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Objective: Risks and benefits of experimental fetal therapies can remain uncertain after initial clinical studies, especially long-term effects. Nevertheless, pregnant individuals may request them, hoping to benefit their future child. Guidance about offering experimental fetal therapies outside research (as "innovative therapy") is limited, despite their ethical complexity. We propose points for clinicians and reviewers to consider when deciding whether and how to offer experimental fetal therapies as innovative therapies after initial clinical studies., Method: We used conceptual analysis and a current case to develop points for consideration, grounded in broader debates on innovative therapy and the unique challenges associated with experimental fetal therapies., Results: Clinicians should evaluate whether offering experimental fetal therapies as innovative therapy is appropriate for a pregnant individual and their fetus. The anticipated risk-benefit ratio for the fetus should be favorable. For the pregnant individual, risks may outweigh benefits, within reasonable limits. Medical resources should be sufficient to ensure appropriate care. Clinicians should support pregnant individuals in making informed choices. Clinicians offering innovative therapies with more than minimal risk should collect and report data on outcomes. Independent review should take place., Conclusion: Considering these points may advance the interests of fetuses, future children, and their families., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: Fetal megacystis generally presents as suspected lower urinary tract obstruction (LUTO), which is associated with severe perinatal morbidity. Genetic etiologies underlying LUTO or a LUTO-like initial presentation are poorly understood. Our objectives are to describe single gene etiologies in fetuses initially ascertained to have suspected LUTO and to elucidate genotype-phenotype correlations., Methods: A retrospective case series of suspected fetal LUTO positive for a molecular diagnosis was collected from five centers in the Fetal Sequencing Consortium. Demographics, sonograms, genetic testing including variant classification, and delivery outcomes were abstracted., Results: Seven cases of initially prenatally suspected LUTO-positive for a molecular diagnosis were identified. In no case was the final diagnosis established as urethral obstruction that is, LUTO. All variants were classified as likely pathogenic or pathogenic. Smooth muscle deficiencies involving the bladder wall and interfering with bladder emptying were identified in five cases: MYOCD (2), ACTG2 (2), and MYH11 (1). Other genitourinary and/or non-genitourinary malformations were seen in two cases involving KMT2D (1) and BBS10 (1)., Conclusion: Our series illustrates the value of molecular diagnostics in the workup of fetuses who present with prenatally suspected LUTO but who may have a non-LUTO explanation for their prenatal ultrasound findings., (© 2023 John Wiley & Sons Ltd.)

