Liver transplant in children and adults with cystic fibrosis: Impact of growth failure and nutritional status.

Nutritional status is known to strongly predict health outcomes in people with cystic fibrosis (CF), but the prevalence of and consequences for CF children with growth failure and underweight CF adults on the liver transplant (LT) waitlist has not been delineated. We utilized UNOS registry data from 2003 to 2017 to investigate the impact of growth failure and underweight on outcomes in liver transplant candidates with CF. Almost 1 in 3 children and adults with CF had growth failure or were underweight, respectively, at listing. Body mass index under-estimated growth failure compared to height and weight z-scores for children. In multivariate analysis of children, growth failure (HR 2.1, 95% CI 1.7-2.6), and CF (HR 2.7, 95% CI 1.6-4.6, vs. Non-CF) were independent risk factors for waitlist death among children; having both increased death risk almost fourfold (SHR 3.88, 95% CI 1.42-10.58). However, among children who did receive a LT, CF was not associated with death within 1-year post-LT. Underweight adult CF candidates were less likely to receive LT, again suggesting the importance of nutritional evaluation and early intervention in this at-risk cohort.

Not everything that counts can be counted: Tracking long-term outcomes in pediatric liver transplant recipients.

For pediatric liver transplant (LT) recipients, an ideal outcome is to survive and thrive into adulthood. However, outcomes reporting for all LT recipients typically rely on much shorter-term outcomes, 1-5 years post-LT. Using Organ Procurement and Transplantation Network (OPTN) registry data from 1990 to 2018, this analysis seeks to determine if long-term follow-up and outcome data are complete for pediatric LT recipients age 0 to 12 years who survive at least 1 year post-LT without graft loss (n = 9309). Of the 7948 pediatric transplant recipients who did not die or require re-LT, 1 in 6 was reported as lost to follow-up by their transplant center during long-term follow-up. Rates of lost to follow-up were highest in those transplanted between 1990 and 1999 and increased in early adulthood for all recipients. Almost 10% of pediatric LT recipients who remained in follow-up required relisting for LT. 8% of children remaining in follow-up had graft failure. Lost to follow-up may bias estimates of long-term outcomes and risk factors for poor outcomes. For those remaining in follow-up, graft failure and death continue to occur in the decades after LT. Continued proactive monitoring, management, and innovations are needed to truly optimize post-LT survival for all children.

Minimizing Antibiotic Use in Urethral Reconstruction.

PURPOSE: There are no established guidelines regarding management of antibiotics for patients specifically undergoing urethral reconstruction. Our aim was to minimize antibiotic use by following a standardized protocol in the pre-, peri- and postoperative setting, and adhere to American Urological Association antibiotic guidelines. We hypothesized that prolonged suppressive antibiotics post-urethroplasty does not prevent urinary tract infection and/or wound infection rates. MATERIALS AND METHODS: We prospectively treated 900 patients undergoing urethroplasty or perineal urethrostomy at 11 centers over 2 years. The first-year cohort A received prolonged postoperative antibiotics. Year 2, cohort B, did not receive prolonged antibiotics. A standardized protocol following the American Urological Association guidelines for perioperative antibiotics was used. The 30-day postoperative infectious complications were determined. We used chi-square analysis to compare the cohorts, and multivariate logistic regression to identify risk factors. RESULTS: The mean age of participants in both cohorts was 49.7 years old and the average stricture length was 4.09 cm. Overall, the rate of postoperative urinary tract infection and wound infection within 30 days was 5.1% (6.7% in phase 1 vs 3.9% in phase 2, p=0.064) and 3.9% (4.1% in phase 1 vs 3.7% in phase 2, p=0.772), respectively. Multivariate logistic regression analysis of patient characteristics and operative factors did not reveal any factors predictive of postoperative infections. CONCLUSIONS: The use of a standardized protocol minimized antibiotic use and demonstrated no benefit to prolonged antibiotic use. There were no identifiable risk factors when considering surgical characteristics. Given the concern of antibiotic over-prescription, we do not recommend prolonged antibiotic use after urethral reconstruction.

Nutritional Deficiencies in Vegetarian, Gluten-Free, and Ketogenic Diets.

Previously, medical diets, including the ketogenic and gluten-free diets, were rare outside of their target population. Subspecialists more familiar with risks and benefits often managed nutrition and any associated shortcomings. With more patients electively following a gluten-free or ketogenic diet for nonmedical needs, as well as the increasing prevalence of vegetarian diets, general pediatricians are seeing more followers of restrictive diets with general well-child care. Increasingly, general pediatricians can be the first provider to witness presenting signs or symptoms of associated nutritional deficiencies. This article reviews signs and symptoms of possible nutrient deficiencies seen with the vegetarian, ketogenic, and gluten-free diets.

