Nan van Geloven

Hemostatic efficacy of pathogen-inactivated- versus untreated- platelets: a randomized controlled trial

Pathogen inactivation of platelet concentrates reduces the risk for blood-borne infections. However, its effect on platelet function and hemostatic efficacy of transfusion is unclear. We conducted a randomized noninferiority trial comparing the efficacy of pathogen-inactivated platelets using riboflavin and UV B illumination technology (intervention) compared with standard plasma-stored platelets (control) for the prevention of bleeding in patients with hematologic malignancies and thrombocytopenia. The primary outcome parameter was the proportion of transfusion-treatment periods in which the patient had grade 2 or higher bleeding, as defined by World Health Organization criteria. Between November 2010 and April 2016, 469 unique patients were randomized to 567 transfusion-treatment periods (283 in the control arm, 284 in the intervention arm). There was a 3% absolute difference in grade 2 or higher bleeding in the intention-to-treat analysis: 51% of the transfusion-treatment periods in the control arm and 54% in the intervention arm (95% confidence interval [CI], -6 to 11; P = .012 for noninferiority). However, in the per-protocol analysis, the difference in grade 2 or higher bleeding was 8%: 44% in the control arm and 52% in the intervention arm (95% CI -2 to 18; P = .19 for noninferiority). Transfusion increment parameters were ∼50% lower in the intervention arm. There was no difference in the proportion of patients developing HLA class I alloantibodies. In conclusion, the noninferiority criterion for pathogen-inactivated platelets was met in the intention-to-treat analysis. This finding was not demonstrated in the per-protocol analysis. This trial was registered at The Netherlands National Trial Registry as #NTR2106 and at www.clinicaltrials.gov as #NCT02783313.

Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (The PATH Study): study protocol for a randomized controlled trial

BackgroundSubcutaneous administration of Ig (SCIg) has gained popularity as an alternative route of administration but has never been rigorously examined in chronic inflammatory demyelinating polyneuropathy (CIDP).Methods/designThe primary objective of the PATH study (Polyneuropathy and Treatment with Hizentra) is to determine the efficacy of two different doses of SCIg IgPro20 (0.2xa0g/kg bw or 0.4xa0g/kg bw) in a 24-week maintenance treatment of CIDP in comparison to placebo. The primary efficacy endpoint will be the proportion of patients who show CIDP relapse (1-point deterioration on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score) or are withdrawn within 24xa0weeks after randomization for any reason. IVIg-dependent adult patients with definite or probable CIDP according to the European Federation of Neurological Societies/Peripheral Nerve Society who fulfil the inclusion and exclusion criteria will be eligible. Based on sample-size calculation and relapse assumptions in the three arms, a sample size of 58 is needed per arm (overall sample size will be 350, of which 174 will be randomized). All eligible patients will progress through three study periods: an IgG dependency period (≤12xa0weeks) to select those who are Ig dependent; an IVIg restabilization period (10 or 13xa0weeks), which will be performed using the 10xa0% IgPro10 product; and an SC treatment period (24xa0weeks, followed by a 1-week completion visit after last follow-up). Patients showing IVIg restabilization will be randomized to demonstrate the efficacy of SCIg IgPro20 maintenance treatment over placebo. After completing the study, subjects are eligible to enter a long-term, open-label, extension study of 1xa0year or return to their previous treatment. In case of CIDP relapse during the 24-week SC treatment period, IgPro10 rescue medication will be offered. Safety, tolerability, and patients’ preference of Ig administration route will be examined.DiscussionThe PATH trial, which started in March 2012, is expected to finish at the end of 2016. The results will increase knowledge about the efficacy, safety, and tolerability of SCIg in maintenance management of CIDP patients.Trial RegistrationClinicalTrials.gov, NCT01545076. Registered on 1 March 2012.