Objective: To describe the clinical and laboratory outcomes of infants with subcutaneous fat necrosis of the newborn (SCFN) and propose a care algorithm., Methods: This single-center, retrospective study of infants diagnosed with SCFN at Ann & Robert H. Lurie Children's Hospital of Chicago from 2009 to 2019., Results: Of 32 infants who met inclusion criteria, most were born full-term (84%), born via cesarean section (58%), had normal weight for gestational age (69%), and experienced delivery complications (53%). Twenty-nine infants (91%) had calcium drawn, and all had hypercalcemia. Three infants developed clinical symptoms of hypercalcemia, two required hospital admission, two developed nephrocalcinosis, and one developed acute kidney injury. The majority of infants (62%) had a peak ionized calcium between 1.5 and 1.6 mmol/L. No infants with peak ionized calcium less than 1.5 mmol/L developed complications of hypercalcemia. Most patients were diagnosed with hypercalcemia (86%) and demonstrated peak ionized calcium levels (59%) within the first 28 days of life. No patients developed hypercalcemia after 3 months of age., Conclusion: Hypercalcemia occurred in 100% of infants who had laboratory monitoring. We recommend obtaining an initial ionized calcium level when SCFN is suspected, and monitoring for the first 3 months of life if hypercalcemia has not been detected. In patients with asymptomatic hypercalcemia less than 1.5 mmol/L, there appears to be low likelihood of related complications. For symptomatic, markedly elevated (>1.6 mmol/L), or persistently elevated levels (>6 months) we suggest coordinated care with endocrinology or nephrology, consider hospitalization, and urinary system ultrasound., (© 2022 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Objective: To develop a realistic simulation model for laparotomy-assisted fetoscopic spina bifida aperta (SBa) surgery, to be used for training purposes and preoperative planning., Methods: The predefined general requirement was a realistic model of an exteriorized uterus, allowing all neurosurgical steps of the intervention. The uterus was modelled using ultrasound and MRI images of a 25 weeks' gravid uterus, consisting of flexible polyurethane foam coated with pigmented silicone. The fetal model, contained an opening on the dorsal side for a customizable spinal insert with all the aspects of a SBa, including a cele, placode, and myofascial and skin layer. The model was assessed in a series of validation experiments., Results: Production costs are low, uterus and fetus are reusable. Placental localization and the level and size of the spinal defect are adjustable, enabling case-specific adaptations. All aspects of the simulator were scored close to realistic or higher for both appearance and functional capacities., Conclusions: This innovative model provides an excellent training opportunity for centers that are starting a fetoscopic SBa repair program. It is the first simulation model with adjustable spinal defect and placental localisation. Further objective validation is required, but the potential for using this model in preoperative planning is promising., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Throughout 2020, the coronavirus disease 2019 (COVID-19) has become a threat to public health on national and global level. There has been an immediate need for research to understand the clinical signs and symptoms of COVID-19 that can help predict deterioration including mechanical ventilation, organ support, and death. Studies thus far have addressed the epidemiology of the disease, common presentations, and susceptibility to acquisition and transmission of the virus; however, an accurate prognostic model for severe manifestations of COVID-19 is still needed because of the limited healthcare resources available., Objective: This systematic review aims to evaluate published reports of prediction models for severe illnesses caused COVID-19., Methods: Searches were developed by the primary author and a medical librarian using an iterative process of gathering and evaluating terms. Comprehensive strategies, including both index and keyword methods, were devised for PubMed and EMBASE. The data of confirmed COVID-19 patients from randomized control studies, cohort studies, and case-control studies published between January 2020 and May 2021 were retrieved. Studies were independently assessed for risk of bias and applicability using the Prediction Model Risk Of Bias Assessment Tool (PROBAST). We collected study type, setting, sample size, type of validation, and outcome including intubation, ventilation, any other type of organ support, or death. The combination of the prediction model, scoring system, performance of predictive models, and geographic locations were summarized., Results: A primary review found 445 articles relevant based on title and abstract. After further review, 366 were excluded based on the defined inclusion and exclusion criteria. Seventy-nine articles were included in the qualitative analysis. Inter observer agreement on inclusion 0.84 (95%CI 0.78-0.89). When the PROBAST tool was applied, 70 of the 79 articles were identified to have high or unclear risk of bias, or high or unclear concern for applicability. Nine studies reported prediction models that were rated as low risk of bias and low concerns for applicability., Conclusion: Several prognostic models for COVID-19 were identified, with varying clinical score performance. Nine studies that had a low risk of bias and low concern for applicability, one from a general public population and hospital setting. The most promising and well-validated scores include Clift et al., 15 and Knight et al., 18 which seem to have accurate prediction models that clinicians can use in the public health and emergency department setting., (© 2022 Society for Academic Emergency Medicine.)

