Membranoproliferative glomerulonephritis type II (MPGN II) is a rare disease characterized by the deposition of abnormal electron-dense material within the glomerular basement membrane of the kidney ...and often within Bruch's membrane in the eye. The diagnosis is made in most patients between the ages of 5 and 15 yr, and within 10 yr, approximately half progress to end-stage renal disease, occasionally with the late comorbidity of visual impairment. The pathophysiologic basis of MPGN II is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade. In most patients, loss of complement regulation is caused by C3 nephritic factor, an autoantibody directed against the C3 convertase of the AP, but in some patients, mutations in the factor H gene have been identified. For the latter patients, plasma replacement therapy prevents renal failure, but for the majority of patients, there is no proven effective treatment. The disease recurs in virtually all renal allografts, and a high percentage of these ultimately fail. The development of molecular diagnostic tools and new therapies directed at controlling the AP of the complement cascade either locally in the kidney or at the systemic level may lead to effective treatments for MPGN II.
The development of clinical treatment protocols usually relies on evidence-based guidelines that focus on randomized, controlled trials. For rare renal diseases, such stringent requirements can ...represent a significant challenge. Dense deposit disease (DDD; also known as membranoproliferative glomerulonephritis type II) is a prototypical rare disease. It affects only two to three people per million and leads to renal failure within 10 yr in 50% of affected children. On the basis of pathophysiology, this article presents a diagnostic and treatment algorithm for patients with DDD. Diagnostic tests should assess the alternative pathway of complement for abnormalities. Treatment options include aggressive BP control and reduction of proteinuria, and on the basis of pathophysiology, animal data, and human studies, plasma infusion or exchange, rituximab, sulodexide, and eculizumab are additional options. Criteria for treatment success should be prevention of progression as determined by maintenance or improvement in renal function. A secondary criterion should be normalization of activity levels of the alternative complement pathway as measured by C3/C3d ratios and C3NeF levels. Outcomes should be reported to a central repository that is now accessible to all clinicians. As the understanding of DDD increases, novel therapies should be integrated into existing protocols for DDD and evaluated using an open-label Bayesian study design.
Objective The aim of the Prospective Observational Trial to Optimize Pediatric Health in IUGR Study was to evaluate the optimal management of fetuses with an estimated fetal weight less than the 10th ...centile. The objective of this secondary analysis was to describe the role of the cerebroplacental ratio (CPR) in the prediction of adverse perinatal outcome. Study Design More than 1100 consecutive singleton pregnancies with intrauterine growth restriction (IUGR) were recruited over 2 years at 7 centers, undergoing serial sonographic evaluation including multivessel Doppler measurement. CPR was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. Results Data for CPR calculation was available in 881 cases, which was performed at a mean gestational age of 33 weeks (interquarile range, 28.7–35.9). Of the 146 cases with CPR less than 1, 18% (n = 27) had an adverse perinatal outcome. This conferred an 11-fold increased risk (odds ratio, 11.7; P < .0001) when compared with cases with normal CPR (2%; 14 of 735). An abnormal CPR was present in all 3 cases of mortality. Prediction of adverse outcomes was comparable when using all definitions of abnormal CPR. Conclusion Irrespective of the CPR calculation used, brain sparing is significantly associated with an adverse perinatal outcome in IUGR. This adds further weight to integrating CPR evaluation into the clinical assessment of IUGR pregnancies. The impact of this finding on long-term neurodevelopmental outcomes in this patient cohort is underway.
Intrauterine growth restriction (IUGR) is the single largest contributing factor to perinatal mortality in non-anomalous fetuses. Advances in antenatal and neonatal critical care have resulted in a ...reduction in neonatal deaths over the past decades, while stillbirth rates have remained unchanged. Antenatal detection rates of fetal growth failure are low, and these pregnancies carry a high risk of perinatal death.
The Prospective Observational Trial to Optimize Paediatric Health in IUGR (PORTO) Study recruited 1,200 ultrasound-dated singleton IUGR pregnancies, defined as EFW <10th centile, between 24+0 and 36+6 weeks gestation. All recruited fetuses underwent serial sonographic assessment of fetal weight and multi-vessel Doppler studies until birth. Perinatal outcomes were recorded for all pregnancies. Case records of the perinatal deaths from this prospectively recruited IUGR cohort were reviewed, their pregnancy details and outcome were analysed descriptively and compared to the entire cohort.