Healthcare professionals' perspectives on the use of medicinal cannabis to manage chronic pain: A systematic search and narrative review.

RATIONALE, AIMS, AND OBJECTIVES: Chronic pain is a global public health problem that negatively impacts individuals' quality of life and imposes a substantial economic burden on societies. The use of medicinal cannabis (MC) is often considered by patients to help manage chronic pain as an alternative or supplement to more conventional treatments, given enabling legalization in a number of countries. However, healthcare professionals involved in providing guidance for patients related to MC are often doing so in the absence of strong evidence and clinical guidelines. Therefore, it is crucial to understand their perspectives regarding the clinical use and relevance of MC for chronic pain. As little is known about attitudes of HCPs with regard to MC use for chronic pain specifically, the aim of this review was to identify and synthesize the published evidence on this topic. METHODS: A systematic search was conducted across six databases: MEDLINE, EMBASE, CINAHL, Scopus, Web of Science, and PubMed from 2001 to March 26, 2021. Three authors independently performed the study selection and data extraction. Thematic analysis was undertaken to identify key themes. RESULTS: A total of 26 studies were included, involving the United States, Israel, Canada, Australia, Ireland, and Norway, and the perspectives of physicians, nurses, and pharmacists. Seven key themes were identified: MC as a treatment option for chronic pain, and perceived indicated uses; willingness to prescribe MC; legal issues; low perceived knowledge and the need for education; comparative safety of MC versus opioids; addiction and abuse; and perceived adverse effects; CONCLUSION: To support best practice in the use of MC for chronic pain, healthcare professionals require education and training, as well as clinical guidelines that provide evidence-based information about efficacy, safety, and appropriate dosage of products for this indication. Until these gaps are addressed, healthcare professionals will be limited in their capacity to make treatment recommendations about MC for people/patients with chronic pain.

The Inpatient Discharge Lounge as a Potential Mechanism to Mitigate Emergency Department Boarding and Crowding.

Delayed access to inpatient beds for admitted patients contributes significantly to emergency department (ED) boarding and crowding, which have been associated with deleterious patient safety effects. To expedite inpatient bed availability, some hospitals have implemented discharge lounges, allowing discharged patients to depart their inpatient rooms while awaiting completion of the discharge process or transportation. This conceptual article synthesizes the evidence related to discharge lounge implementation practices and outcomes. Using a conceptual synthesis approach, we reviewed the medical and gray literature related to discharge lounges by querying PubMed, Google Scholar, and Google and undertaking backward reference searching. We screened for articles either providing detailed accounts of discharge lounge implementations or offering conceptual analysis on the subject. Most of the evidence we identified was in the gray literature, with only 3 peer-reviewed articles focusing on discharge lounge implementations. Articles generally encompassed single-site descriptive case studies or expert opinions. Significant heterogeneity exists in discharge lounge objectives, features, and apparent influence on patient flow. Although common barriers to discharge lounge performance have been documented, including underuse and care team objections, limited generalizable solutions are offered. Overall, discharge lounges are widely endorsed as a mechanism to accelerate access to inpatient beds, yet the limited available evidence indicates wide variation in design and performance. Further rigorous investigation is required to identify the circumstances under which discharge lounges should be deployed, and how discharge lounges should be designed to maximize their effect on hospitalwide patient flow, ED boarding and crowding, and other targeted outcomes.

Cholangitis in Patients With Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study.

INTRODUCTION: Biliary atresia (BA) is a progressive form of liver disease in the neonatal period usually requiring hepatoportoenterostomy (HPE). Cholangitis is a common sequelae of HPE but data about which patients are at risk for this complication are limited. OBJECTIVE: The objective of the study was to determine risk factors associated with cholangitis in a large retrospective cohort after HPE. METHODS: The Pediatric Health Information System (PHIS) was queried for BA (ICD-9 975.61) and HPE (ICD-9-CM 51.37) admissions from 2004 to 2013. We performed univariate analysis and linear regression with dependent variables of ≥ 2 or ≥ 5 episodes of cholangitis, and independent variables of age at time of HPE, race, ethnicity, gender, insurance, ursodeoxycholic acid (UDCA) use, steroid use, presence of esophageal varices (EV), and portal hypertension (PH). RESULTS: We identified 1112 subjects with a median age at HPE of 63 days and median number of cholangitis episodes of 2 within 2 years. On multiple regression analysis, black race (odds ratio (OR) 1.51, P = 0.044) and presence of PH (OR 2.24, P < 0.001) were associated with increased risk of ≥ 2 episodes of cholangitis, whereas HPE at >90 days was associated with less risk (OR 0.46, P = 0.001). Among those with ≥5 episodes, Asian race (OR 2.66, P = 0.038), public insurance (OR 1.72, P = 0.043), EV (OR 1.81, P = 0.017), and PH (OR 2.88, P < 0.001) were associated with higher risk. CONCLUSIONS: Complications, such as cholangitis remain a common problem for patients, after HPE, with median of 2 episodes within 2 years. Higher rates of cholangitis are associated with portal hypertension whereas lower rate is associated with age at HPE of >90 days. Asians, patients with public insurance, and those with portal hypertension are more likely to have recurrent cholangitis.