Since the completion of the Management of Myelomeningocoele Study, maternal-fetal surgery for spina bifida has become a valid option for expecting parents. More recently, multiple groups are exploring a minimally invasive approach and recent outcomes have addressed many of the initial concerns with this approach. Based on a previously published framework, we attempt to delineate the developmental stage of the surgical techniques. Furthermore, we discuss the barriers of performing randomized controlled trials comparing two surgical interventions and suggest that data collection through registries is an alternative method to gather high-grade evidence., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Purpose: This article outlines how current nursing research can utilize technology to advance symptom and self-management science for precision health and provides a roadmap for the development and use of technologies designed for this purpose., Approach: At the 2018 annual conference of the National Institute of Nursing Research (NINR) Research Centers, nursing and interdisciplinary scientists discussed the use of technology to support precision health in nursing research projects and programs of study. Key themes derived from the presentations and discussion were summarized to create a proposed roadmap for advancement of technologies to support health and well-being., Conclusions: Technology to support precision health must be centered on the user and designed to be desirable, feasible, and viable. The proposed roadmap is composed of five iterative steps for the development, testing, and implementation of technology-based/enhanced self-management interventions. These steps are (a) contextual inquiry, focused on the relationships among humans, and the tools and equipment used in day-to-day life; (b) value specification, translating end-user values into end-user requirements; (c) design, verifying that the technology/device can be created and developing the prototype(s); (d) operationalization, testing the intervention in a real-world setting; and (e) summative evaluation, collecting and analyzing viability metrics, including process data, to evaluate whether the technology and the intervention have the desired effect., Clinical Relevance: Interventions using technology are increasingly popular in precision health. Use of a standard multistep process for the development and testing of technology is essential., (© 2019 Sigma Theta Tau International.)

Background: The published literature demands examples of health-care systems designed with the active engagement of patients to explore the application of this complex phenomenon in practice., Methods: This case study explored how the voice of patients was incorporated into the process of redesigning an element of the health-care system, a centralized system for intake of referrals from primary care to rheumatologists for patients with suspected rheumatoid arthritis (RA)-centralized intake. The phenomenon of patient engagement using "patient and community engagement researchers" (PaCERs) in research and the process of redesigning centralized intake were selected as the case. In-depth evaluation of the case was undertaken through the triangulation of findings from the document review and participants' reflection on the case., Results: In this case, patients and PaCERs participated in multiple activities including an initial meeting of key stakeholders to develop the project vision; a patient-to-patient PaCERs study to gather perspectives of patients with RA on the challenges they face in accessing and navigating the health-care system, and what they see as key elements of an effective system that would be responsive to their needs; the development of an evaluation framework for future centralized intake; and the choice of candidate centralized intake strategies to be evaluated., Conclusions: The described feasible multistep approach to active patient engagement in health-care system redesign contributes to an understanding of the application of this complex phenomenon in practice. Therefore, the manuscript serves as one more step towards a patient-centred health-care system that is redesigned with active patient engagement., (© 2018 The Authors Health Expectations published by John Wiley & Sons Ltd.)

Fetoscopic endotracheal occlusion (FETO) is a prenatal treatment that may increase survival in severe congenital diaphragmatic hernia (CDH). In the USA, FETO is offered for isolated severe left-sided CDH in the context of an FDA-approved feasibility study. FETO in non-isolated cases of severe CDH is only performed with a compassionate use exemption from US regulatory bodies. Anomalies frequently associated with CDH include congenital cystic lesions of the lung and cardiac defects. We describe two cases of non-isolated severe left-sided CDH that underwent prenatal FETO, survived after birth and underwent postnatal surgical repair. The potential benefit of FETO in this setting is discussed. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

The ductus venosus has a central role in the distribution of highly oxygenated umbilical venous blood to the heart. Its waveform is related to the pressure-volume changes in the cardiac atria and it is therefore important in the monitoring of any fetal condition that may affect forward cardiac function. The cardiovascular parameters that can influence forward cardiac function include afterload, myocardial performance and preload. Decreased forward flow during atrial systole (a-wave) is the most sensitive and ubiquitous finding when any of these parameters is affected. In contrast, decreased forward velocities during end-systolic relaxation (v-wave) are more specifically related to myocardial performance. The ductus venosus pulsatility index alone does not accurately reflect cardiac function, and in cases of suspected fetal cardiac dysfunction, echocardiography is required to identify the underlying mechanism. The role of ductus venosus Doppler in the assessment of fetal growth restriction, supraventricular tachycardia, fetal hydrops, complicated monochorionic twins and congenital heart disease is discussed with these considerations in mind., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

Prader-Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating-related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting-state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low-frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting-state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre-/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating., (Copyright © 2013 John Wiley & Sons, Ltd.)

