Application of a modified clinical classification for pulmonary arterial hypertension associated with congenital heart disease in children: emphasis on atrial septal defects and transposition of the great arteries. An analysis from the TOPP registry.

Aims: A proportion of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) do not fit in the current classification. We aimed to analyse the applicability of an adapted clinical classification of PAH-CHD to pediatric patients using the TOPP-1 registry (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) and focus on atrial septal defects (ASD) and transposition of the great arteries (TGA). Methods and results: Hemodynamic and clinical data of all patients with PAH-CHD in the TOPP cohort were reviewed. Patients were classified according to predefined ABCDE categories (A: Eisenmenger syndrome, B: left-to-right shunt, C: coincidental defects, including all ASDs, D: corrected CHD, E: TGA), or as complex CHD (group 5), by 2 independent investigators. In case of disagreement, a third reviewer could either settle a final decision, or the patient was deemed not classifiable. Survival curves were calculated for each group and compared to idiopathic PAH patients of the registry. A total of 223 out of 531 patients in the registry had PAH-CHD, and 193 were categorized to the following groups: A 39(20%), B 27(14%), C 62(32%) including 43 ASDs, D 58(30%), E 7(4%), whereas 6 patients were categorized as group 5, and 10 patients were unable to be classified. No survival difference could be demonstrated between the groups. Conclusions: This modified classification seems to be more applicable to pediatric PAH-CHD patients than the previous classification, but some patients with PAH-CHD who never had a shunt remain unclassifiable. The role of ASD in pediatric PH should be reconsidered.

Long-term outcome of children with newly diagnosed pulmonary arterial hypertension: results from the global TOPP registry.

BACKGROUND AND AIMS: The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global network established to gain insights into the disease course and long-term outcomes of paediatric pulmonary arterial hypertension (PAH). Previously published cohorts in paediatric PAH are obscured by survival bias due to the inclusion of both prevalent (previously diagnosed) and incident (newly diagnosed) patients. The current study aims to describe long-term outcome and its predictors in paediatric PAH, exclusively of newly diagnosed patients. METHODS AND RESULTS: Five hundred thirty-one children with confirmed pulmonary hypertension, aged ≥3 months and <18 years, were enrolled in the real-world TOPP registry at 33 centres in 20 countries, from 2008 to 2015. Of these, 242 children with newly diagnosed PAH with at least one follow-up visit were included in the current outcome analyses. During long-term follow-up, 42 (17.4%) children died, 9 (3.7%) underwent lung transplantation, 3 (1.2%) atrial septostomy, and 9 (3.7%) Potts shunt palliation (event rates: 6.2, 1.3, 0.4, and 1.4 events per 100 person-years, respectively). One-, three-, and five-year survival free from adverse outcome was 83.9%, 75.2%, and 71.8%, respectively.Overall, children with open (unrepaired or residual) cardiac shunts had the best survival rates. Younger age, worse World Health Organization functional class, and higher pulmonary vascular resistance index were identified as independent predictors of long-term adverse outcome. Younger age, higher mean right atrial pressure, and lower systemic venous oxygen saturation were specifically identified as independent predictors of early adverse outcome (within 12 months after enrolment). CONCLUSION: This comprehensive analysis of survival from time of diagnosis in a large exclusive cohort of children newly diagnosed with PAH describes current-era outcome and its predictors.

Rare Case of Refractory Hypoxia and Severe Multiorgan Failure from Secondary Lymphohistiocytosis Successfully Bridged to Treatment with Extracorporeal Membrane Oxygenation Support.

