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BackgroundDecision-making in initiating life-sustaining health technology is complex and often conducted at time-critical junctures in clinical care. Many of these decisions have profound, often irreversible, consequences for the child and family, as well as potential benefits for functioning, health and quality of life. Yet little is known about what influences these decisions. A systematic review of reasoning identified the range of reasons clinicians give in the literature when initiating technology dependence in a child, and as a result helps determine the range of influences on these decisions.MethodsMedline, EMBASE, CINAHL, PsychINFO, Web of Science, ASSIA and Global Health Library databases were searched to identify all reasons given for the initiation of technology dependence in a child. Each reason was coded as a broad and narrow reason type, and whether it supported or rejected technology dependence.Results53 relevant papers were retained from 1604 publications, containing 116 broad reason types and 383 narrow reason types. These were grouped into broad thematic categories: clinical factors, quality of life factors, moral imperatives and duty and personal values; and whether they supported, rejected or described the initiation of technology dependence. The majority were conceptual or discussion papers, less than a third were empirical studies. Most discussed neonates and focused on end-of-life care.ConclusionsThere is a lack of empirical studies on this topic, scant knowledge about the experience of older children and their families in particular; and little written on choices made outside ‘end-of-life’ care. This review provides a sound basis for empirical research into the important influences on a child’s potential technology dependence.

In children with neurological complex chronic conditions (CCC) undergoing hip surgery we aimed to: estimate the rate of postoperative pneumonia, determine the effect of pneumonia on postoperative hospital resource use, and identify predictors of postoperative pneumonia.A retrospective cohort study was conducted utilizing the Pediatric Health Information System database for 2609 children (1081 females, 1528 males) aged 4 years and older with a neurological CCC who underwent hip surgery (i.e. reconstruction surgery or salvage procedure) between 2016 and 2018 in 41 US children's hospitals. Multivariable, mixed-effects logistic regression was used to assess patient characteristics and risk of pneumonia.Mean age at hip surgery was 10 years 1 month (SD 4y 8mo). The postoperative pneumonia rate was 1.6% (n=42). Median length of stay (LOS) was longer for children with pneumonia and the 30-day all-cause unplanned readmission rate and costs were higher. Variability in rates of pneumonia ranged from 1.1% to 2.8% across hospitals. Significant predictors of postoperative pneumonia were osteotomy type (p=0.005) and number of chronic conditions (p≤0.001).Postoperative pneumonia after hip surgery in children with a neurological CCC is associated with longer LOS, readmissions, and higher costs. Children undergoing pelvic osteotomies and who have multimorbidity need additional clinical support to prevent postoperative pneumonia and decrease resource utilization.Pneumonia is a major postoperative complication in children with neurological complex chronic conditions (CCC). Forty-two (1.6%) children with neurological CCC developed pneumonia after hip surgery. Length of stay, readmissions, and costs were significantly higher in the group with pneumonia. Variability in pneumonia rates existed across hospitals. Predictors of developing pneumonia include osteotomy type and number of CCC.

Objective To assess the performance of previously published high-intensity neurologic impairment (NI) diagnosis codes in identification of hospitalized children with clinical NI. Methods Retrospective study of 500 randomly selected discharges in 2019 from a freestanding children's hospital. All charts were reviewed for 1) NI discharge diagnosis codes and 2) documentation of clinical NI (a neurologic diagnosis and indication of functional impairment like medical technology). Test statistics of clinical NI were calculated for discharges with and without an NI diagnosis code. A sensitivity analysis varied the threshold for “substantial functional impairment.” Secondary analyses evaluated misclassified discharges and a more stringent definition for NI. Results Diagnosis codes identified clinically documented NI with 88.1% (95% confidence interval [CI]: 84.7, 91) specificity, and 79.4% (95% CI: 67.3, 88.5) sensitivity; negative predictive value (NPV) was 96.7% (95% CI: 94.8, 98.0), and positive predictive value (PPV) was 49% (95% CI: 42, 56.1). Including children with milder functional impairment (lower threshold) resulted in NPV of 95.7% and PPV of 77.5%. Restricting to children with more severe functional impairment (higher threshold) resulted in NPV of 98.2% and PPV of 44.1%. Misclassification was primarily due to inclusion of children without functional impairments. A more stringent NI definition including diagnosis codes for NI and feeding tubes had a specificity of 98.4% (95% CI: 96.7–99.3) and sensitivity of 28.6% (19.4–41.3). Conclusions All scenarios evaluated demonstrated high NPV and low-to-moderate PPV of the diagnostic code list. To maximize clinical utility, NI diagnosis codes should be used with strategies to mitigate the risk of misclassification.