The clinical and histopathological features of cutaneous herpes simplex virus (HSV) infection have been well described. Genital herpetic infections are largely induced by HSV type 2, but 30% of cases can be caused by HSV type 1. Immunocompromised patients are known to exhibit atypical patterns of clinical presentation with variable lesion morphology and anatomic location. A subset of patients may show morphology such as nodules or verrucous lesions. Analogously, some biopsy specimens may show unusual microscopical features, such as a lack of keratinocyte cytopathology, lymphocyte infiltration or vasculopathic changes that are expected irrespective of the patient's immune status. We present the case of a patient carrying a previous diagnosis of pemphigus vulgaris, status posttreatment with methotrexate and prednisone, who developed a perineal ulcer exhibiting significant numbers of plasma cells, many of which were cytologically atypical. This morphology was suggestive of a hematopoietic malignancy. Immunoperoxidase staining for HSV decorated a focal collection of keratinocytes that lacked appreciable viral changes expected of HSV infection., (Copyright © 2011 John Wiley & Sons A/S.)

The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.

Widespread contamination of California water bodies by the organophosphate insecticides diazinon and chlorpyrifos is well documented. While their usage has decreased over the last few years, a concomitant increase in pyrethroid usage (e.g., permethrin) (replacement insecticides) has occurred. Vegetated agricultural drainage ditches (VADD) have been proposed as a potential economical and environmentally efficient management practice to mitigate the effects of pesticides in irrigation and storm runoff. Three ditches were constructed in Yolo County, California for a field trial. A U-shaped vegetated ditch, a V-shaped vegetated ditch, and a V-shaped unvegetated ditch were each amended for 8 h with a mixture of diazinon, permethrin, and suspended sediment simulating an irrigation runoff event. Water, sediment, and plant samples were collected spatially and temporally and analyzed for diazinon and permethrin concentrations. Pesticide half-lives were similar between ditches and pesticides, ranging from 2.4 to 6.4 h. Differences in half-distances (distance required to reduce initial pesticide concentration by 50%) among pesticides and ditches were present, indicating importance of vegetation in mitigation. Cis-permethrin half-distances in V ditches ranged from 22 m (V-vegetated) to 50 m (V-unvegetated). Half-distances for trans-permethrin were similar, ranging from 21 m (V-vegetated) to 55 m (V-unvegetated). Diazinon half-distances demonstrated the greatest differences (55 m for V-vegetated and 158 m for V-unvegetated). Such economical and environmentally successful management practices will offer farmers, ranchers, and landowners a viable alternative to more conventional (and sometimes expensive) practices.

This open-label, randomized, placebo-controlled, incomplete-block, 3-period crossover pilot study investigated the effects of peroxisome proliferator-activated receptor alpha- and gamma-agonists on biomarkers of lipid and glucose metabolism in 12 nondiabetic subjects. Plasma samples were collected before and after each 14-day treatment with placebo, fenofibrate (201 mg/d), rosiglitazone (4 mg twice daily), and combined fenofibrate (201 mg/d) plus rosiglitazone (4 mg twice daily). Except for triglycerides (P < .042) and free fatty acids (P < .074), no significant interaction was demonstrated between fenofibrate and rosiglitazone; thus, the effect due to each drug alone was evaluated (presence/absence of drug). Fenofibrate significantly (P < .050) increased lipoprotein lipase activity (35%) and decreased apolipoproteins B (13%) and C-III (20%). Rosiglitazone significantly (P < .050) decreased fasting glucose (7.3%) and increased apolipoprotein C-III (19%) and adiponectin (137%). Fenofibrate and rosiglitazone also produced effects on triglycerides and free fatty acids, but it was not possible to determine if these effects were synergistic in nature.