Neural circuits underlying mother's voice perception predict social communication abilities in children.

The human voice is a critical social cue, and listeners are extremely sensitive to the voices in their environment. One of the most salient voices in a child's life is mother's voice: Infants discriminate their mother's voice from the first days of life, and this stimulus is associated with guiding emotional and social function during development. Little is known regarding the functional circuits that are selectively engaged in children by biologically salient voices such as mother's voice or whether this brain activity is related to children's social communication abilities. We used functional MRI to measure brain activity in 24 healthy children (mean age, 10.2 y) while they attended to brief (<1 s) nonsense words produced by their biological mother and two female control voices and explored relationships between speech-evoked neural activity and social function. Compared to female control voices, mother's voice elicited greater activity in primary auditory regions in the midbrain and cortex; voice-selective superior temporal sulcus (STS); the amygdala, which is crucial for processing of affect; nucleus accumbens and orbitofrontal cortex of the reward circuit; anterior insula and cingulate of the salience network; and a subregion of fusiform gyrus associated with face perception. The strength of brain connectivity between voice-selective STS and reward, affective, salience, memory, and face-processing regions during mother's voice perception predicted social communication skills. Our findings provide a novel neurobiological template for investigation of typical social development as well as clinical disorders, such as autism, in which perception of biologically and socially salient voices may be impaired.

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.

Brain State Differentiation and Behavioral Inflexibility in Autism.

Autism spectrum disorders (ASDs) are characterized by social impairments alongside cognitive and behavioral inflexibility. While social deficits in ASDs have extensively been characterized, the neurobiological basis of inflexibility and its relation to core clinical symptoms of the disorder are unknown. We acquired functional neuroimaging data from 2 cohorts, each consisting of 17 children with ASDs and 17 age- and IQ-matched typically developing (TD) children, during stimulus-evoked brain states involving performance of social attention and numerical problem solving tasks, as well as during intrinsic, resting brain states. Effective connectivity between key nodes of the salience network, default mode network, and central executive network was used to obtain indices of functional organization across evoked and intrinsic brain states. In both cohorts examined, a machine learning algorithm was able to discriminate intrinsic (resting) and evoked (task) functional brain network configurations more accurately in TD children than in children with ASD. Brain state discriminability was related to severity of restricted and repetitive behaviors, indicating that weak modulation of brain states may contribute to behavioral inflexibility in ASD. These findings provide novel evidence for a potential link between neurophysiological inflexibility and core symptoms of this complex neurodevelopmental disorder.

Underconnectivity between voice-selective cortex and reward circuitry in children with autism.

Individuals with autism spectrum disorders (ASDs) often show insensitivity to the human voice, a deficit that is thought to play a key role in communication deficits in this population. The social motivation theory of ASD predicts that impaired function of reward and emotional systems impedes children with ASD from actively engaging with speech. Here we explore this theory by investigating distributed brain systems underlying human voice perception in children with ASD. Using resting-state functional MRI data acquired from 20 children with ASD and 19 age- and intelligence quotient-matched typically developing children, we examined intrinsic functional connectivity of voice-selective bilateral posterior superior temporal sulcus (pSTS). Children with ASD showed a striking pattern of underconnectivity between left-hemisphere pSTS and distributed nodes of the dopaminergic reward pathway, including bilateral ventral tegmental areas and nucleus accumbens, left-hemisphere insula, orbitofrontal cortex, and ventromedial prefrontal cortex. Children with ASD also showed underconnectivity between right-hemisphere pSTS, a region known for processing speech prosody, and the orbitofrontal cortex and amygdala, brain regions critical for emotion-related associative learning. The degree of underconnectivity between voice-selective cortex and reward pathways predicted symptom severity for communication deficits in children with ASD. Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.