Mutations assessed at VICC.

Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune therapy in melanoma. We identified 229 patients with melanoma treated with immune therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1 (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 patients with melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild type. The NRAS-mutant cohort had superior or a trend to superior outcomes compared with the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P = 0.07), clinical benefit (response + stable disease lasting ≥24 weeks; 50% vs. 31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P = 0.09). Benefit from anti–PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared with other genotypes (8/12 vs. 9/20 samples with ≥1% expression; 6/12 vs. 6/20 samples with ≥5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression. Cancer Immunol Res; 3(3); 288–95. ©2015 AACR.

To describe epidemiology, interventions, outcomes, and the health services experience for a cohort of children with pulmonary hypertension (PH) who underwent tracheostomy placement and to identify risk factors for inhospital mortality and 30-day readmissions.Retrospective cohort study of the Pediatric Health Information System database.Thirty-seven freestanding U.S. children's hospitals.Patients 31 days to 21 years old who were discharged from the hospital between January 1, 2009, and December 31, 2017, with a diagnosis of primary or secondary PH, and who underwent tracheostomy placement. Outcomes were examined over a 2-year period from the time of discharge from the index encounter.None.There were 793 patients with PH who underwent tracheostomy placement. The overall inhospital mortality rate was 23.7%. Secondary PH due to congenital heart disease (CHD) was significantly associated with overall inhospital mortality (adjusted odds ratio [OR], 2.36; 95% CI, 1.38-4.04). The rate of 30-day readmissions for patients over the 2-year follow-up period was 33.3%. Tracheostomy during the index encounter and the diagnosis of secondary PH due to CHD were significantly associated with lower rates of 30-day readmissions (adjusted OR, 0.34; 95% CI, 0.19-0.61; and adjusted OR, 0.43; 95% CI, 0.24-0.77, respectively).In the context of expanding utilization of tracheostomy and long-term ventilation, children with PH are among the highest risk cohorts for extended and repeated hospitalization and death. Tracheostomy placement during the index encounter was associated with fewer 30-day readmissions over the 2-year follow-up period. Further understanding of which subgroups may benefit from earlier intervention and which subgroups are at highest risk may offer important clinical insight when considering optimal timing of tracheostomy and may enhance informed decision-making for all stakeholders.

BACKGROUND It is well established that young infants have the highest risk of severe pertussis, which often results in hospitalization. Since the 2012 recommendation of administering tetanus toxoid, diphtheria toxoid, and acellular pertussis (Tdap) vaccine for every pregnancy, evaluation of pertussis hospitalizations among young infants in the United States has been limited. METHODS In this ecological study, we used the Kids’ Inpatient Database, the largest all-payer pediatric inpatient database in the United States, to study pertussis hospitalizations among infants RESULTS The overall rate of pertussis hospitalizations before the Tdap vaccination recommendation was 5.06 per 100 000 infants (95% confidence interval, 4.36–5.76) and 2.15 per 100 000 infants (95% confidence interval, 1.49–2.81) afterward. CONCLUSIONS This study supports maternal vaccination against pertussis as an important strategy in protecting young infants, and continued evaluation is needed to assess the long-term trends in hospitalization.

Solution phase titrations are made easy by multi-nuclear FlowNMR spectroscopy with automated, continuous titre addition to give accurate insights into Brønsted acid/base, hydrogen bonding, Lewis acid/base and metal/ligand binding equilibria under native conditions.

