Predictive ability of fetal growth charts in identifying kindergarten-age developmental challenges: a cohort study.

BACKGROUND: The Society for Maternal-Fetal Medicine recommends defining fetal growth restriction as an estimated fetal weight or abdominal circumference <10th percentile of a population-based reference. However, because multiple references are available, an understanding of their ability to identify infants at increased risk due to fetal growth restriction is critical. Previous studies have focused on the ability of different population references to identify short-term outcomes, but fetal growth restriction also has longer-term consequences for child development. OBJECTIVE: This study aimed to estimate the association between estimated fetal weight percentiles on the INTERGROWTH-21st and World Health Organization fetal growth charts and kindergarten-age childhood development, and establish the charts' discriminatory ability in predicting kindergarten-age developmental challenges. STUDY DESIGN: We conducted a retrospective cohort study linking obstetrical ultrasound scans conducted at BC Women's Hospital, Vancouver, Canada, with population-based standardized kindergarten test results. The cohort was limited to nonanomalous, singleton fetuses scanned at ≥28 weeks' gestation from 2000 to 2011, with follow-up until 2017. We classified estimated fetal weight into percentiles using the INTERGROWTH-21st and World Health Organization charts. We used generalized additive modeling to link estimated fetal weight percentile with routine province-wide kindergarten readiness test results. We calculated the area under the receiver-operating characteristic curve and other measures of diagnostic accuracy with 95% confidence intervals at select percentile cut-points of the charts. We repeated analyses using the Hadlock chart to help contextualize findings. The main outcome measure was the total Early Development Instrument score (/50). Secondary outcomes were Early Development Instrument subdomain scores for language and cognitive development, and for communication skills and general knowledge, as well as designation of "developmentally vulnerable" or "special needs". RESULTS: Among 3418 eligible fetuses, those with lower estimated fetal weight percentiles had systematically lower Early Development Instrument scores and increased risks of developmental vulnerability. However, the clinical significance of differences was modest in magnitude (eg, total Early Development Instrument score -2.8 [95% confidence interval, -5.1 to -0.5] in children with an estimated fetal weight in 3rd-9th percentile of INTERGROWTH-21st chart [vs reference of 31st-90th]). The charts' predictive abilities for adverse child development were limited (eg, area under the receiver-operating characteristic curve <0.53 for all 3 charts). CONCLUSION: Lower estimated fetal weight percentiles on the INTERGROWTH-21st and World Health Organization charts indicate increased risks of adverse kindergarten-age child development at the population level, but are not accurate individual-level predictors of adverse child development.

NECTAR: A New Algorithm for Characterizing and Correcting Noise in QToF-Mass Spectrometry Imaging Data.

A typical mass spectrometry imaging experiment yields a very high number of detected peaks, many of which are noise and thus unwanted. To select only peaks of interest, data preprocessing tasks are applied to raw data. A statistical study to characterize three types of noise in MSI QToF data (random, chemical, and background noise) is presented through NECTAR, a new NoisE CorrecTion AlgoRithm. Random noise is confirmed to be dominant at lower m/z values (∼50-400 Da) while systematic chemical noise dominates at higher m/z values (>400 Da). A statistical approach is presented to demonstrate that chemical noise can be corrected to reduce its presence by a factor of ∼3. Reducing this effect helps to determine a more reliable baseline in the spectrum and therefore a more reliable noise level. Peaks are classified according to their spatial S/N on the single ion images, and background noise is thus removed from the list of peaks of interest. This new algorithm was applied to MALDI and DESI QToF data generated from the analysis of a mouse pancreatic tissue section to demonstrate its applicability and ability to filter out these types of noise in a relevant data set. PCA and t-SNE multivariate analysis reviews of the top 4000 peaks and the final 744 and 299 denoised peak list for MALDI and DESI, respectively, suggests an effective removal of uninformative peaks and proper selection of relevant peaks.

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.

Dystrophinopathy Phenotypes and Modifying Factors in DMD Exon 45-55 Deletion.

OBJECTIVE: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. METHODS: This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. RESULTS: The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. INTERPRETATION: We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-806.