Introduction: Acute respiratory distress syndrome (ARDS) is an uncommon complication of hemophagocytic lymphohistiocytosis (HLH). Non-specific findings that mimic other diseases make timely diagnosis and treatment challenging. We present a rare case of severe ARDS and multiorgan failure from secondary HLH due to peripheral T-cell lymphoma. Case presentation: A middle-aged female presented with dry cough and fever for three days. On presentation, the patient was febrile to 105°F and hypoxic to 88% on room air. Chest X-ray showed bilateral interstitial infiltrates. Laboratory investigations showed lymphopenia and elevated inflammatory markers. The viral panel, including coronavirus disease-2019 (COVID-19), influenza, and respiratory syncytial virus (RSV), was negative. Her respiratory status progressively worsened, requiring invasive mechanical ventilation for ARDS. Despite lung-protective ventilation, prone positioning, and the use of paralytic agents, the patient continued to remain hypoxic, necessitating extracorporeal membrane oxygenation (ECMO) support. The patient was started on antibiotics and high-dose steroid. Thereafter, she developed a leukemoid reaction, and the ferritin level started rising; raising suspicion for lymphophagocytosis. During this time, she also developed acute liver and kidney failure and required multiple vasopressors and renal replacement therapy. Eventually, a diagnosis of mature peripheral T-cell lymphoma was established. Subsequently, her respiratory status and multiorgan failure significantly improved, and ECMO was explanted after 2 weeks. She was started on etoposide and steroid, and eventually discharged after 6 weeks. Discussion: This is the first case describing a successful implementation of ECMO in an adult diagnosed with ARDS secondary to mature peripheral T-cell lymphoma; allowing for recovery of respiratory status, which was compromised during the initial cytokine storm and provided time to establish the diagnosis and initiate appropriate treatment of secondary HLH mature due to peripheral T-cell lymphoma, and in the end, prevented a fatality. We believe that ECMO may be appropriately instituted in rapidly deteriorating patients with an unknown illness refractory to conventional therapy, to allow for end-organ recovery, to reach a diagnosis, and to administer appropriate therapy. How to cite this article: Hundal J, Bowers D, Gadela NV, Jaiswal A. Rare Case of Refractory Hypoxia and Severe Multiorgan Failure from Secondary Lymphohistiocytosis Successfully Bridged to Treatment with Extracorporeal Membrane Oxygenation Support. Indian J Crit Care Med 2022;26(8):970-973. Statement of Ethics: This is a case report and does not contain any images or patient identifying information.

Impact on Quality of Life After Parathyroidectomy for Asymptomatic Primary Hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with a poorer quality of life. The role of neuropsychiatric symptoms in asymptomatic patients who do not display classical features of PHPT remains undefined. It is unclear whether parathyroidectomy provides immediate benefit beyond the long-term risk reduction of adverse effects. The aim of the study is to assess the effect on quality of life in patients with asymptomatic PHPT undergoing parathyroidectomy. METHODS: Consecutive patients with PHPT undergoing parathyroidectomy by a single surgeon were recruited from a single center between 2014 and 2019. All patients prospectively completed the validated EQ-5D-3L health status questionnaire preoperatively and postoperatively, comprising two components: (i) five domains including physical and mental health and (ii) visual analog scale (VAS). Biochemical and clinical indices were recorded. RESULTS: Seventy-eight patients were included, 72% female (n = 56), median age 62 y (interquartile range (IQR): 52-70), and 28 (36%) asymptomatic. A global improvement in health-related quality of life was observed with a VAS score increase from 70 (IQR: 50-80) to 80 (IQR: 70-90); P < 0.001. VAS scores also improved significantly in asymptomatic patients increasing from 77 to 85 (P = 0.014), with an overall improvement in all five domains of quality of life. The symptomatic group showed a significant improvement in anxiety/depression levels (P < 0.01), although this was not the primary complaint in any of the cases. CONCLUSIONS: Parathyroidectomy is associated with a significant improvement in the quality of life of patients with asymptomatic PHPT. In symptomatic patients, this includes a reduction in anxiety and depression. Benefits are observed as early as 2 mo postoperatively, and results suggest a potentially important cognitive and social aspect of this disease.

Fatty acid-like Pt(IV) prodrugs overcome cisplatin resistance in ovarian cancer by harnessing CD36.

Resistance to the platinum-based chemotherapy drug, cisplatin, is a significant setback in ovarian cancer. We engineered fatty acid-like Pt(iv) prodrugs that harness the fatty acid transporter CD36 to facilitate their entry to ovarian cancer cells. We show that these novel constructs effectively kill cisplatin-resistant ovarian cancer cells.

Engineering liposomal nanoparticles of cholesterol-tethered amphiphilic Pt(iv) prodrugs with prolonged circulation time in blood.