To investigate the influence of modifying in vivo cytochrome P450 3A (CYP3A) activity on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, and of etoricoxib administration on CYP3A activity, a 3-part, randomized, crossover study was conducted in 3 panels of healthy volunteers. In part I, 8 subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 400 mg ketoconazole, a known strong inhibitor of CYP3A. In part II, 8 different subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 600 mg rifampin, a known strong inducer of CYP3A. In parts I and II, plasma samples were collected following each etoricoxib dose and analyzed for etoricoxib. In part III, 8 different subjects were administered 120 mg etoricoxib or placebo once daily for 11 days, and the erythromycin breath test was administered on day 11 of each period. Coadministration of etoricoxib with daily doses of ketoconazole resulted in an average 43% increase in etoricoxib AUC; based on previous studies, this increase would not be expected to have any clinically meaningful effect. In contrast, coadministration of etoricoxib with daily doses of rifampin had a potentially clinically important effect on etoricoxib pharmacokinetics (average 65% decrease in etoricoxib AUC). Etoricoxib had no effect on hepatic CYP3A activity, as assessed by the erythromycin breath test., (Copyright 2004 American College of Clinical Pharmacology)

The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1-week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (%CV) bioavailability of 77.7(11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration. Elimination profiles were comparable between all three routes. The concentration-time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.

To assess dose proportionality of etoricoxib across the anticipated clinical dose range, a single panel of 12 healthy subjects was administered single oral doses of etoricoxib of 5, 10, 20, 40, and 120 mg in an open, two-part, five-period crossover study. Plasma samples were collected aftereach dose and analyzed for etoricoxib concentrations. The pharmacokinetics of etoricoxib appear to be linear over the entire dose range examined, from 5 to 120 mg. Etoricoxib was found to be well tolerated across the 5 to 120 mg dose range.

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

Background: To evaluate the possible benefits of the addition of intermediate-acting insulin administered at bedtime to therapy with daytime sulfonylureas in patients with non-insulin-dependent diabetes mellitus for whom maximal doses of oral hypoglycemic agents have not been successful., Methods: Study subjects were 16 consecutive obese patients aged from 44 to 78 years (mean age, 62 years) with histories of non-insulin-dependent diabetes mellitus for a mean of 9 years. None of the subjects had been able to control their diabetes with maximal doses of oral hypoglycemic agents. All patients received 20 mg glipizide or 10 mg glyburide twice a day, as well as education about the American Diabetes Association diet. Neutral protamine Hagedorn (NPH) insulin was empirically added in doses from 0.1 to 0.2 units/kg given at bedtime. The dose was adjusted on the basis of fasting blood glucose levels., Results: Mean fasting blood glucose decreased from 13.7 +/- 3.4 to 8.3 +/- 2.7 mmol/L at 3 months and 7.3 + 2.0 mmol/L at 1 year. Glycosylated hemoglobin decreased from 9.0% +/- 1.9% to 6.2% +2- 1.16% at 3 months and 6.3% +/- 1.22% at 1 year., Conclusion: A late-night dose of NPH insulin was added to a regimen of daytime sulfonylureas in a group of obese patients with type II diabetes whose hyperglycemia was not controlled with maximal doses of oral hypoglycemic agents. This treatment proved to be beneficial and is a useful alternative to conventional insulin therapy in this group of patients.

Closed needle liver biopsy routinely provides 60-100 mg tissue from rhesus monkeys (Macaca mulatta). No mortality or morbidity was observed in over 400 needle biopsies during a two-year period in which some monkeys were biopsied over 30 times. Biopsy tissue was used as enzyme source in low-volume in vitro systems for measurement of hepatic monooxygenase activity.