Which chart and which cut-point: deciding on the INTERGROWTH, World Health Organization, or Hadlock fetal growth chart.

OBJECTIVE: To determine how various centile cut points on the INTERGROWTH-21st (INTERGROWTH), World Health Organization (WHO), and Hadlock fetal growth charts predict perinatal morbidity/mortality, and how this relates to choosing a fetal growth chart for clinical use. METHODS: We linked antenatal ultrasound measurements for fetuses > 28 weeks' gestation from the British Columbia Women's hospital ultrasound unit with the provincial perinatal database. We estimated the risk of perinatal morbidity/mortality (decreased cord pH, neonatal seizures, hypoglycemia, and perinatal death) associated with select centiles on each fetal growth chart (the 3rd, 10th, the centile identifying 10% of the population, and the optimal cut-point by Youden's Index), and determined how well each centile predicted perinatal morbidity/mortality. RESULTS: Among 10,366 pregnancies, the 10th centile cut-point had a sensitivity of 11% (95% CI 8, 14), 13% (95% CI 10, 16), and 12% (95% CI 10, 16), to detect fetuses with perinatal morbidity/mortality on the INTERGROWTH, WHO, and Hadlock charts, respectively. All charts performed similarly in predicting perinatal morbidity/mortality (area under the curve [AUC] =0.54 for all three charts). The statistically optimal cut-points were the 39th, 31st, and 32nd centiles on the INTERGROWTH, WHO, and Hadlock charts respectively. CONCLUSION: The INTERGROWTH, WHO, and Hadlock fetal growth charts performed similarly in predicting perinatal morbidity/mortality, even when evaluating multiple cut points. Deciding which cut-point and chart to use may be guided by other considerations such as impact on workflow and how the chart was derived.

Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels.

The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido[4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Cavα2δ-1 versus Cavα2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.

Design of a Multifunctional Nanoengineered PLLA Surface by Maximizing the Synergies between Biochemical and Surface Design Bactericidal Effects.

Nanotechnology, the manipulation of matter on atomic, molecular, and supramolecular scales, has become the most appealing strategy for biomedical applications and is of great interest as an approach to preventing microbial risks. In this study, we utilize the antimicrobial performance and the drug-loading ability of novel nanoparticles based on silicon oxide and strontium-substituted hydroxyapatite to develop nanocomposite antimicrobial films based on a poly(l-lactic acid) (PLLA) polymer. We also demonstrate that nanoimprint lithography (NIL), a process adaptable to industrial application, is a feasible fabrication technique to modify the surface of PLLA, to alter its physical properties, and to utilize it for antibacterial applications. Various nanocomposite PLLA films with nanosized (black silicon) and three-dimensional (hierarchical) hybrid domains were fabricated by thermal NIL, and their bactericidal activity against Escherichia coli and Staphylococcus aureus was assessed. Our findings demonstrate that besides hydrophobicity the nanoparticle antibiotic delivery and the surface roughness are essential factors that affect the biofilm formation.

Design of Hierarchical Surfaces for Tuning Wetting Characteristics.

Patterned surfaces with tunable wetting properties are described. A hybrid hierarchical surface realized by combining two different materials exhibits different wetting states, depending on the speed of impingement of the water droplets. Both "lotus" (high contact angle and low adhesion) and "petal" (high contact angle and high adhesion) states were observed on the same surface without the need of any modification of the surface. The great difference between the capillary pressures exerted by the microstructures and nanostructures was the key factor that allowed us to tailor effectively the adhesiveness of the water droplets. Having a low capillary pressure for the microstructures and a high capillary pressure for the nanostructures, we allow to the surface the possibility of being in a lotus state or in a petal state.

Determinants of research engagement in academic obstetrics and gynaecology.