Persistent Pulmonary Hypertension of the Newborn in Twin-Twin Transfusion Syndrome: A Case-Control Study

Background: Persistent pulmonary hypertension of the newborn (PPHN) is associated with severe morbidity and mortality. Twin-twin transfusion syndrome (TTTS) is suggested to increase the risk of PPHN. Objectives: To describe the incidence of PPHN in TTTS twins and to identify risk factors in TTTS twins for the development of severe PPHN. Methods: Cases with severe PPHN were extracted from our monochorionic twin database (2002-2016). Severe PPHN was defined as severe hypoxaemia requiring mechanical ventilation and inhaled nitric oxide (iNO) treatment, confirmed by strict echocardiographic criteria. A case-control comparison within TTTS survivors was conducted to identify risk factors for PPHN. Results: The incidence of PPHN in TTTS twins was 4% (24/598, 95% confidence interval [CI] 2.7-5.9%) and 0.4% (2/493, 95% CI 0.1-1.5%) in uncomplicated monochorionic twins (odds ratio [OR] 10.3, 95% CI 2.4-43.9; p = 0.002). Two risk factors were independently associated with PPHN: severe prematurity (OR 3.3, 95% CI 1.0-11.4) and recipient status (OR 3.9, 95% CI 1.4-11.0). In TTTS recipients, another risk factor for PPHN is anaemia at birth (OR 7.2, 95% CI 1.8-29.6). Conclusion: Clinicians caring for neonates with TTTS should be aware of the 10-fold increased risk of PPHN compared to uncomplicated monochorionic twins. PPHN occurs more often in case of premature delivery and in recipient twins, particularly in the presence of anaemia at birth. As the development of severe PPHN is difficult to predict, we advise that all TTTS twins should be delivered in a tertiary care centre with iNO treatment options.

Accuracy of Pulse Oximetry Screening for Critical Congenital Heart Defects after Home Birth and Early Postnatal Discharge

Objective To assess the accuracy of pulse oximetry screening for critical congenital heart defects (CCHDs) in a setting with home births and early discharge after hospital deliveries, by using an adapted protocol fitting the work patterns of community midwives. Study design Pre‐ and postductal oxygen saturations (SpO2) were measured ≥1 hour after birth and on day 2 or 3. Screenings were positive if the SpO2 measurement was <90% or if 2 independent measures of pre‐ and postductal SpO2 were <95% and/or the pre‐/postductal difference was >3%. Positive screenings were referred for pediatric assessment. Primary outcomes were sensitivity, specificity, and false‐positive rate of pulse oximetry screening for CCHD. Secondary outcome was detection of noncardiac illnesses. Results The prenatal detection rate of CCHDs was 73%. After we excluded these cases and symptomatic CCHDs presenting immediately after birth, 23 959 newborns were screened. Pulse oximetry screening sensitivity in the remaining cohort was 50.0% (95% CI 23.7‐76.3) and specificity was 99.1% (95% CI 99.0‐99.2). Pulse oximetry screening was false positive for CCHDs in 221 infants, of whom 61% (134) had noncardiac illnesses, including infections (31) and respiratory pathology (88). Pulse oximetry screening did not detect left‐heart obstructive CCHDs. Including cases with prenatally detected CCHDs increased the sensitivity to 70.2% (95% CI 56.0‐81.4). Conclusion Pulse oximetry screening adapted for perinatal care in home births and early postdelivery hospital discharge assisted the diagnosis of CCHDs before signs of cardiovascular collapse. High prenatal detection led to a moderate sensitivity of pulse oximetry screening. The screening also detected noncardiac illnesses in 0.6% of all infants, including infections and respiratory morbidity, which led to early recognition and referral for treatment.