OBJECTIVE To assess risk factors associated with 30-day hospital readmission after a prolonged neonatal intensive care stay. STUDY DESIGN Retrospective analysis of 57,035 infants discharged >14 days from the NICU between 2013 and 2016. Primary outcome was 30-day, all-cause hospital readmission. Adjusted likelihood of readmission accounting for demographic and clinical characteristics, including chronic conditions was also estimated. RESULTS The 30-day readmission rate was 10.7%. Respiratory problems accounted for most (31.0%) readmissions. In multivariable analysis, shunted hydrocephalus [OR 2.2 (95%CI 1.8-2.7)], gastrostomy tube [OR 2.0 (95%CI 1.8-2.3)], tracheostomy [OR 1.5 (95%CI 1.2-1.8)], and use of public insurance [OR 1.3 (95%CI 1.2-1.4)] had the highest likelihood of readmission. Adjusted hospital readmission rates varied significantly (p

Noyori-Ikariya type [(arene)RuCl(TsDPEN)] (TsDPEN, sulfonated diphenyl ethylenediamine) complexes are widely used C=O and C=N reduction catalysts that produce chiral alcohols and amines via a key ruthenium-hydride intermediate that determines the stereochemistry of the product. Whereas many details about the interactions of the pro-chiral substrate with the hydride complex and the nature of the hydrogen transfer from the latter to the former have been investigated over the past 25 years, the role of the stereochemical configuration at the stereogenic ruthenium center in the catalysis has not been elucidated so far. Using operando FlowNMR spectroscopy and nuclear Overhauser effect spectroscopy, we show the existence of two diastereomeric hydride complexes under reaction conditions, assign their absolute configurations in solution, and monitor their interconversion during transfer hydrogenation catalysis. Configurational analysis and multifunctional density functional theory (DFT) calculations show the λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to be both thermodynamically and kinetically favored over its λ-(R,R)RRu isomer with the opposite configuration at the metal. Computational analysis of both diastereomeric catalytic manifolds show the major λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to dominate asymmetric ketone reduction catalysis with the minor λ-(R,R)RRu [(mesitylene)RuH(TsDPEN)] stereoisomer being both less active and less enantioselective. These findings also hold true for a tethered catalyst derivative with a propyl linker between the arene and TsDPEN ligands and thus show enantioselective transfer hydrogenation catalysis with Noyori-Ikariya complexes to proceed via a lock-and-key mechanism.

Nutrition status plays a critical role in pressure injury (PI) healing and yet the available literature, especially in pediatric patients, is limited. Critically ill pediatric patients are at an increased risk of skin integrity compromise and PI development. Adequate nutritional intake can often be challenging to achieve in this population and immobility and illness present additional obstacles to maintaining skin integrity in this vulnerable population. Despite the unique nutritional challenges and needs of this group, there is no standardized approach to macro- and micronutrient management and monitoring. Here, several key vitamins and minerals believed to play a role in PI healing are discussed and an approach to nutritional management and monitoring for PI healing in pediatric patients is proposed. Registered dietitians (RD) are essential to assess individual patient macro and micronutrient requirements, to identify gaps and make recommendations to optimize nutritional therapy that may exist and impact wound healing. We used a scoping review to focus on the interplay of nutrition and PI healing and inform a multidisciplinary approach to PI identification and management. Through this review, we propose a strategy for the nutritional management of pediatric patients

BACKGROUND AND OBJECTIVESClinicians evaluating for herpes simplex virus (HSV) in febrile infants must balance detection with overtesting, and there is no universally accepted approach to risk stratification. We aimed to describe variation in diagnostic evaluation and empirical acyclovir treatment of infants aged 0 to 60 days presenting with fever and determine the association between testing and length of stay (LOS).METHODSIn this retrospective 44-hospital observational study, we used the Pediatric Health Information System database to identify infants aged ≤60 days evaluated for fever in emergency departments from January 2016 through December 2017. We described hospital-level variation in laboratory testing, including HSV, imaging and other diagnostic evaluations, acyclovir use, and LOS. We assessed the relationship between HSV testing and LOS using generalized linear mixed effects models adjusted for age and illness severity.RESULTSIn 24 535 encounters for fever, the median HSV testing frequency across hospitals was 35.6% (interquartile range [IQR]: 28.5%–53.5%) for infants aged 0 to 21 days and 12% (IQR: 8.6%–15.7%) for infants aged 22 to 60 days. Among HSV-tested patients, median acyclovir use across hospitals was 79.2% (IQR: 68.1%–89.7%) for those aged 0 to 21 days and 63.6% (IQR: 44.1%–73%) for those aged 22 to 60 days. The prevalence of additional testing varied substantially by hospital and age group. Risk-adjusted LOS for HSV-tested infants was significantly longer than risk-adjusted LOS for those not tested (2.6 vs 1.9 days, P < .001).CONCLUSIONSSubstantial variation exists in diagnostic evaluation and acyclovir use, and infants who received HSV testing had a longer LOS than infants who did not. This variability supports the need for further studies to help clinicians better risk-stratify febrile infants and to guide HSV testing and treatment decisions.