Of 1,116 non-anomalous singleton infants with EFW <10th centile, 6 resulted in perinatal deaths including 3 stillbirths and 3 early neonatal deaths. Perinatal deaths occurred between 24+6 and 35+0 weeks gestation corresponding to birthweights ranging from 460 to 2260 grams. Perinatal deaths occurred more commonly in pregnancies with severe growth restriction (EFW <3rd centile) and associated abnormal Doppler findings resulting in earlier gestational ages at delivery and lower birthweights. All of the described pregnancies were complicated by either significant maternal comorbidities, e.g. hypertension, systemic lupus erythematosus (SLE) or diabetes, or poor obstetric histories, e.g. prior perinatal death, mid-trimester or recurrent pregnancy loss. Five of the 6 mortalities occurred in women of non-Irish ethnic backgrounds. All perinatal deaths showed abnormalities on placental histopathological evaluation.
The PNMR in this cohort of prenatally identified IUGR cases was 5.4/1,000 and compares favourably to the overall national rate of 4.1/1,000 births, which can be attributed to increased surveillance and timely delivery. Despite antenatal recognition of IUGR and associated maternal risk factors, not all perinatal deaths can be prevented.
The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied ...this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth's continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes.
Objective We sought to determine the cause of adverse perinatal outcome in fetal growth restriction (FGR) where umbilical artery (UA) Doppler was normal, as identified from the Prospective ...Observational Trial to Optimize Pediatric Health (PORTO). We compared cases of adverse outcome where UA Doppler was normal and abnormal. Study Design The PORTO study was a national multicenter study of >1100 ultrasound-dated singleton pregnancies with an estimated fetal weight <10th centile. Each pregnancy underwent intensive ultrasound, including multivessel Doppler. UA Doppler was considered abnormal when the pulsatility index was >95th centile or end-diastolic flow was absent/reversed. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, or death. Results In all, 57 (5.0%) of the 1116 fetuses had an adverse perinatal outcome. Nine (1.3%) of 698 fetuses with normal UA Doppler had an adverse outcome, compared with 48 (11.5%) of 418 with abnormal UA Doppler ( P < .0001). There were 2 perinatal deaths in the normal group and 6 in the abnormal group ( P = .01). The perinatal deaths in the normal group were 1 case of pulmonary hypoplasia after prolonged preterm rupture of the membranes from 12 weeks’ gestation and a case of placental abruption. Gestation at delivery was 33 ± 3 vs 31 ± 4 weeks ( P = .05) and mean birthweight was 1830 ± 737 vs 1146 ± 508 g ( P = .001) in the respective groups. Neonatal sepsis was the commonest adverse outcome in both groups: 0.1% and 0.4%, respectively ( P = .01). Conclusion Adverse perinatal outcome is uncommon in FGR with normal UA Doppler. The cases we identified were associated with heterogenous pathologies. FGR with normal UA blood flow is a largely benign condition.
To evaluate the feasibility of an RCT of a pedometer-driven walking program and education/advice to remain active compared with education/advice only for treatment of chronic low back pain (CLBP).
...Fifty-seven participants with CLBP recruited from primary care were randomly allocated to either: (1) education/advice (E, n=17) or (2) education/advice plus an 8-week pedometer-driven walking program (EWP, n=40). Step targets, actual daily step counts, and adverse events were recorded in a walking diary over the 8 weeks of intervention for the EWP group only. All other outcomes (eg, functional disability using the Oswestry Disability Questionnaire (ODQ), pain scores, physical activity (PA) measurement etc.) were recorded at baseline, week 9 (immediately post-intervention), and 6 months in both groups.
The recruitment rate was 22% and the dropout rate was lower than anticipated (13% to 18% at 6 mo). Adherence with the EWP was high, 93% (n=37/40) walked for ≥ 6 weeks, and increased their steps/day (mean absolute increase in steps/d, 2776, 95% confidence interval CI, 1996-3557) by 59% (95% CI, 40.73%-76.25%) from baseline. Mean percentage adherence with weekly step targets was 70% (95% CI, 62%-77%). Eight (20%) minor-related adverse events were observed in 13% (5/40) of the participants. The EWP group participants demonstrated an 8.2% point improvement (95% CI, -13 to -3.4) on the ODQ at 6 months compared with 1.6% points (95% CI, -9.3 to 6.1) for the E group (between group d=0.44). There was also a larger mean improvement in pain (d=0.4) and a larger increase in PA (d=0.59) at 6 months in EWP.
