Correlation of Serum Cancer Antigen-125 (CA-125) Levels with Severity of Pre-eclampsia.

Background: Pre-eclampsia is often associated with unfavourable feto-maternal outcomes. There is a lacuna in its pathophysiology, which emphasizes the need to research for tests, which can predict or correlate with the severity of pre-eclampsia. Cancer antigen-125 (CA-125) is a simple, readily available biomarker with evidence of its secretion at the choriodecidual unit and may have a possible role. This study compared serum CA-125 levels between normal pregnant and pre-eclamptic women and determined its clinical usefulness in correlating with the severity of pre-eclampsia. Methods: A case-control study was conducted enrolling 58 women with pre-eclampsia further divided into severe and non-severe groups and 62 gestational age-matched healthy, pregnant controls. Serum CA-125 levels were compared between the two groups. Results: The mean serum CA-125 in the controls was 16.44 ± 8.28 IU/ml, 13.82 ± 9.18 IU/ml in the non-severe and 23.55 ± 30.55 IU/ml in the severe pre-eclampsia group (p = 0.134). Serum CA-125 had a significant association with systolic blood pressure (SBP) p = 0.002), diastolic blood pressure (DBP) (p = 0.026), foetal growth restriction (p = 0.025), pre-term birth (p = 0.039) and a highly significant association with 24-h urinary protein, liver enzymes, placental abruption, need of maternal intensive care as well as with poor neonatal outcome including stillbirth and neonatal mortality (p < 0.001). Conclusion: Serum CA-125 levels were found to be higher in the severe pre-eclampsia group as compared to non-severe pre-eclampsia and normotensive group, but the difference was not statistically significant. More studies on a larger scale are required to prove the usefulness of this marker with respect to maternal and perinatal outcome as well as its association with pre-eclampsia and its severity.

Treatment Guideline Nonadherence Pretransport Associated With Need for Higher Level of Care in Children Transferred to a Pediatric Tertiary Care Center for Status Epilepticus.

OBJECTIVES: We sought to investigate the association between adherence to the American Epilepsy Society (AES) 2016 guidelines for management of convulsive status epilepticus (SE) and clinical outcomes among children requiring interhospital transport for SE. We hypothesized that pretransport guideline nonadherence would be associated with needing higher level of care posttransfer. METHODS: This was a retrospective cohort study of children aged 30 days to 18 years transferred to our pediatric tertiary center from 2017 to 2019 for management of SE. Their care episodes were classified as 2016 American Epilepsy Society guideline adherent or nonadherent. There were 40 referring hospitals represented in this cohort. RESULTS: Of 260 care episodes, 55 (21%) were guideline adherent, 184 (71%) were guideline nonadherent, and 21 (8%) had insufficient data to determine guideline adherence. Compared with the adherent group, patients in the nonadherent care group had longer hospitalizations (32 hours [17-68] vs 21 hours [7-48], P = 0.006), were more likely to require intensive care unit admission (47% vs 31%), and less likely to be discharged home from the emergency department (16% vs 35%; χ 2 test, P = 0.01). Intubation rates did not differ significantly between groups (25% vs 18%, P = 0.37). When we fit a multivariable model to adjust for confounding variables, guideline nonadherence was associated with need for higher level of care (odds ratio, 2.04; 95% confidence interval, 1.04-3.99). Treatment guideline adherence did not improve over the 3-year study period (2017: 22%, 2018: 19%, 2019: 29% [χ 2 test for differences between any 2 years, P = 0.295]). CONCLUSIONS: Guideline nonadherence pretransport was associated with longer hospitalizations and need for higher level of care among children transferred for SE at our institution. These findings suggest a need to improve SE guideline adherence through multifaceted quality improvement efforts targeting both the prehospital and community hospital settings.

Cellular uptake of metal oxide-based nanocomposites and targeting of chikungunya virus replication protein nsP3.