BACKGROUND: To identify the determinants of research engagement among faculty in an academic department of Obstetrics and Gynaecology. METHODS: All members of the Department of Obstetrics and Gynaecology at the University of British Columbia were mailed an online version of the Edmonton Research Orientation Survey (EROS) in 2011 and in 2014. High scores on overall research engagement and on each of the 4 subscales, namely, value of research, value of innovation, research involvement and research utilization/evidence-based practice were quantified. Analyses were carried out on both surveys combined and on the 2014 survey separately. Logistic regression was used to identify determinants of high levels of research engagement. RESULTS: The overall response rate was 37% (130 responses; 54 respondents in 2011 and 76 respondents in 2014). The average EROS score was 140 (range 54 to 184) and 35% of respondents had a score ≥150. Significant determinants of positive research engagement based on the overall EROS scale included being paid for research work (adjusted odds ratio [AOR] 22.1, 95% confidence interval [CI] 2.47-197.7) and carrying out research during unpaid hours (AOR 6.41, 95% CI 1.97-20.9). Age <50 years (AOR 11.0, 95% CI 1.35-89.9) and clinical experience <20 years (AOR 19.7, 95% CI 2.18-178.8) were positively associated, while journal reading during unpaid hours (AOR 0.21, 95% CI 0.07-0.62) was negatively associated with specific EROS subscales. CONCLUSIONS: In a setting with a positive research orientation, research engagement among the faculty was associated with paid research time, research work and journal reading during unpaid hours and more recent entry into clinical practice.

Synthesis and structure-activity relationship study of a new series of selective σ(1) receptor ligands for the treatment of pain: 4-aminotriazoles.

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ1 receptor (σ1R) ligands are reported. The compounds were prepared using a 4-5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ1R, and the selectivity over the σ2R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ1R potency a minimum lipophilicity was required, while limiting to a defined range of cLogP avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.

Synthesis and biological evaluation of a new series of hexahydro-2H-pyrano[3,2-c]quinolines as novel selective σ1 receptor ligands.

The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.

Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862).

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.

Total solid-phase synthesis of the azathiocoraline class of symmetric bicyclic peptides.

Thiocoraline is a potent antitumor agent isolated from the marine organism Micromonospora sp. This symmetric bicyclic depsipeptide binds the minor groove of DNA. Here we report two solid-phase strategies for the syntheses of azathiocoraline and its analogues. The thioester linkage was replaced by an amide bond to improve the compound's pharmacokinetic properties. The first strategy is based on a convergent (4+4) approach, whilst the second is a stepwise synthesis, cyclizations in both approaches occurring on the solid support. These two strategies were designed to overcome problems caused by the presence of consecutive noncommercial N-methyl amino acids, to avoid epimerization during cyclization and/or fragment condensation, and to form the disulfide bridge under solid-phase conditions. The heterocyclic moiety was added in the last step of the synthesis to assist the preparation of libraries of new compounds with potential therapeutic applications.

Community participation in a multisectoral intervention to address health determinants in an inner-city community in central Havana.

It is increasingly acknowledged that the process of community involvement is critical to the successful implementation of community-based health interventions. Between 1995 and 1999, a multisectoral intervention called Plan Cayo Hueso was launched in the inner-city community of Cayo Hueso in Havana, Cuba, to address a variety of health determinants. To provide a better understanding of the political structures and processes involved, the Cuban context is described briefly. The interventions included improvements in housing, municipal infrastructure, and social and cultural activities. A qualitative study, consisting of interviews of key informants as well as community members, was conducted to evaluate the community participatory process. Questions from an extensive household survey pre- and postintervention that had been conducted in Cayo Hueso and a comparison community to assess the effectiveness of the intervention also informed the analysis of community participation, as did three community workshops held to choose indicators for evaluating effectiveness and to discuss findings. It was found that formal leaders led the interventions, providing the institutional driving force behind the plan. However, extensive community involvement occurred as the project took advantage of the existing community-based organizations, which played an active role in mobilizing community members and enhanced linkage systems critical to the project's success. Women played fairly traditional roles in interventions outside their households, but had equivalent roles to men in interventions within their household units. Most impressive about this project was the extent of mobilization to participate and the multidimensional ecosystem approach adopted. Indeed, Plan Cayo Hueso involved a massive mobilization of international, national, and community resources to address the needs of this community. This, as well as the involvement of community residents in the evaluation process, was seen as resulting in improved social interactions and community well-being and enhanced capacity for future action. While Cuba is unique in many respects, the lessons learned about enhancing community participation in urban health intervention projects, as well as in their evaluation, are applicable worldwide.