Cisplatin is a platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors. However, a major challenge in the use of cisplatin and in the development of cisplatin derivatives, namely Pt(iv) prodrugs, is their premature reduction in the bloodstream before reaching cancer cells. To circumvent this problem, we designed liposomal nanoparticles coupled with a cholesterol-tethered amphiphilic Pt(iv) prodrug. The addition of cholesterol served to stabilize the formation of the liposome, while selectively incorporating cholesterol as the axial ligand also allowed the Pt(iv) prodrug to readily migrate into the liposomal bilayer. Notably, upon embedding into the nanoparticles, the Pt(iv) prodrug showed marked resistance against premature reduction in human plasma in vitro. Pharmacokinetic analysis in a mouse model also showed that the nanoparticles significantly extend the half-life of the Pt(iv) prodrug to 180 min, which represents a >6-fold increase compared to cisplatin. Importantly, such lipid modification did not compromise the genotoxicity of cisplatin, as the Pt(iv) prodrug induced DNA damage and apoptosis in ovarian cancer cell lines efficiently. Taken together, our strategy provides a novel insight as to how to stabilize a platinum-based compound to increase the circulation time in vivo, which is expected to enhance the efficacy of drug treatment.

Dual-action organoplatinum polymeric nanoparticles overcoming drug resistance in ovarian cancer.

Drug resistance to the conventional platinum chemotherapy remains a major challenge for treating ovarian cancer. Herein, we present a novel approach to overcome the drug resistance by utilizing "dual-action" organometallic polymeric nanoparticles (OPNPs). The OPNPs were formed by the assembly of the organoplatinum payloads and the anionic block copolymer, methoxy polyethylene glycol-block-polyglutamic acid (MPEG5k-PGA50). The OPNPs enhance the solubility and biocompatibility of the hydrophobic organoplatinum payloads. The OPNPs enter the cancer cells via endocytosis, and the payloads loaded in the core of the nanoparticles are slowly released under the acidic conditions of endosomes. Unlike conventional platinum therapeutics, the organoplatinum compound exhibits a "dual-action" attack by triggering nuclear DNA damage and mitochondrial damage. As a result, drug-resistant ovarian cancer cells become vulnerable to the organoplatinum payloads.

A spermine-conjugated lipophilic Pt(iv) prodrug designed to eliminate cancer stem cells in ovarian cancer.

We developed a spermine-conjugated lipophilic Pt(iv) prodrug that is able to reduce the cancer stem cell population in ovarian cancer. The therapeutic effect is attributed to the hydrophobic tail and cationic spermine head group, the combination of which allows the Pt(iv) prodrug to localize in mitochondria and induce corresponding damage.

Nanoparticles of Metal-Organic Cages Overcoming Drug Resistance in Ovarian Cancer.

A long-standing challenge in the treatment of ovarian cancer is drug resistance to standard platinum-based chemotherapy. Recently, increasing attention has been drawn to the use of self-assembled metal-organic complexes as novel therapeutics for cancer treatment. However, high hydrophobicity that is often associated with these structures lowers their solubility and hinders their clinical translation. In this article, we present a proof-of-concept study of using nanoprecipitation to formulate the hydrophobic metal-organic cages and facilitate their use in treating chemoresistant ovarian cancer. The Pt6L4 Cage 1 is an octahedral cage formed by self-assembly of six 1,10-phenanthroline-Pt(II) centers and four 2,4,6-tris(4-pyridyl)-1,3,5-triazine ligands (L). Cage 1 is able to trigger DNA damage and exhibits promising in vitro potency against a panel of human ovarian cancer cell lines. However, due to the large portion of aromatic components, this cage structure has very limited solubility in cell culture media (<20µM). Notably, upon nanoformulation by using fluorescein (2) and a pegylated anionic polymer (3), the concentration of Cage 1 can reach up to 0.4 mM. Production of the nanoparticles of metal-organic cages (nMOC) is driven by the formation of the 1:1 host-guest complex of 1 and 2 in aqueous solution, which then form nanoprecipitation in presence of poly glutamic acid-b-poly ethylene glycol (3). The resulted nMOC are about 100 nm in diameter, and they serve as a delivery platform that slowly releases the therapeutic content. The use of fluorescein facilitates monitoring cell entry of nMOC and drug release using flow cytometry. Finally, comparing to cisplatin, the nMOC exhibit comparable in vitro efficacy against a panel of human cancer cell lines, and notably, it shows a much lower resistance factor against chemoresistant ovarian cancer cell lines.

Coordination-driven self-assembly of a Pt(iv) prodrug-conjugated supramolecular hexagon.

This article presents a new strategy to engage coordination-driven self-assembly for platinum drug delivery. The self-assembled supramolecular hexagon is conjugated with three equivalents of Pt(iv) prodrugs and displays a superior therapeutic index compared to cisplatin against a panel of human cancer cell lines.

Nanoparticles of metal-organic cages designed to encapsulate platinum-based anticancer agents.