Emergence of new pathogenic viruses along with adaptive potential of RNA viruses has become a major public health concern. Therefore, it is increasingly crucial to investigate and assess the antiviral potential of nanocomposites, which is constantly advancing area of medical biology. In this study, two types of nanocomposites: Ag/NiO and Ag2O/NiO/ZnO with varying molar ratios of silver and silver oxide, respectively have been synthesised and characterised. Three metal/metal oxide (Ag/NiO) composites having different amounts of Ag nanoparticles (NPs) anchored on NiO octahedrons are AN-5 % (5 % Ag), AN-10 % (10 % Ag) and AN-15 % (15 % Ag)) and three ternary metal oxide nanocomposites (Ag2O/NiO/ZnO) i.e., A/N/Z-1, A/N/Z-2, and A/N/Z-3 with different molar ratios of silver oxide (10 %, 20 % and 30 %, respectively) were evaluated for their antiviral potential. Cellular uptake of nanocomposites was confirmed by ICP-MS. Intriguingly, molecular docking of metal oxides in the active site of nsP3 validated the binding of nanocomposites to chikungunya virus replication protein nsP3. In vitro antiviral potential of nanocomposites was tested by performing plaque reduction assay, cytopathic effect (CPE) analysis and qRT-PCR. The nanocomposites showed significant reduction in virus titre. Half-maximal inhibitory concentration (IC50) for A/N/Z-3 and AN-5 % were determined to be 2.828 and 3.277 µg/mL, respectively. CPE observation and qRT-PCR results were consistent with the data obtained from plaque reduction assay for A/N/Z-3 and AN-5 %. These results have opened new avenues for development of nanocomposites based antiviral therapies.

Biochemical and Biophysical Characterisation of the Hepatitis E Virus Guanine-7-Methyltransferase.

Hepatitis E virus (HEV) is an understudied pathogen that causes infection through fecal contaminated drinking water and is prominently found in South Asian countries. The virus affects ~20 million people annually, leading to ~60,000 infections per year. The positive-stranded RNA genome of the HEV genotype 1 has four conserved open reading frames (ORFs), of which ORF1 encodes a polyprotein of 180 kDa in size, which is processed into four non-structural enzymes: methyltransferase (MTase), papain-like cysteine protease, RNA-dependent RNA polymerase, and RNA helicase. MTase is known to methylate guanosine triphosphate at the 5'-end of viral RNA, thereby preventing its degradation by host nucleases. In the present study, we cloned, expressed, and purified MTase spanning 33-353 amino acids of HEV genotype 1. The activity of the purified enzyme and the conformational changes were established through biochemical and biophysical studies. The binding affinity of MTase with magnesium ions (Mg2+) was studied by isothermal calorimetry (ITC), microscale thermophoresis (MST), far-UV CD analysis and, fluorescence quenching. In summary, a short stretch of nucleotides has been cloned, coding for the HEV MTase of 37 kDa, which binds Mg2+ and modulate its activity. The chelation of magnesium reversed the changes, confirming its role in enzyme activity.

Ag nanoparticles anchored on NiO octahedrons (Ag/NiO composite): An efficient catalyst for reduction of nitro substituted phenols and colouring dyes.

The development of an efficient sustainable catalyst for effective removal of hazardous chemicals, viz. nitrophenols and organic dyes, from wastewater is a challenging task. Herein, facile synthesis of Ag/NiO composites by anchoring Ag nanoparticles (NPs) on NiO octahedrons with different amounts of Ag NPs (AN-5% (5% Ag), AN-10% (10% Ag) and AN-15% (15% Ag)) has been demonstrated. SEM (scanning electron microscopic) and TEM (transmission electron spectroscopic) images ensured the proper anchoring of spherical Ag NPs (particle size = 16.54 ± 1.88 nm) on octahedron particles of NiO, which was also ensured by XPS (X-ray photoelectron spectroscopy) analysis. Moreover, the resulting composites have an average surface area (49-52 m2g‒1) and pore size (2.39-2.26 nm). All three synthesized Ag/NiO composites (100 µL) catalyzed the complete reduction of para-np (4-nitrophenol: 0.1587 mM) within 2-3 min in the presence of 0.04 M NaBH4. Among them, AN-5% has been chosen because of the lowest anchored Ag (5%) to obtain the optimized catalyst's amount (50 µL) and concentration of para-np (0.1587 mM). AN-5% also exhibited excellent catalytic activity towards different nitro substituted phenols, viz. ortho-np (2-nitrophenol), meta-np (3-nitrophenol), para-np (4-nitrophenol) and tri-np (2,4,6-trinitrophenol). AN-5% displayed ∼100% catalytic efficiency for reducing meta-np in 2 min with the apparent first order rate constant (kapp) and normalized rate constant (Knor) as 1.99 s-1 and 398.14 s-1 g-1, respectively. Additionally, AN-5% (29.41 µg mL-1) reduced >95% of the colouring dyes (10 ppm) such as CONG-R (congo red: 95% in 6 min), METH-O (methyl orange: 97.5% in 7 min), METH-B (methylene blue: 98.3% in 10 min) and RHOD-B (rhodamine B: 99.2% in 5 min). AN-5% not only demonstrated catalytic reduction towards individual pollutants, but also showed excellent activity for reduction of the mixtures of nitrophenols/dyes and for treatment of simulated industrial effluent samples (EFF1, EFF2) and a real industrial sample (textile dye-bath effluent). AN-5% can also be reused up to several cycles with almost same efficiency and followed the Langmuir-Hinshelwood apparent first order kinetics model.