Repetitive versus standard tactile stimulation of preterm infants at birth – A randomized controlled trial

AIMnTo evaluate the direct effect of repetitive tactile stimulation on breathing effort of preterm infants at birth.nnnMETHODSnThis randomized controlled trial compared the effect of repetitive stimulation on respiratory effort during the first 4u202fmin after birth with standard stimulation based on clinical indication in preterm infants with a gestational age of 27-32 weeks. All details of the stimulation performed were noted. The main study parameter measured was respiratory minute volume, other study parameters assessed measures of respiratory effort; tidal volumes, rate of rise to maximum tidal volumes, percentage of recruitment breaths, and oxygenation of the infant.nnnRESULTSnThere was no significant difference in respiratory minute volume in the repetitive stimulation group when compared to the standard group. Oxygen saturation was significantly higher (87.6u202f±u202f3.3% vs 81.7u202f±u202f8.7%, pu202f=u202f.01) while the amount of FiO2 given during transport to the NICU was lower (28.2 (22.8-35.0)% vs 33.6 (29.4-44.1)%, pu202f=u202f.04). There was no significant difference in administration of positive pressure ventilation (52% vs 78%, pu202f=u202f.13), or the duration of ventilation (median (IQR) time 8 (0-118)s vs 35 (13-131)s, pu202f=u202f.23). Caregivers decided less often to administer caffeine in the delivery room to stimulate breathing in the repetitive stimulation group (10% vs 39%, pu202f=u202f.036).nnnCONCLUSIONnAlthough the increase in respiratory effort during repetitive stimulation did not reach significance, oxygenation significantly improved with a lower level of FiO2 at transport to the NICU. Repetitive tactile stimulation could be of added value to improve breathing effort at birth.

Transplant as a competing risk in the analysis of dialysis patients

Abstract Time‐to‐event analyses are frequently used in nephrology research, for instance, when recording time to death or time to peritonitis in dialysis patients. Many papers have pointed out the important issue of competing events (or competing risks) in such analyses. For example, when studying one particular cause of death it can be noted that patients also die from other causes. Such competing events preclude the event of interest from occurring and thereby complicate the statistical analysis. The Kaplan‐Meier approach to calculating the cumulative probability of the event of interest yields invalid results in the presence of competing risks, thus the alternative cumulative incidence competing risk (CICR) approach has become the standard. However, when kidney transplant is the competing event that prevents observing the outcome of interest, CICR may not always be the matter of interest. We discuss situations where both the Kaplan‐Meier and the CICR approach are not suitable for the purpose and point out alternative analysis methods for such situations. We also look at the suitability and interpretation of different estimators for relative risks. In the presence of transplant as a competing risk, one should very clearly state the research question and use an analysis method that targets this question.

Long-Term Prognosis of Patients With Intramural Course of Coronary Arteries Assessed With CT Angiography

OBJECTIVESnThe aim of the present study was to evaluate, in low-to-intermediate pre-test probability patients who were referred for coronary computed tomography angiography (CTA) and did not show obstructive coronary artery disease (CAD), whether an intramural course of a coronary artery is associated with worse outcome compared with patients without an intramural course of the coronary arteries.nnnBACKGROUNDnThe prognostic value of an intramural course of the coronary arteries on coronary CTA in patients without obstructive CAD is not well-known.nnnMETHODSnThe study population consisted of 947 patients with a low-to-intermediate pre-test probability who werexa0referred for coronary CTA and who did not have obstructive CAD. During follow-up, the occurrence of unstablexa0angina pectoris that required hospitalization, nonfatal myocardial infarction, and all-cause mortality was evaluated.nnnRESULTSnOn coronary CTA, 210 patients (22%) had an intramural course of a coronary artery. The median depth of the intramural course was 1.9 mm (interquartile range: 1.4 to 2.6 mm). In 84 patients (40%), the depth of the intramural course was considered deep (>2 mm surrounded by myocardium). During a median follow-up of 4.9 years (interquartile range: 3.2 to 6.9 years), a total of 43 events occurred: hospitalization due to unstable angina pectoris in 13 patients (1.4%); 7 patients (0.7%) had a nonfatal myocardial infarction; and 23 patients died (2.4%). The 6-year cumulative event rate of unstable angina pectoris requiring hospitalization (0.0% vs. 1.1%), nonfatal myocardial infarction (0.5% vs. 0.4%), all-cause mortality (1.9% vs. 2.2%) as well as the combined endpoint of all 3 events (2.4% vs. 3.7%) was similar in patients with and without an intramural course of a coronary artery.nnnCONCLUSIONSnIn patients without obstructive CAD on coronary CTA, the presence of an intramural course of a coronary artery was not associated with worse outcome.

Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn

BACKGROUND: Intrauterine transfusion for severe alloimmunization in pregnancy performed <20 weeks’ gestation is associated with a higher fetal death rate. Intravenous immunoglobulins may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions. OBJECTIVE: We evaluated whether maternal treatment with intravenous immunoglobulins defers the development of severe fetal anemia and its consequences in a retrospective cohort to which 12 fetal therapy centers contributed. STUDY DESIGN: We included consecutive pregnancies of alloimmunized women with a history of severe hemolytic disease and by propensity analysis compared index pregnancies treated with intravenous immunoglobulins (n = 24) with pregnancies managed without intravenous immunoglobulins (n = 28). RESULTS: In index pregnancies with intravenous immunoglobulin treatment, fetal anemia developed on average 15 days later compared to previous pregnancies (8% less often <20 weeks’ gestation). In pregnancies without intravenous immunoglobulin treatment anemia developed 9 days earlier compared to previous pregnancies (10% more <20 weeks), an adjusted 4‐day between‐group difference in favor of the immunoglobulin group (95% confidence interval, –10 to +18; P = .564). In the subcohort in which immunoglobulin treatment was started <13 weeks, anemia developed 25 days later and 31% less <20 weeks’ gestation (54% compared to 23%) than in the previous pregnancy. Fetal hydrops occurred in 4% of immunoglobulin‐treated pregnancies and in 24% of those without intravenous immunoglobulin treatment (odds ratio, 0.03; 95% confidence interval, 0–0.5; P = .011). Exchange transfusions were given to 9% of neonates born from pregnancies with and in 37% without immunoglobulin treatment (odds ratio, 0.1; 95% confidence interval, 0–0.5; P = .009). CONCLUSION: Intravenous immunoglobulin treatment in mothers pregnant with a fetus at risk for hemolytic disease seems to have a potential clinically relevant, beneficial effect on the course and severity of the disease. Confirmation in a multicenter randomized trial is needed.

Posttraumatic Stress Disorder and Somatic Complaints in a Deployed Cohort of Georgian Military Personnel: Mediating Effect of Depression and Anxiety: PTSD and Somatic Complaints in Georgian Veterans

Several studies have shown the relationship between symptoms of posttraumatic stress disorder (PTSD), somatic symptoms, and the mediating effect of depression and anxiety. The following study was conducted to investigate the relationship between PTSD symptoms and somatic complaints through underlying symptoms of depression and anxiety. The participants of the study were 2,799 veterans who were examined after a 6-month deployment. They were assessed using the PTSD Checklist (PCL-5) and Patient Health Questionnaire (PHQ) for depression, anxiety, and somatic complaints. To check the indirect effect of PTSD on somatic complaints through depression and anxiety, mediation model 4 (parallel mediation) of the SPSS PROCESS macro was used. There was a significant total indirect effect of PTSD through depression and anxiety on somatic complaints, b = 0.14, 95% confidence interval (CI) [0.12, 0.16], from which an indirect effect of PTSD on somatic complaints through depression was b = 0.08, 95% CI [0.06, 0.10], and through anxiety it equaled b = 0.06, 95% CI [0.04, 0.07]. The ratio of indirect to total effect was 0.66, 95% CI [0.59, 0.75]. The present study helps us to understand the role of depression and anxiety symptoms when the symptoms of PTSD and somatic complaints are present. These new findings may have implications for the management as well as treatment of PTSD because they recognize the importance of symptoms of anxiety and depression when somatic complaints are present.