We present a novel design to use metal-organic cages (MOCs) to encapsulate Pt-based anticancer agents for delivery. A fluorescein-conjugated Pt(iv) prodrug of cisplatin is developed for its encapsulation in a cationic MOC via host-guest interactions, which then forms drug-loaded nanoparticles with an anionic polymer.

Optical closure in marine waters from in situ inherent optical property measurements.

Optical closure using radiative transfer simulations can be used to determine the consistency of in situ measurements of inherent optical properties (IOPs) and radiometry. Three scattering corrections are applied to in situ absorption and attenuation profile data for a range of coastal and oceanic waters, but are found to have only very limited impact on subsequent closure attempts for these stations. Best-fit regressions on log-transformed measured and modelled downwards irradiance, Ed, and upwards radiance, Lu, profiles have median slopes between 0.92 - 1.24, revealing a tendency to underestimate Ed and Lu with depth. This is only partly explained by non-inclusion of fluorescence emission from CDOM and chlorophyll in the simulations. There are several stations where multiple volume scattering function related data processing steps perform poorly which suggests the potential existence of unresolved features in the modelling of the angular distribution of scattered photons. General optical closure therefore remains problematic, even though there are many cases in the data set where the match between measured and modelled radiometric data is within 25% RMS%E. These results are significant for applications that rely on optical closure e.g. assimilating ocean colour data into coupled physical-ecosystem models.

Therapist Differentiation and Couple Clients' Perceptions of Therapeutic Alliance.

Therapeutic alliance has been acknowledged as one of the catalysts for change within a therapeutic relationship. The contributions of therapists' characteristics to alliance are not often studied. From a Bowen System's Theory perspective, the therapist's level of differentiation would be highly relevant to the development of a therapeutic alliance. The hypothesis for this study was that therapists who are able to take a more differentiated stance in therapy will build a stronger therapeutic alliance. To test this hypothesis, multilevel modeling procedures were performed, using data from nine therapists and 93 couple cases collected at a large, Midwestern university. Therapist differentiation of self was found to be weakly associated with the clients' perception of therapeutic alliance across the early sessions of therapy, but not in the expected direction. Although the results were unexpected, this study provides an example of the potential of examining therapist characteristics from within one model of therapy, that can be applied across various clients and various models of therapy.

The growing threat of carbapenem resistant enterobacteriaceae (CRE) within in-patient spinal rehabilitation units.

This case report highlights the present threat and challenges with treatment and transmission of infections caused by carbepenem-resistant enterobacteriaceae (CRE) within in-patient spinal rehabilitation units. The setting is within the Spinal Cord Injury Unit, Royal North Shore Hospital, Sydney, Australia. We report the case of a 45-year-old female with T9 complete paraplegia who developed CRE urinary tract infection (UTI) and sepsis 1 month post injury while in an in-patient spinal rehabilitation unit. We describe the challenges in treatment with colistin, the implications of infection on her rehabilitation and challenges in containing the spread of CRE to other patients in the unit. We present our experience with the management of CRE bactaeraemia in a spinal rehabilitation unit and the enhanced importance of infection control and surveillance strategies required to successfully contain risk of transmission.

Structure and conformation of the medium-sized chlorophosphazene rings.

Medium-sized cyclic oligomeric phosphazenes [PCl2N]m (where m = 5-9) that were prepared from the reaction of PCl5 and NH4Cl in refluxing chlorobenzene have been isolated by a combination of sublimation/extraction and column chromatography from the predominant products [PCl2N]3 and [PCl2N]4. The medium-sized rings [PCl2N]m have been characterized by electrospray ionization-mass spectroscopy (ESI-MS), their (31)P chemical shifts have been reassigned, and their T1 relaxation times have been obtained. Crystallographic data has been recollected for [PCl2N]5, and the crystal structures of [PCl2N]6, and [PCl2N]8 are reported. Halogen-bonding interactions were observed in all the crystal structures of cyclic [PCl2N]m (m = 3-5, 6, 8). The crystal structures of [P(OPh)2N]7 and [P(OPh)2N]8, which are derivatives of the respective [PCl2N]m, are also reported. Comparisons of the intermolecular forces and torsion angles of [PCl2N]8 and [P(OPh)2N]8 with those of three other octameric rings are described. The comparisons show that chlorophosphazenes should not be considered prototypical, in terms of solid-state structure, because of the strong influence of halogen bonding.