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

Aim To identify the highest-priority clinical research areas related to children with neurological impairment and medical complexity among clinicians and caregivers. Method A modified, three-stage Delphi study using online surveys and guided by a steering committee was completed. In round 1, clinicians and family caregivers suggested clinical topics and related questions that require research to support this subgroup of children. After refinement of the suggestions by the steering committee, participants contributed to 1 (family caregivers) or 2 (clinicians) subsequent rounds to develop a prioritized list. Results A diverse international expert panel consisting of 49 clinicians and 12 family caregivers provided 601 responses. Responses were distilled into 26 clinical topics comprising 126 related questions. The top clinical topics prioritized for research were irritability and pain, child mental health, disorders of tone, polypharmacy, sleep, aspiration, behavior, dysautonomia, and feeding intolerance. The clinician expert panel also prioritized 10 specific research questions. Interpretation Study findings support a research agenda for children with neurological impairment and medical complexity focused on addressing clinical questions, prioritized by an international group of clinicians and caregivers.

Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.

Silicone breast augmentation remains one of the most common aesthetic surgery procedures, and 2022 marks the 60th anniversary of the first case. Recent studies suggest a link between double capsule (DC) formation and macro-textured devices.Between 2010 and 2015, 268 aesthetic patients underwent bilateral mammary prosthesis exchange for indications including PIP exchange, adverse capsular contracture and ultrasonographic evidence of rupture. All surgery, in the form of implant exchange and capsulectomy, was undertaken by the senior author using standard techniques. A retrospective review was undertaken, and data analysed with descriptive statistics and Fisher's exact and Mann-Whitney U tests.Of 268 patients identified, 40 (14.9%) showed some degree of capsular duplication and bilateral involvement was marginally more common (52.5%). Two macroscopic patterns of duplication were observed: complete and subtotal. Complete DCs correlated with a clinical triad of extreme firmness, mobility and minimal-to-no pain. Whilst a wide range of manufacturers was represented, macro-textured devices were associated with the highest DC prevalence (58.3% vs. 5.6%) (Fisher's exact test p0.00001). Patients with DC had been implanted for less than half the time, median 52 versus. 120 months (p = 0.0003) of those without.An elevated prevalence of duplicate capsules in macro-textured prostheses is reconfirmed in addition to a novel symptom constellation that may assist with clinical diagnosis. Our study reinforces the aetiopathogenic influence of the elastomer in DC formation and reports DC for the first time in non-macrotextured implants. Single-surgeon cohort of 268 consecutive patients with 532 implants Statistically significant association of macro-textured devices with DC Statistically significant reduced duration of implantation of macro-textured devices First report of DC in non-macro-textured devices LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

*Correspondence - Stephen Kaye: S.B.Kaye@liverpool.ac.uk INTRODUCTION:Expression levels of pcrV (T3SS needle component) from ExoU-expressing PA103 and ExoS-expressing PA76026 after 16h incubation in each antimicrobial was detected using western blotting. qRT PCR detected mRNA levels of ExoU, ExoS, pcrV and ExsA (T3SS activating factor) after PA103 and PA76026 were exposed to tobramycin and moxifloxacin. LIVE/DEAD and LDH assays after 24h evaluated how the antimicrobials influenced acute cytotoxicity in a HCE-T cell scratch and infection model.Tobramycin significantly reduced pcrV in both strains by 50.5-74.0% compared to the fluoroquinolones (p=0.001 and 0.003), even at low concentrations. Fluoroquinolones significantly increased pcrV by 57.0-81.8% (p=0.004 and 0.003). mRNA levels of ExoU, ExoS, pcrV and ExsA were reduced by tobramycin but moxifloxacin increased pcrV, ExsA and ExoS. Tobramycin, despite more bacterial expansion compared to the same relative concentrations of fluoroquinolones, reduced ExoU/ExoS cytotoxicity and allowed complete wound healing.Tobramycin downregulates T3SS expression and reduces ExoS/ExoU mediated cytotoxicity which protects infected HCE-T cells even at low concentrations. Fluoroquinolones however upregulated T3SS and do not negate the cytotoxic effects.