This preliminary study demonstrated that a main RCT is feasible. EWP was safe and produced a real increase in walking; CLBP function and pain improved, and participants perceived a greater improvement in their PA levels. These improvements require confirmation in a fully powered RCT.
Intrauterine growth restriction accounts for a significant proportion of perinatal morbidity and mortality currently encountered in obstetric practice. The primary goal of antenatal care is the early ...recognition of such conditions to allow treatment and optimization of both maternal and fetal outcomes. Management of pregnancies complicated by intrauterine growth restriction remains one of the greatest challenges in obstetrics. Frequently, however, clinical evidence of underlying uteroplacental dysfunction may only emerge at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the at-risk fetus in both intrauterine growth restriction and the appropriate-for-gestational-age setting. The cerebroplacental ratio quantifies the redistribution of the cardiac output resulting in a brain-sparing effect. The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect is significantly associated with an adverse perinatal outcome in the intrauterine growth restriction cohort.
The aim of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction study was to evaluate the optimal management of fetuses with an estimated fetal weight <10th centile. The objective of this secondary analysis was to evaluate if normalizing cerebroplacental ratio predicts adverse perinatal outcome.
In all, 1116 consecutive singleton pregnancies with intrauterine growth restriction completed the study protocol over 2 years at 7 centers, undergoing serial sonographic evaluation and multivessel Doppler measurement. Cerebroplacental ratio was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Abnormal cerebroplacental ratio was defined as <1.0. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death.
Data for cerebroplacental ratio calculation were available in 881 cases, with a mean gestational age of 33 (interquartile range, 28.7-35.9) weeks. Of the 87 cases of abnormal serial cerebroplacental ratio with an initial value <1.0, 52% (n = 45) of cases remained abnormal and 22% of these (n = 10) had an adverse perinatal outcome. The remaining 48% (n = 42) demonstrated normalizing cerebroplacental ratio on serial sonography, and 5% of these (n = 2) had an adverse perinatal outcome. Mean gestation at delivery was 33.4 weeks (n = 45) in the continuing abnormal cerebroplacental ratio group and 36.5 weeks (n = 42) in the normalizing cerebroplacental ratio group (P value <.001).
The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect was significantly associated with an adverse perinatal outcome in our intrauterine growth restriction cohort. It was hypothesized that a normalizing cerebroplacental ratio would be a further predictor of an adverse outcome due to the loss of this compensatory mechanism. However, in this subanalysis we did not demonstrate an additional poor prognostic effect when the cerebroplacental ratio value returned to a value >1.0. Overall, this secondary analysis demonstrated the importance of a serial abnormal cerebroplacental ratio value of <1 within the <34 weeks’ gestation population. Contrary to our proposed hypothesis, we recognize that reversion of an abnormal cerebroplacental ratio to a normal ratio is not associated with a heightened degree of adverse perinatal outcome.
To examine the validity of a growth trajectory method to discriminate between pathologically and constitutionally undergrown fetuses using repeated measures of estimated fetal weight.
In a ...prospective, observational, multicenter study in Ireland, 1,116 women with a growth-restricted fetus diagnosed participated with the objective of evaluating ultrasound findings as predictors of pediatric morbidity and mortality. Fetal growth trajectories were based on estimated fetal weight.
Between 22 weeks of gestation and term, two fetal growth trajectories were identified: normal (96.7%) and pathologic (3.3%). Compared with the normal trajectory, the pathologic trajectory was associated with an increased risk for preeclampsia (odds ratio OR 8.1, 95% confidence interval CI 2.6-23.4), increased umbilical artery resistance at 30 weeks of gestation (OR 12.6, 95% CI 4.6-34.1) or 34 weeks of gestation (OR 28.0, 95% CI 8.9-87.7), reduced middle cerebral artery resistance at 30 weeks of gestation (OR 0.33, 95% CI 0.12-0.96) or 34 weeks of gestation (OR 0.14, 95% CI 0.03-0.74), lower gestational age at delivery (mean 32.02 weeks of gestation compared with 38.02 weeks of gestation; P<.001), and higher perinatal complications (OR 21.5, 95% CI 10.5-44.2). In addition, 89.2% of newborns with pathologic fetal growth were admitted to neonatal intensive care units compared with 25.9% of those with normal growth.
Fetal growth trajectory analysis reliably differentiated fetuses with a pathologic growth pattern among a group of women with growth-restricted fetuses. With further development, this approach could provide clarity to how we define, identify, and ultimately manage pathologic fetal growth.
II.