Optically significant particle sizes in seawater.

Small particles (<10 µm) are often considered to play the dominant role in controlling scattering and absorption due to their relatively large numbers, which are typically found in the ocean. Here we present an approach for quantifying the size range of particles that contribute significantly to bulk inherent optical properties. We present a numerical assessment of the variability in optically significant particle sizes for simplistic populations that conform to the assumptions of homogeneous, spherical particles, and power-law size distributions. We use numerical predictions from Mie theory to suggest minimum and maximum particle sizes required for accurate predictions and observations of ocean optics for different particle size distributions (PSDs). When considering observed ranges of PSDs, our predictions suggest the need for measurements of optical properties and particles to capture information from particle sizes between diameters of 0.05-2000 µm in order to properly constrain relationships between particles and their associated optical properties. Natural particle populations in the ocean may present more complex PSDs that could be analyzed using the method presented here to establish optically significant size classes.

Review of the Evolution of Medical Information in Light of Changes in the External Landscape.

Over the past 25 years, biopharmaceutical companies have faced and adapted to an external landscape that has grown increasingly complex and challenging. Medical information departments have played a fundamental role in the globalization process through their development of multichannel customer-facing resources that address the complexities with innovative solutions. The authors conducted a survey to determine key components of the globalization of medical information departments in large biopharmaceutical companies. In this article, they present survey findings and propose key components to the globalization process in medical information. Finally, they offer considerations for providing more patient-focused responses and processes for evaluating the impact of the medical information department in a global framework through the multifaceted measurement of customer satisfaction.

Medical Information Contact Centers: Challenges and Best Practices.

Today's medical information contact centers face a number of complex challenges. A recent survey of the DIA Medical Communications Special Interest Area Community (SIAC) members indicated that budgetary pressures, employee training, preparing for product launches, and ensuring business continuity are all concerns for the majority of contact centers. Additionally, more than one third of contact centers mentioned mergers and acquisitions. This article will review the results of the survey and discuss best practices for addressing the 3 most common topics noted in the survey: budget, training, and supporting product launches. The article is intended as a resource for contact center managers and to help encourage the sharing of best practices within the industry.

Magnification's effect on endodontic fine motor skills.

INTRODUCTION: The purpose of this study was to quantitatively investigate the effect of magnification on fine motor skills used in endodontics. METHODS: This study used a novel manual dexterity test that was performed with and without magnification. An 8x operating microscope and 2.5x dental loupes were used for the magnification tests. Forty subjects, 20 with microscope experience and 20 without, participated in the study. Performance on the test was evaluated by using an accuracy scoring system, and the time needed to complete the test was recorded for each subject. RESULTS: A significant increase in accuracy score with each level of magnification was demonstrated (P

Differential correlates of multi-type maltreatment among urban youth.

OBJECTIVE: The aim of this study was to examine the differential effects of multi-types of maltreatment in an adolescent sample. Different combinations of maltreatment (emotional, sexual, physical, neglect) were examined in relation to both negative affect and externalizing symptoms in male and female youth. METHOD: One thousand four hundred fifty-two middle and high school youth were recruited from urban schools and a mandated early warning truancy program. Youth completed an anonymous survey that included measures of child maltreatment, depression, suicide proneness, hopelessness, delinquency, hostility, substance use, and promiscuity. Respondents were categorized into groups of different combinations of maltreatment by their reports of sexual abuse, physical abuse, neglect (emotional and physical), and emotional abuse. RESULTS: Nearly two-thirds of boys and girls reported some form of maltreatment, and multi-type maltreatment was common (e.g., 13% reported experiencing both physical and sexual abuse and neglect). Individuals with maltreatment histories were more depressed (F=52.78, p<.0001), suicide prone (F=24.29, p<.001), and hopeless (F=32.07, p<.0001) than non-abused individuals. Maltreated adolescents were also more hostile (F=35.03, p<.0001), and they engaged in more delinquent behavior (F=26.76, p<.0001), promiscuity (F=8.54, p<.0001), and drug and alcohol use (F=9.61, p<.0001). Individuals experiencing multi-type maltreatment were the most symptomatic, particularly youth with histories of physical abuse, sexual abuse, and neglect. In general, gender differences in effects were not observed. CONCLUSIONS: The results highlight the importance of studying combined types of maltreatment, as well as understanding the particularly deleterious effects of neglect and emotional abuse. The results are generally consistent with an additive model of maltreatment effects.