change the pain response. The two training groups did not differ in effects of exercise training. Exercise capacity before training was below the gender- and age-matched reference range and improved by 34% with training to a level not different from the reference range. Onset of pain was delayed by 100% from 3 +/- 2 to 6 +/- 3 min (p < 0.05) while maximum pain did not change. Thus the pain-response-to-exercise curve was shifted to the right. Syndrome X patients showed a hypersensitivity to low-dose adenosine infusion compared to healthy age- and gender-matched controls (p < 0.0001) that did not change with exercise training. Endothelium-dependent blood flow increase was at baseline within reference range and tended to increase (p < 0.06) following training. In Group A the concentration of cortisol in urine decreased by 53% after body-awareness training (p < 0.05), and this change from baseline remained after physical exercise training (p < 0.05). A similar decrease occurred with only exercise training (Group B). CONCLUSIONS: Physical deconditioning with lower exertional threshold for pain is a prominent feature in Syndrome X. Physical training in Syndrome X results in an increased exercise capacity with lesser anginal pain. We suggest physical training as an effective treatment in Syndrome X.

Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder.

We used positron emission tomography to investigate local cerebral metabolic rates for glucose (LCMRG1c) in patients with obsessive-compulsive disorder before and after treatment with either fluoxetine hydrochloride or behavior therapy. After treatment, LCMRG1c in the head of the right caudate nucleus, divided by that in the ipsilateral hemisphere (Cd/hem), was decreased significantly compared with pretreatment values in responders to both drug and behavior therapy. These decreases in responders were also significantly greater than right Cd/hem changes in nonresponders and normal controls, in both of whom values did not change from baseline. Percentage change in obsessive-compulsive disorder symptom ratings correlated significantly with the percent of right Cd/hem change with drug therapy and there was a trend to significance for this same correlation with behavior therapy. By lumping all responders to either treatment, right orbital cortex/hem was significantly correlated with ipsilateral Cd/hem and thalamus/hem before treatment but not after, and the differences before and after treatment were significant. A similar pattern was noted in the left hemisphere. A brain circuit involving these brain regions may mediate obsessive-compulsive disorder symptoms.

The animal rule: The role of clinical pharmacology in determining an effective dose in humans.

Development of drugs and biologics for which adequate and well-controlled efficacy studies in humans cannot be ethically conducted or are not feasible poses significant challenges. For these agents, clinical pharmacology information is used to translate preclinical efficacy findings to humans and is a cornerstone that supports a human dose. This article focuses on the role of clinical pharmacology in determining the human dose for new drugs and biologics under the Animal Rule regulatory pathway.

Characterization of photodamage to Escherichia coli in optical traps.

Optical tweezers (infrared laser-based optical traps) have emerged as a powerful tool in molecular and cell biology. However, their usefulness has been limited, particularly in vivo, by the potential for damage to specimens resulting from the trapping laser. Relatively little is known about the origin of this phenomenon. Here we employed a wavelength-tunable optical trap in which the microscope objective transmission was fully characterized throughout the near infrared, in conjunction with a sensitive, rotating bacterial cell assay. Single cells of Escherichia coli were tethered to a glass coverslip by means of a single flagellum: such cells rotate at rates proportional to their transmembrane proton potential (Manson et al.,1980. J. Mol. Biol. 138:541-561). Monitoring the rotation rates of cells subjected to laser illumination permits a rapid and quantitative measure of their metabolic state. Employing this assay, we characterized photodamage throughout the near-infrared region favored for optical trapping (790-1064 nm). The action spectrum for photodamage exhibits minima at 830 and 970 nm, and maxima at 870 and 930 nm. Damage was reduced to background levels under anaerobic conditions, implicating oxygen in the photodamage pathway. The intensity dependence for photodamage was linear, supporting a single-photon process. These findings may help guide the selection of lasers and experimental protocols best suited for optical trapping work.

Prostanoid-induced expression of matrix metalloproteinase-1 messenger ribonucleic acid in rat osteosarcoma cells.

