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OBJECTIVE: To explore the extent and type of pregnancy and lactation data of newly approved prescription drugs and assess whether the presented recommendations are data-driven, as required by the US Food and Drug Administration Pregnancy and Lactation Labeling Rule implemented in 2015. STUDY DESIGN: In this descriptive analysis, we reviewed pregnancy and lactation data of all new molecular entities approved between 2001 and 2020 in their most updated labeling. Information was collected regarding the pregnancy and lactation risk statements, the source of pregnancy and lactation data, and the design and methods of pregnancy and lactation studies in the labeling. RESULTS: Of the 422 new molecular entities, the key advisory statement for use of 133 (32%) drugs in pregnancy and 194 (46%) drugs in lactation were classified as "against use." Less than 2% of all drugs had a key advisory statement that supported their use during pregnancy or lactation. The sources of data regarding use in pregnancy were studies in human and animals in 46 (11%) and 348 (82%) drugs, respectively. For use during lactation, data included studies in human and animals in 23 (5%) and 251 (59%) drugs, respectively. The key advisory recommendation was consistent with the available human information in 4 (8%) drugs in pregnancy and 3 (13%) drugs in lactation. Prescription drug labeling contains limited data to support informed decision-making for the use of prescription drugs during pregnancy/lactation. Close collaboration among stakeholders is required to enhance the availability of data in this population.

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STUDY DESIGN: Retrospective review of 2532 adults who underwent elective surgery for cervical radiculopathy or myelopathy with intraoperative neuromonitoring (IONM) with motor evoked potentials (MEPs) between 2017 and 2019. OBJECTIVE: Evaluate attainability of monitorable MEPs across demographic, health history, and patient-reported outcomes measure (PROM) factors. SUMMARY OF BACKGROUND DATA: When baseline IONM responses cannot be obtained, the value of IONM on mitigating the risk of postoperative deficits is marginalized and a clinical decision to proceed must be made based, in part, on the differential diagnosis of the unmonitorable MEPs. Despite known associations with baseline MEPs and anesthetic regimen or preoperative motor strength, little is known regarding associations with other patient factors. METHODS: Demographics, health history, and PROM data were collected preoperatively. MEP baseline responses were reported as monitorable or unmonitorable at incision. Multivariable logistic regression estimated the odds of having at least one unmonitorable MEP from demographic and health history factors. RESULTS: Age [odds ratio (OR)=1.031, P <0.001], sex (male OR=1.572, P =0.007), a primary diagnosis of myelopathy (OR=1.493, P =0.021), peripheral vascular disease (OR=2.830, P =0.009), type II diabetes (OR=1.658, P =0.005), and hypertension (OR=1.406, P =0.040) were each associated with increased odds of unmonitorable MEPs from one or more muscles; a history of thyroid disorder was inversely related (OR=0.583, P =0.027). P atients with unmonitorable MEPs reported less neck-associated disability and pain ( P <0.036), but worse SF-12 physical health and lower extremity (LE) and upper extremity function ( P <0.016). Compared with radiculopathy, unmonitorable MEPs in myelopathy patients more often involved LE muscles. Cord function was monitorable in 99.1% of myelopathic patients with no reported LE dysfunction and no history of hypertension or diabetes. CONCLUSION: Myelopathy, hypertension, peripheral vascular disease, diabetes, and/or symptomatic LE dysfunction increased the odds of having unmonitorable baseline MEPs. Unmonitorable baseline MEPs was uncommon in patients without significant LE weakness, even in the presence of myelopathy.

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OBJECTIVES: To determine the applicability of the 4Ts score and the Heparin-Induced Thrombocytopenia (HIT) Expert Probability (HEP) score in children with suspected HIT and to estimate the number of children potentially at risk of HIT. STUDY DESIGN: We retrospectively estimated 4Ts and HEP scores in a cohort of 50 children referred for laboratory screening with enzyme immunoassay. In addition, minor modifications were introduced to the 4Ts score (modified 4Ts score) to adapt it for use in the pediatric setting. All patients with positive enzyme immunoassays were tested with serotonin release assay. We also extracted the number of patients started on heparins in a similar period of time. RESULTS: The median age at the time of testing was 4 years (25th-75th percentile, 8.7 months to 13.5 years); 78% of patients had low and 22% had intermediate risk pretest probability scores using the original 4Ts score; 86% had low risk and 14% had intermediate risk scores using the modified 4Ts score; 54% of children had a HEP score of ≥2. Six patients (12%) had a positive (≥0.40 optical density units) enzyme immunoassay, but none had a positive serotonin release assay. Based on anticoagulation dose, there were 1-2 new daily potentially high-risk exposures to heparinoids at our institution. CONCLUSIONS: The modified 4Ts and original 4Ts scores may be more adequate than the HEP score to determine HIT pretest probability in children. Despite the number of patients potentially at risk, HIT is rare in pediatrics.