Heterogeneity of TERT promoter mutations status in squamous cell carcinomas of different anatomical sites.

Squamous cell carcinoma (SCC) can arise from different anatomical sites including the skin, head and neck, lung, esophagus, genital area, and so on. Despite the same histopathologic features and immunohistochemistry profile, the SCCs of different body sites can show tremendous differences in their presenting symptoms, risk factor associations, natural history, prognosis, and response to treatment. This may reflect the fact that SCCs are heterogenous and likely have unique molecular characteristics at different anatomical sites. Recurrent somatic mutations in the TERT promoter region were first reported in human melanomas. Subsequently, other tumors including cutaneous SCC were found to demonstrate high frequencies of the same mutations. However, the incidences of TERT promoter mutation in noncutaneous SCCs have not been systemically studied. We investigated the TERT promoter mutation status among SCCs from different sites. We collected 84 cases of SCC from the skin (27), head and neck (12), lung (25), and cervix (10), as well as 10 cases of urothelial carcinoma with squamous differentiation (UC-SqD). We found that the frequencies of TERT promoter mutation among SCC of different sits are quite heterogenous: ~70% in skin SCC and UC-SqD, 16.67% in head and neck SCC, and 0% in lung and cervix SCC. These results may support the hypothesis of different carcinogenesis mechanisms of SCC in different sites. It also indicates that TERT promoter mutation could be a biomarker for distinguishing skin SCC or UC-SqD vs pulmonary SCC.

Rising incidence of morbidly adherent placenta and its association with previous caesarean section: a 15-year analysis in a tertiary hospital in Hong Kong.

OBJECTIVES: To identify the incidence of morbidly adherent placenta in the context of a rising caesarean delivery rate within a single institution in the past 15 years, and to determine the contribution of morbidly adherent placenta to the incidence of massive postpartum haemorrhage requiring hysterectomy. SETTING: A regional obstetric unit in Hong Kong. PATIENTS: Patients with a morbidly adherent placenta with or without previous caesarean section scar from 1999 to 2013. RESULTS: A total of 39 patients with morbidly adherent placenta were identified during 1999 to 2013. The overall rate of morbidly adherent placenta was 0.48/1000 births, which increased from 0.17/1000 births in 1999-2003 to 0.79/1000 births in 2009-2013. The rate of morbidly adherent placenta with previous caesarean section scar and unscarred uterus also increased significantly. Previous caesarean section (odds ratio=24) and co-existing placenta praevia (odds ratio=585) remained the major risk factors for morbidly adherent placenta. With an increasing rate of morbidly adherent placenta, more patients had haemorrhage with a consequent increased need for peripartum hysterectomy. No significant difference in the hysterectomy rate of morbidly adherent placenta in caesarean scarred uterus (19/25) compared with unscarred uterus (8/14) was noted. This may have been due to increased detection of placenta praevia by ultrasound and awareness of possible adherent placenta in the scarred uterus, as well as more invasive interventions applied to conserve the uterus. CONCLUSION: Presence of a caesarean section scar remained the main risk factor for morbidly adherent placenta. Application of caesarean section should be minimised, especially in those who wish to pursue another future pregnancy, to prevent the subsequent morbidity consequent to a morbidly adherent placenta, in particular, massive postpartum haemorrhage and hysterectomy.

The ATP-dependent chromatin remodeling enzyme CHD7 regulates pro-neural gene expression and neurogenesis in the inner ear.

Inner ear neurogenesis is positively regulated by the pro-neural bHLH transcription factors Ngn1 and NeuroD, but the factors that act upstream of this regulation are not well understood. Recent evidence in mouse and Drosophila suggests that neural development depends on proper chromatin remodeling, both for maintenance of neural stem cells and for proper neuronal differentiation. Here, we show that CHD7, an ATP-dependent chromatin remodeling enzyme mutated in human CHARGE syndrome, is necessary for proliferation of inner ear neuroblasts and inner ear morphogenesis. Conditional deletion of Chd7 in the developing otocyst using Foxg1-Cre resulted in cochlear hypoplasia and complete absence of the semicircular canals and cristae. Conditional knockout and null otocysts also had reductions in vestibulo-cochlear ganglion size and neuron number in combination with reduced expression of Ngn1, Otx2 and Fgf10, concurrent with expansion of the neural fate suppressor Tbx1 and reduced cellular proliferation. Heterozygosity for Chd7 mutations had no major effects on expression of otic patterning genes or on cell survival, but resulted in decreased proliferation within the neurogenic domain. These data indicate that epigenetic regulation of gene expression by CHD7 must be tightly coordinated for proper development of inner ear neuroblasts.

Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis.

Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.

A family of intermediate filament-like proteins is sequentially assembled into the cytoskeleton of Toxoplasma gondii.

The intracellular protozoan parasite Toxoplasma gondii divides by a unique process of internal budding that involves the assembly of two daughter cells within the mother. The cytoskeleton of Toxoplasma, which is composed of microtubules associated with an inner membrane complex (IMC), has an important role in this process. The IMC, which is directly under the plasma membrane, contains a set of flattened membranous sacs lined on the cytoplasmic side by a network of filamentous proteins. This network contains a family of intermediate filament-like proteins or IMC proteins. In order to elucidate the division process, we have characterized a 14-member subfamily of Toxoplasma IMC proteins that share a repeat motif found in proteins associated with the cortical alveoli in all alveolates. By creating fluorescent protein fusion reporters for the family members we determined the spatiotemporal patterns of all 14 IMC proteins through tachyzoite development. This revealed several distinct distribution patterns and some provide the basis for novel structural models such as the assembly of certain family members into the basal complex. Furthermore we identified IMC15 as an early marker of budding and, lastly, the dynamic patterns observed throughout cytokinesis provide a timeline for daughter parasite development and division.

Imaging of Smoking and Vaping Related Diffuse Lung Injury.

Lung injury associated with smoking tobacco or other substances results in a variety of clinical presentations and imaging patterns, depending on mechanism of injury and substance inhaled. Patients may present in the acute setting, as in the case of acute eosinophilic pneumonia, e-cigarette or vaping product use-associated lung injury, crack lung, or heroin inhalation. They may present with subacute shortness of breath and demonstrate findings of pulmonary Langerhans cell histiocytosis, respiratory bronchiolitis, or desquamative interstitial pneumonia. Alternatively, they may present with chronic dyspnea and demonstrate findings of emphysema or smoking-related interstitial lung fibrosis.

Examining long-term intervention effects to promote teacher problem-solving and communication skills in the rural context.

Conjoint behavioral consultation (CBC), a teacher-parent partnership intervention, has been shown to yield immediate improvements in problem-solving skills and communication quality with parents for kindergarten through third grade teachers in rural schools. The purpose of the present study was to determine whether CBC can yield maintained effects on teacher skills and communication over a 1-year follow-up period. We used an experimental design to examine maintenance effects of CBC (nCBC = 84, nControl = 68). Outcomes were assessed four times: baseline, 12-week posttest (immediate effects), and twice during a 1-year follow-up period (maintenance effects). Longitudinal growth modeling revealed that immediate improvements in perceived problem-solving competence and communication quality with parents for teachers in the CBC condition compared to teachers in the control condition were maintained 1-year postintervention. CBC appears to support teachers' professional practices over time. Implications for enhancing families' and schools' capacities to address student behavior concerns are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Antibiotic Stewardship and Postoperative Infections in Urethroplasties.

OBJECTIVE: To determine surgical site infection and urinary tract infection (UTI) rates in the setting of urethroplasty. Given significant variation in the utilization of antibiotics, there is an opportunity to improve antibiotic stewardship. This study aims to elucidate the rate of both UTI and surgical site infection after urethroplasty on a standardized perioperative antibiotic regimen, and to obtain patient and operative characteristics that may predict infection. METHODS: We prospectively treated 390 patients undergoing urethroplasty at 11 centers with a standardized perioperative antibiotic protocol. Patients had a urine culture or urine analysis within 3 weeks of surgery. After surgery, patients were discharged with an indwelling catheter, removed per usual surgeon practice. All were given nitrofurantoin from discharge until catheter removal. Logistic regression analyses were performed to determine the correlation between patient characteristics or operative categories with post-operative infection. RESULTS: The rates of postoperative UTI and wound infection within 30 days were 6.7% and 4.1%, respectively. On multivariate analysis of demographics, comorbidities, and stricture characteristics and repair, only preoperative UTI (P = .012), history of cardiovascular disease (P = .015), and performing a membranous urethroplasty (0.018) were significant predictors of a UTI within 30 days postoperatively. Location of repair nor graft use increased the risk of UTI. There were no factors predictive of postoperative wound infection. CONCLUSION: A standardized antibiotic protocol was created to narrow and limit excess antibiotic use. This protocol, with clear definitions of UTI and wound infection, allowed determination of accurate infection rates in urethroplasties. Preoperative UTI, even when properly treated, increases the risk of postoperative UTI.