OBJECTIVES To compare the effectiveness of dexamethasone versus prednisone or prednisolone on hospital resource utilization for children hospitalized with acute croup. METHODS This is a retrospective cohort study of the Pediatric Health Information System database on children aged 6 months to RESULTS A total of 11 740 hospitalizations met inclusion criteria; dexamethasone was used in 95.9%; prednisone or prednisolone was used in 4.1%. In the matched cohort (n = 960), the length of stay was not significantly different between the dexamethasone and prednisone or prednisolone groups (21.3 vs 18.5 hours, P = .35). Although the rates bronchoscopy did not differ between the 2 groups, the dexamethasone cohort was more likely to require ICU transfer (P = .007). The rates of 7-day emergency department returns (2.3% vs 1.3%, P = .24) and readmissions (3.1% vs. 2.1%, P = .37) were low and not statistically different. CONCLUSIONS Hospital resource utilization did not differ significantly for children receiving dexamethasone or prednisone or prednisolone for acute croup. Both corticosteroids may be considered reasonable choices for the treatment of children hospitalized with acute croup.

Hip reconstruction surgery in patients with neurological complex chronic conditions (CCC) is associated with prolonged hospitalization and extensive resource utilization. This population is vulnerable to cognitive, developmental, and medical comorbidities which can increase length of stay (LOS). The aims of this study were to characterize barriers to discharge for a cohort of children with neurological CCC undergoing hip reconstruction surgery and to identify patient risk factors for prolonged hospitalization and delayed discharge.Retrospective chart review of nonambulatory patients with neurological CCC undergoing hip reconstruction surgery between 2007-2016 was conducted. Hospitalization ≥1 day past medical clearance was characterized as delayed discharge. Barriers were defined as unresolved issues at the time of medical clearance and categorized as pertaining to the caregiver and patient education, durable medical equipment, postdischarge transportation/placement, and patient care needs.The cohort of 116 patients was 53% male, 16% non-English speaking, and 49% Gross Motor Function Classification System (GMFCS) V with the mean age at surgery of 9.1±3.64 years. Median time from admission to medical clearance was 5 days with median LOS of 6 days. Approximately three-quarters of patients experienced delayed discharge (73%) with barriers identified for 74% of delays. Most prevalent barriers involved education (30%) and durable medical equipment (29%). Postdischarge transportation and placement accounted for 26% of barriers and 3.5 times longer delays ( P0.001). Factors associated with delayed discharge included increased medical comorbidities ( P0.05) and GMFCS V ( P0.001). Longer LOS and medical clearance times were found for female ( P =0.005), older age ( P0.001), bilateral surgery ( P =0.009), GMFCS V ( P =0.003), and non-English-speaking patients ( P0.001).Patients with neurological CCC frequently encounter postoperative barriers contributing to increased LOS and delayed discharge. Patients that may be at higher risk for prolonged hospitalization and greater resource utilization include those who are female sex, adolescent, GMFCS V, non-English speaking, have additional comorbidities, and are undergoing bilateral surgery. Standardized preoperative assessment of educational needs, perioperative equipment requirements, and posthospital transportation may decrease the LOS, reduce caregiver and patient burden/distress, cost, and ultimately reduce variation in care delivery.Level III, Retrospective Case Series.

Here, we present a rare case of a patient who developed multiple primary melanomas within the boundaries of two nevi depigmentosa. The melanomas were excised, and as a preventive measure, the remainder of the nevi depigmentosa were removed. We performed whole-exome sequencing on excised tissue from the nevus depigmentosus, adjacent normal skin, and saliva to explain this intriguing phenomenon. We also performed a GeneTrails Comprehensive Solid Tumor Panel analysis on one of the melanoma tissues. Genetic analysis revealed germline MC1R V92M and TYR R402Q polymorphisms and a MET E168D germline mutation that may have increased the risk of melanoma development. This genetic predisposition, combined with a patient-reported history of substantial sun exposure and sunburns, which were more severe within the boundaries of the nevi depigmentosa due to the lack of photoprotective melanin, produced numerous somatic mutations in the melanocytes of the nevi depigmentosa. Fitting with this paradigm for melanoma development in chronically sun-damaged skin, the patient's melanomas harbored somatic mutations in CDKN2A (splice site), NF1, and ATRX and had a tumor mutation burden in the 90-95th percentile for melanoma.