Individual prostanoids have distinct potencies in activating intracellular signaling pathways and regulating gene expression in osteoblastic cells. The E-series prostaglandins (PGs) are known to stimulate matrix metalloproteinase-1 (MMP-1) synthesis and secretion in certain rodent and human osteoblastic cells, yet the intracellular events involved remain unclear. To further characterize this response and its signal transduction pathway(s), we examined prostanoid-induced expression of the MMP-1 gene in the rat osteoblastic osteosarcoma cell line UMR 106-01. Northern blot analysis demonstrated that prostaglandin E2 (PGE2) and PGE1 were very potent stimulators (40-fold) of MMP-1 transcript abundance, PGF2 alpha and prostacyclin were weak stimulators (4-fold), and thromboxane-B2 had no effect. The marked increase in MMP-1 transcript abundance after PGE2 treatment was first detected at 2 h, became maximal at 4 h, and persisted beyond 24 h. This response was dose dependent and elicited maximal and half-maximal effects with concentrations of 10(-6) and 0.6 x 10(-7) M, respectively. Cycloheximide, a protein synthesis inhibitor, completely blocked this effect of PGE2, suggesting that the expression of other genes is required. Nuclear run-on experiments demonstrated that PGE2 rapidly activates MMP-1 gene transcription, with a maximal increase at 2-4 h. The second messenger analog, 8-bromo-cAMP, mimicked the effects of PGE2 by stimulating a dose-dependent increase in MMP-1 messenger RNA (mRNA) levels, with a maximal effect quantitatively similar to that observed with PGE2. Thus, in UMR 106-01 cells, different prostanoids have distinct potencies in stimulating MMP-1 mRNA abundance. Our data suggest that PGE2 stimulation of MMP-1 synthesis is due to activation of MMP-1 gene transcription and a subsequent marked increase in MMP-1 mRNA abundance. This effect is dependent on de novo protein synthesis and is mimicked by protein kinase-A activation.

Response to estradiol inhibition of tonic luteinizing hormone secretion decreases during the final stage of puberty in the rhesus monkey.

This investigation was conducted to determine if a decrease in responsiveness to estradiol inhibition of tonic LH secretion occurs in the female rhesus monkey during the late stages of sexual maturation. The study was conducted during the several month period between menarche and first ovulation. Serum LH was measured in postmenarchial females (n = 8) before and after ovariectomy and insertion of estradiol implants that achieved subadult concentrations (10-30 pg/ml) of the steroid. Removal of the ovaries 1-4 months after menarche (31 +/- 1 months) produced a prompt 3- to 5-fold rise in circulating LH. This was prevented by estradiol replacement therapy beginning at ovariectomy. Similarly, insertion of estradiol implants after the castration response was established decreased the high concentrations of circulating LH to preoperative levels where they remained for several months. At 42 +/- 1 months of age, and in the face of unchanging peripheral estradiol, circulating LH rose severalfold in the ovariectomized females (n = 7). At a similar age (44 +/- 2 months, n = 4), ovulations began in untreated females. The results indicate that subadult concentrations of peripheral estradiol which are capable of suppressing LH secretion before the age of first ovulation are ineffective in this regard afterward. This provides compelling evidence for a decrease in estradiol inhibition of tonic LH secretion during puberty in the primate female.

Retinoic acid stimulates interstitial collagenase messenger ribonucleic acid in osteosarcoma cells.

The rat osteoblastic osteosarcoma cell line UMR 106-01 secretes interstitial collagenase in response to retinoic acid (RA). The present study demonstrates by Northern blot analysis that RA causes an increase in collagenase messenger RNA (mRNA) at 6 h, which is maximal at 24 h (20.5 times basal) and declines toward basal level by 72 h. This stimulation is dose dependent, with a maximal response at 5 x 10(-7) M RA. Nuclear run-on assays show a greater than 20-fold increase in the rate of collagenase mRNA transcription between 12-24 h after RA treatment. Cycloheximide blocks RA stimulation of collagenase mRNA, demonstrating the need for de novo protein synthesis. RA not only causes an increase in collagenase secretion, but is known to decrease collagen synthesis in UMR 106-01 cells. In this study, the increase in collagenase mRNA is accompanied by a concomitant decrease in the level of alpha 1(I) procollagen mRNA, which is maximal at 24 h (70% decrease), with a return to near-control levels by 72 h. Nuclear run-on assays demonstrated that the decrease in alpha 1 (I) procollagen expression does not have a statistically significant transcriptional component. RA did not statistically decrease the stability of alpha 1 (I) procollagen mRNA (calculated t1/2 = 8.06 +/- 0.30 and 9.01 +/- 0.62 h in the presence and absence of RA, respectively). However, transcription and stability together probably contribute to the major decrease in stable alpha 1 (I) procollagen mRNA observed. Cycloheximide treatment inhibits basal level alpha 1 (I) procollagen mRNA accumulation, demonstrating the need for on-going protein synthesis to maintain basal expression of this gene.

Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography.