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Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes.IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.

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OBJECTIVE: To assess the validity of existing clinical scales assessing the presence of physical and functional abnormalities for diagnosing post-thrombotic syndrome (PTS) in children, including specific evaluation of use in children with congenital heart disease (CHD). STUDY DESIGN: One hundred children aged >2 years (average age, 6 years), including 33 with CHD and previously proven extremity deep vein thrombosis (DVT), 37 with CHD and no previous DVT, and 30 healthy siblings, were blindly assessed for PTS using the modified Villalta Scale (MVS). All patients aged <6 years underwent neurodevelopmental testing and an age-appropriate quality of life assessment. RESULTS: The MVS identified mild PTS in 20 children and moderate PTS in 1 child (including 14 of 33 [42%] in the CHD/DVT group, 5 of 37 [14%] in the CHD/no DVT group, and 2 of 30 controls [7%]). The diagnosis of PTS was confirmed clinically in 14 patients, all of whom had previous thrombosis and 1 of whom was MVS-negative. MVS had an accuracy of 91% and performed reasonably well as a screening tool but poorly as a diagnostic tool. MVS reliability was acceptable. Children with PTS had similar quality of life as those without PTS but had higher rates of neurodevelopmental delays in gross motor skills (70% vs 24%; P = .02) and problem-solving indicators (60% vs 15%; P = .008). CONCLUSIONS: Using the MVS scale for PTS screening in children with CHD is feasible and reliable, and the scale has good correlation with a clinical diagnosis of PTS despite a high prevalence of false-positive findings. Further research is needed to determine the clinical relevance of PTS in this population.

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BACKGROUND: Evidence for the use of telephone consultation in childhood inflammatory bowel disease (IBD) is lacking. We aimed to assess the effectiveness and cost consequences of telephone consultation compared with the usual out-patient face-to-face consultation for young people with IBD. METHODS: We conducted a randomised-controlled trial in Manchester, UK, between July 12, 2010 and June 30, 2013. Young people (aged 8-16 years) with IBD were randomized to receive telephone consultation or face-to-face consultation for 24 months. The primary outcome measure was the paediatric IBD-specific IMPACT quality of life (QOL) score at 12 months. Secondary outcome measures included patient satisfaction with consultations, disease course, anthropometric measures, proportion of consultations attended, duration of consultations, and costs to the UK National Health Service (NHS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02319798. FINDINGS: Eighty six patients were randomised to receive either telephone consultation (n = 44) or face-to-face consultation (n = 42). Baseline characteristics of the two groups were well balanced. At 12 months, there was no evidence of difference in QOL scores (estimated treatment effect in favour of the telephone consultation group was 5.7 points, 95% CI - 2.9 to 14.3; p = 0.19). Mean consultation times were 9.8 min (IQR 8 to 12.3) for telephone consultation, and 14.3 min (11.6 to 17.0) for face-to-face consultation with an estimated reduction (95% CI) of 4.3 (2.8 to 5.7) min in consultation times (p < 0.001). Telephone consultation had a mean cost of UK£35.41 per patient consultation compared with £51.12 for face-face consultation, difference £15.71 (95% CI 11.8-19.6; P < 0.001). INTERPRETATION: We found no suggestion of inferiority of telephone consultation compared with face-to-face consultation with regard to improvements in QOL scores, and telephone consultation reduced consultation time and NHS costs. Telephone consultation is a cost-effective alternative to face-to-face consultation for the routine outpatient follow-up of children and adolescents with IBD. FUNDING: Research for Patient Benefit Programme, UK National Institute for Health Research.

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Ad libitum feeding causes excessive follicular development and is associated with extensive metabolic changes in broiler - breeder hens. Restricting feed intake reduces excessive follicular development, but the mechanisms mediating this response are unknown. In the present study, the effects of feeding on follicular development in immature broil er - breeder hens were examined. There was an increase in the proportion of follicles 100 - 300, 300 - 500 and >500 μ m in diameter and a decrease in follicles <100 μ m in full - fed (FF) compared to restricted - fed (RF) hens. Increased follicular development in FF hens was associated with a greater expression of steroidogenic transcripts ( STAR, CYP11A1, HSD3B , and CYP19 ) within the ovarian cortex of FF hens. These transcripts represent markers of more advanced follicular development. However, increased follicular development in FF hens was not associated with changes in the expression of other factors previously implicated in follicular development, including those encoding TGF - beta ligands ( AMH, BMP6, BMP15 , or GDF9 ) or their signaling proteins (SMAD2/3 or SMAD1/5/9). Changes in histone modifications associated with proliferation, including trimethylated histone H3K4, trimethylated histone H3K27 , and acetylated histone H3K9 , we re also not different between treatment groups. However, feed restriction caused serine phosphorylation to localize strongly to the ovarian stroma of FF hens compared to RF hens. In contrast, phosphorylation of tyrosine residues localized more prominently to the surface of granulosa cells from RF hens. Thus, restricted feeding may enhance the efficiency of reproduction by suppressing early follicular development which is associated with changes in granulosa cell protein phosphorylation status.