Diagnostic Discordance in Pediatric Critical Care Transport: A Single-Center Experience.

OBJECTIVES: The aims of the study were to describe diagnostic discordance rates at our pediatric tertiary care center between the reason for transfer of critically ill/injured children (determined by the referring institution) and the inpatient admission diagnosis (determined by our accepting institution), to identify potential factors associated with discordance, and to determine its impact on patient outcomes. METHODS: We conducted a retrospective chart review of all critically ill/injured children transferred to the Johns Hopkins Children's Center between July 1, 2017, and June 30, 2018. All patients whose initial inpatient disposition was the pediatric intensive care unit were included. RESULTS: Six hundred forty-three children (median age, 51 months) from 57 institutions (median pediatric capability level: 3) met inclusion criteria: 46.8% were transported during nighttime, 86.5% by ground, and 21.2% accompanied by a physician. Nearly half (43.4%) had respiratory admission diagnoses. The rest included surgical/neurosurgical (14.2%), neurologic (11.2%), cardiovascular/shock (8.7%), endocrine (8.2%), infectious disease (6.8%), poisoning (3.1%), hematology-oncology (2.2%), gastrointestinal/metabolic (1.9%), and renal (0.3%). Forty-six (7.2%) had referral-to-admission diagnostic discordance: 25 of 46 had discordance across different diagnostic groups and 21 of 46 had clinically significant discordance within the same diagnostic group. The discordant group had higher need for respiratory support titration in transport (43.9% vs 27.9%, p = 0.02); more invasive procedures and vasopressor needs during the day of admission (26.1% vs 11.6%, P = 0.008; 19.6% vs 7%, P = 0.006); and longer intensive care unit (ICU) and hospital stays (5 vs 2 days; 11 vs 3 days, P < 0.001). When compared with respiratory admission diagnoses, patients with cardiovascular/shock and neurologic diagnoses were more likely to have discordant diagnoses (odds ratio [95% confidence interval], 13.24 [5.41-35.05]; 6.47 [2.48-17.75], P < 0.001). CONCLUSIONS: Seven percent of our critically ill/injured pediatric cohort had clinically significant referral-to-admission diagnostic discordance. Patients with cardiovascular/shock and neurologic diagnoses were particularly at risk. Those with discordant diagnoses had more in-transit events; a higher need for ICU interventions postadmission; and significantly longer ICU stays and hospitalizations, deserving further investigation.

Engaging patients to improve quality of care: a systematic review.

BACKGROUND: To identify the strategies and contextual factors that enable optimal engagement of patients in the design, delivery, and evaluation of health services. METHODS: We searched MEDLINE, EMBASE, CINAHL, Cochrane, Scopus, PsychINFO, Social Science Abstracts, EBSCO, and ISI Web of Science from 1990 to 2016 for empirical studies addressing the active participation of patients, caregivers, or families in the design, delivery and evaluation of health services to improve quality of care. Thematic analysis was used to identify (1) strategies and contextual factors that enable optimal engagement of patients, (2) outcomes of patient engagement, and (3) patients' experiences of being engaged. RESULTS: Forty-eight studies were included. Strategies and contextual factors that enable patient engagement were thematically grouped and related to techniques to enhance design, recruitment, involvement and leadership action, and those aimed to creating a receptive context. Reported outcomes ranged from educational or tool development and informed policy or planning documents (discrete products) to enhanced care processes or service delivery and governance (care process or structural outcomes). The level of engagement appears to influence the outcomes of service redesign-discrete products largely derived from low-level engagement (consultative unidirectional feedback)-whereas care process or structural outcomes mainly derived from high-level engagement (co-design or partnership strategies). A minority of studies formally evaluated patients' experiences of the engagement process (n = 12; 25%). While most experiences were positive-increased self-esteem, feeling empowered, or independent-some patients sought greater involvement and felt that their involvement was important but tokenistic, especially when their requests were denied or decisions had already been made. CONCLUSIONS: Patient engagement can inform patient and provider education and policies, as well as enhance service delivery and governance. Additional evidence is needed to understand patients' experiences of the engagement process and whether these outcomes translate into improved quality of care. REGISTRATION: N/A (data extraction completed prior to registration on PROSPERO).

Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets.

In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment.

Microbial synthetic biology for human therapeutics.

The emerging field of synthetic biology holds tremendous potential for developing novel drugs to treat various human conditions. The current study discusses the scope of synthetic biology for human therapeutics via microbial approach. In this context, synthetic biology aims at designing, engineering and building new microbial synthetic cells that do not pre-exist in nature as well as re-engineer existing microbes for synthesis of therapeutic products. It is expected that the construction of novel microbial genetic circuitry for human therapeutics will greatly benefit from the data generated by 'omics' approaches and multidisciplinary nature of synthetic biology. Development of novel antimicrobial drugs and vaccines by engineering microbial systems are a promising area of research in the field of synthetic biology for human theragnostics. Expression of plant based medicinal compounds in the microbial system using synthetic biology tools is another avenue dealt in the present study. Additionally, the study suggest that the traditional medicinal knowledge can do value addition for developing novel drugs in the microbial systems using synthetic biology tools. The presented work envisions the success of synthetic biology for human therapeutics via microbial approach in a holistic manner. Keeping this in view, various legal and socio-ethical concerns emerging from the use of synthetic biology via microbial approach such as patenting, biosafety and biosecurity issues have been touched upon in the later sections.

Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.

Congenital hyperinsulinism (HI) is most commonly caused by recessive mutations of the pancreatic beta-cell ATP-sensitive potassium channel (K(ATP)), encoded by two genes on chromosome 11p, SUR1 and Kir6.2. The two mutations that have been best studied, SUR1 g3992-9a and SUR1 delF1388, are null mutations yielding nonfunctional channels and are characterized by nonresponsiveness to diazoxide, a channel agonist, and absence of acute insulin responses (AIRs) to tolbutamide, a channel antagonist, or leucine. To examine phenotypes of other K(ATP) mutations, we measured AIRs to calcium, leucine, glucose, and tolbutamide in infants with recessive SUR1 or Kir6.2 mutations expressed as diffuse HI (n = 8) or focal HI (n = 14). Of the 24 total mutations, at least seven showed evidence of residual K(ATP) channel function. This included positive AIR to both tolbutamide and leucine in diffuse HI cases or positive AIR to leucine in focal HI cases. One patient with partial K(ATP) function also responded to treatment with the channel agonist, diazoxide. Six of the seven patients with partial defects had amino acid substitutions or insertions; whereas, the other patient was compound heterozygous for two premature stop codons. These results indicate that some K(ATP) mutations can yield partially functioning channels, including cases of hyperinsulinism that are fully responsive to diazoxide therapy.

Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation.

Infants with congenital hyperinsulinism often require pancreatectomy. Recessive mutations of the ATP-dependent plasma membrane potassium channel (K(ATP)) genes, SUR1 and K(ir)6.2, cause diffuse hyperinsulinism. K(ATP) channel mutations can also cause focal disease through loss of heterozygosity for maternal 11p, resulting in expression of a paternal mutation. This study evaluated whether focal vs. diffuse hyperinsulinism could be diagnosed by acute insulin response (AIR) tests and whether arterial calcium stimulation/venous sampling (ASVS) could localize focal lesions. Fifty infants with diazoxide-unresponsive hyperinsulinism were studied. Focal lesions occurred in 70% of the cases. Positive AIR calcium occurred in 17 of 30 focal and 10 of 13 diffuse cases (P < 0.04). Positive AIR tolbutamide occurred in 27 of 30 focal vs. seven of 13 diffuse cases (P < 0.02); K(ATP) channel mutations were identified in four of the latter. ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse disease in only four of 13 cases. These results indicate that preoperative AIR tests do not distinguish focal vs. diffuse disease because some K(ATP) channel mutations retain responsiveness to tolbutamide. The ASVS test can be used to localize focal lesions in infants. The combination of ASVS, careful intraoperative histologic analysis, and surgical expertise succeeded in correcting hypoglycemia in 86% of the infants with focal hyperinsulinism.