PURPOSE: Recent clinical investigations have shown a strong correlation between pretreatment tumor hypoxia and poor response to radiotherapy. These observations raise questions about standard assumptions of tumor reoxygenation during radiotherapy, which has been poorly studied in human cancers. Positron emission tomography (PET) imaging of [F-18]fluoromisonidazole (FMISO) uptake allows noninvasive assessment of tumor hypoxia, and is amenable for repeated studies during fractionated radiotherapy to systematically evaluate changes in tumor oxygenation. METHODS AND MATERIALS: Seven patients with locally advanced nonsmall cell lung cancers underwent sequential [F-18]FMISO PET imaging while receiving primary radiotherapy. Computed tomograms were used to calculate tumor volumes, define tumor extent for PET image analysis, and assist in PET image registration between serial studies. Fractional hypoxic volume (FHV) was calculated for each study as the percentage of pixels within the analyzed imaged tumor volume with a tumor:blood [F-18]FMISO ratio > or = 1.4 by 120 min after injection. Serial FHVs were compared for each patient. RESULTS: Pretreatment FHVs ranged from 20-84% (median 58%). Subsequent FHVs varied from 8-79% (median 29%) at midtreatment, and ranged from 3-65% (median 22%) by the end of radiotherapy. One patient had essentially no detectable residual tumor hypoxia by the end of radiation, while two others showed no apparent decrease in serial FHVs. There was no correlation between tumor size and pretreatment FHV. CONCLUSIONS: Although there is a general tendency toward improved oxygenation in human tumors during fractionated radiotherapy, these changes are unpredictable and may be insufficient in extent and timing to overcome the negative effects of existing pretreatment hypoxia. Selection of patients for clinical trials addressing radioresistant hypoxic cancers can be appropriately achieved through single pretreatment evaluations of tumor hypoxia.

Long-term treatment of severe familial hypercholesterolemia in children: effect of sitosterol and bezafibrate.

Seven prepubertal children (age range 5.3 to 10.8 years) with severe heterozygous familial hypercholesterolemia (serum cholesterol concentration 416 +/- 85 mg/dL and low-density lipoprotein [LDL] cholesterol concentration 360 +/- 90 mg/dL) were first treated by dietary intervention, second by sitosterol (3 x 2 g/d), and third by bezafibrate (2 x 200 mg/d). Each treatment period lasted 3 months. Subsequently, a treatment combining half the dose of sitosterol and bezafibrate was administered for the following 24 months. Diet alone reduced total and LDL cholesterol values by 4.5% (not significant) and 6.6% (P less than .05), respectively. Sitosterol lowered total and LDL cholesterol values by 17% (P less than .05) when compared with diet alone. Compared with sitosterol, bezafibrate produced a more pronounced effect on total and LDL cholesterol values (-18% and -28%, P less than .05), and high-density lipoprotein cholesterol concentration increased significantly from 48 mg/dL to 55 mg/dL. Combined treatment with half the dose each of sitosterol and bezafibrate was as effective as the higher dose of bezafibrate, and reduction averaged almost 40% and 50% for total and LDL cholesterol values; this lipid-lowering effect persisted for the next 24 months. Laboratory safety parameters and physical examination revealed no obvious side effects. This study indicates that the combination of sitosterol (3 x 1 g/d) plus bezafibrate (1 x 200 mg/d) is an alternate, acceptable, safe, and effective therapeutic approach for treatment of severe hypercholesterolemia in children with high-risk familial hypercholesterolemia.

Methylation of rat and mouse DNA by the mushroom poison gyromitrin and its metabolite monomethylhydrazine.

Consumption of false morel (Gyromitra esculenta Fr.) has been associated not only with acute poisoning, but also with a carcinogenic risk. The hydrolysis of acetaldehyde-N-methyl-N-formylhydrazone (gyromitrin, the main toxic component of false morel) results in the formation of the methylating agents N-methyl-N-formylhydrazine (MFH) and N-methylhydrazine (MMH) (by further hydrolysis of MFH). This study reports traces of N-7-methylguanine (N7MeGu) in liver DNA from mice and a rat treated with gyromitrin. After repeated administration of MMH, N7MeGu was identified in rat liver DNA. In mice exposed to MMH according to a dosing scheme identical to that reported to induce tumours in this species, O6-methylguanine was present in liver and kidney DNA. The results indicate that a relatively low carcinogenic risk is associated with false morel consumption. The risk may be greater in individuals with a decreased detoxification rate (acetylation) of MFH, in whom larger amounts of MMH are formed from gyromitrin.

PET imaging in obsessive compulsive disorder with and without depression.

Obsessive compulsive disorder (OCD) is a classic psychoneurosis which is frequently complicated by major depression. Recent positron emission tomography neuroimaging studies, when taken in the context of a variety of other data, implicate a brain dysfunction involving the orbital prefrontal cortex and the striatum in the mediation of OCD behaviors and those of the related Gilles de la Tourette's syndrome. The anterolateral prefrontal cortex is implicated in the secondary major depressions often complicating OCD.

Atropine-induced psychosis. An unusual complication of therapy with inhaled atropine sulfate.

An acute organic brain syndrome occurred in a patient being treated with inhaled atropine sulfate. Immediate reversal of the patient's mental status was achieved with intravenous administration of physostigmine.