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Ad libitum feeding causes excessive follicular development and is associated with extensive metabolic changes in broiler - breeder hens. Restricting feed intake reduces excessive follicular development, but the mechanisms mediating this response are unknown. In the present study, the effects of feeding on follicular development in immature broil er - breeder hens were examined. There was an increase in the proportion of follicles 100 - 300, 300 - 500 and >500 μ m in diameter and a decrease in follicles <100 μ m in full - fed (FF) compared to restricted - fed (RF) hens. Increased follicular development in FF hens was associated with a greater expression of steroidogenic transcripts ( STAR, CYP11A1, HSD3B , and CYP19 ) within the ovarian cortex of FF hens. These transcripts represent markers of more advanced follicular development. However, increased follicular development in FF hens was not associated with changes in the expression of other factors previously implicated in follicular development, including those encoding TGF - beta ligands ( AMH, BMP6, BMP15 , or GDF9 ) or their signaling proteins (SMAD2/3 or SMAD1/5/9). Changes in histone modifications associated with proliferation, including trimethylated histone H3K4, trimethylated histone H3K27 , and acetylated histone H3K9 , we re also not different between treatment groups. However, feed restriction caused serine phosphorylation to localize strongly to the ovarian stroma of FF hens compared to RF hens. In contrast, phosphorylation of tyrosine residues localized more prominently to the surface of granulosa cells from RF hens. Thus, restricted feeding may enhance the efficiency of reproduction by suppressing early follicular development which is associated with changes in granulosa cell protein phosphorylation status.(AU)

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OBJECTIVES: To describe the incidence of thrombotic complications across all 3 stages of single ventricle palliation and the association between thromboprophylaxis use and thrombotic risk. STUDY DESIGN: Two separate cross-sectional studies were performed that included 195 patients born between 2003-2008 and 162 patients who underwent Fontan after 2000. RESULTS: The incidence of thrombotic complications was 40% and 28% after initial palliation and superior cavopulmonary connection (SCPC), respectively; 5-year freedom from thrombotic complications after Fontan was 79%. Thromboprophylaxis was initiated for 70%, 46%, and 94% of patients after initial palliation, SCPC, and Fontan, respectively. Thromboprophylaxis with enoxaparin (vs no thromboprophylaxis) was associated with a reduction in risk of thrombotic complications after initial palliation (hazard ratio [HR] 0.5, P = .05) and SCPC (HR 0.2, P = .04). Thromboprophylaxis with warfarin was associated with a reduction in thrombotic complications after Fontan (HR 0.27, P = .05 vs acetylsalicylic acid; HR 0.18, P = .02 vs no thromboprophylaxis). Thrombotic complications were associated with increased mortality after initial palliation (HR 5.5, P < .001) and SCPC (HR 12.5, P < .001). Three patients experienced major bleeding complications without permanent sequelae (2 enoxaparin, 1 warfarin). CONCLUSIONS: Given the negative impact of thrombotic complications on survival, the low risk of serious bleeding complications, and the association between thromboprophylaxis and lowered thrombotic complication risk across all 3 palliative stages, routine use of thromboprophylaxis from the initial palliation to the early post-Fontan period in this population may be indicated.

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This study investigates the effects of noise distraction on the different components and sources of laser-evoked potentials (LEPs) whilst attending to either the spatial component (localisation performance task) or the affective component (unpleasantness rating task) of pain. LEPs elicited by CO2 laser stimulation of the right forearm were recorded from 64 electrodes in 18 consenting healthy volunteers. Subjects reported either pain location or unpleasantness, in the presence and absence of distraction by continuous 85 dBa white noise. Distributed sources of the LEP peaks were identified using Low Resolution Electromagnetic Tomography (LORETA). Pain unpleasantness ratings and P2 (430 ms) peak amplitude were significantly reduced by distraction during the unpleasantness task, whereas the localisation ability and the corresponding N1/N2 (310 ms) peak amplitude remained unchanged. Noise distraction (at 310 ms) reduced activation in the anterior cingulate cortex (ACC) and precuneus during attention to localisation and unpleasantness, respectively. This suggests a complimentary role for these two areas in the control of attention to pain. In contrast, activation of the occipital pole and SII were enhanced by noise during the localisation and unpleasantness task, respectively, suggesting that the presence of noise was associated with increased spatial attentional load. This study has shown selective modulation of affective pain processing by noise distraction, indicated by a reduction in the unpleasantness ratings and P2 peak amplitude and associated activity within the medial pain system. These results show that processing of the affective component of pain can be differentially modulated by top-down processes, providing a potential mechanism for therapeutic intervention.

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Vibration analysis of free standing silicon nanoparticles, with sizes ranging from 0.732 to 4.223 nm, are calculated using two different methods: molecular mechanics and classical continuum elasticity. Three different geometries are studied: cubes, spheres, and tetrahedrons. Continuum mechanics methods provide good estimates of the lowest natural frequency of particles having at least 836 (R>1.5 nm) and 800 (R>1.28 nm) atoms for cube- and tetrahedron-shaped nanostructures, respectively. Equations for vibrational frequencies of smaller particles as a function of size are proposed. The vibrational modes obtained from both methods were practically the same for the sphere- and tetrahedron-shaped particles with a large number of atoms. However, for the cube geometry only the shape of the modes corresponding to the lowest couple of frequencies occur in the same order. In general, vibrational modes shapes obtained using both methods are the same although the order in which they appear may be shifted.

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OBJECTIVE: To refine the disease-specific health-related quality of life measure in immune (idiopathic) thrombocytopenic purpura (ITP) and to determine its validity, reliability, and responsiveness to change. STUDY DESIGN: The initial phase involved cognitive debriefing of 12 families, on the basis of which the measure was modified and then named Kids' ITP Tools (KIT). The measure was administered on 2 occasions with the Pediatric Quality of Life Inventory (PedsQL) to 41 patients with acute ITP and 49 patients with chronic ITP, 2 to 18 years old, and their parents (proxy-respondents) at 6 North American centers. RESULTS: Patients with acute ITP had lower scores when compared with patients with chronic ITP (child 64 versus 76, proxy 69 versus 77). The KIT moderately correlated with the PedsQL. Child versus proxy KIT scores showed moderate correlation, and the KIT was superior to the PedsQL. Test-retest reliability was substantial in the child report, but only moderate for the proxy report, similar to the PedsQL. The KIT showed a mean score change of 13 in the child and 15 in the proxy, which was greater than the PedsQL child's change of 7 and proxy change of 5. CONCLUSION: The KIT is valid, with good distinction between acute and chronic ITP and a moderate correlation with the PedsQL. The KIT demonstrated reliability comparable with that of the PedsQL, yet it was more responsive to change. Therefore the KIT can be used as an outcome measure in future clinical trials of childhood ITP.

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Rivers are generally supersaturated with respect to carbon dioxide, resulting in large gas evasion fluxes that can be a significant component of regional net carbon budgets. Amazonian rivers were recently shown to outgas more than ten times the amount of carbon exported to the ocean in the form of total organic carbon or dissolved inorganic carbon. High carbon dioxide concentrations in rivers originate largely from in situ respiration of organic carbon, but little agreement exists about the sources or turnover times of this carbon. Here we present results of an extensive survey of the carbon isotope composition (13C and 14C) of dissolved inorganic carbon and three size-fractions of organic carbon across the Amazonian river system. We find that respiration of contemporary organic matter (less than five years old) originating on land and near rivers is the dominant source of excess carbon dioxide that drives outgassing in medium to large rivers, although we find that bulk organic carbon fractions transported by these rivers range from tens to thousands of years in age. We therefore suggest that a small, rapidly cycling pool of organic carbon is responsible for the large carbon fluxes from land to water to atmosphere in the humid tropics.

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Terrestrial ecosystems in the humid tropics play a potentially important but presently ambiguous role in the global carbon cycle. Whereas global estimates of atmospheric CO2 exchange indicate that the tropics are near equilibrium or are a source with respect to carbon, ground-based estimates indicate that the amount of carbon that is being absorbed by mature rainforests is similar to or greater than that being released by tropical deforestation (about 1.6 Gt C yr-1). Estimates of the magnitude of carbon sequestration are uncertain, however, depending on whether they are derived from measurements of gas fluxes above forests or of biomass accumulation in vegetation and soils. It is also possible that methodological errors may overestimate rates of carbon uptake or that other loss processes have yet to be identified. Here we demonstrate that outgassing (evasion) of CO2 from rivers and wetlands of the central Amazon basin constitutes an important carbon loss process, equal to 1.2 +/- 0.3 Mg C ha-1 yr-1. This carbon probably originates from organic matter transported from upland and flooded forests, which is then respired and outgassed downstream. Extrapolated across the entire basin, this flux-at 0.5 Gt C yr-1-is an order of magnitude greater than fluvial export of organic carbon to the ocean. From these findings, we suggest that the overall carbon budget of rainforests, summed across terrestrial and aquatic environments, appears closer to being in balance than would be inferred from studies of uplands alone.

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