Congenital lymphatic dysplasia and severe bone disease in a term neonate with a novel homozygous PIEZO1 variant.

We report a patient with nonimmune fetal hydrops and multiple pathologic fractures. RNA analysis revealed a novel PIEZO1 variant. This report is the first to elucidate PIEZO1's role as a critical regulator of bone mass and strength.

Congenital glottic stenosis as a clinical manifestation of FREM1-associated disorders in a neonate with respiratory distress and aphonia.

A female infant born at 38 weeks and 2 days via induced vaginal delivery was admitted to the neonatal intensive care unit for respiratory distress soon after birth. Noted to have aphonia on examination, the patient underwent direct laryngoscopy and was diagnosed with an anterior glottic web and subglottic stenosis. The patient underwent a genetic workup including whole exome sequencing which resulted in a diagnosis of a FREM1-associated disorder. Congenital glottic webs and subglottic stenoses have not been previously described as clinical manifestations of FREM1-associated disorders.

In Vitro Cytotoxicity of Antiresorptive and Antiangiogenic Compounds on Oral Tissues Contributing to MRONJ: Systematic Review.

BACKGROUND: Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear. METHODS: In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells. RESULTS: Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration. CONCLUSIONS: Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ.

A provider survey of cystic fibrosis related diabetes screening and management practices at North American CF centers.

Background: Cystic Fibrosis Foundation (CFF) Guidelines recommend annual screening for cystic fibrosis related diabetes (CFRD) with an oral glucose tolerance test (OGTT). However, screening rates remain consistently low. We conducted surveys of 1) US CF center directors and 2) Endocrinologists affiliated with the CFF-sponsored EnVision program to characterize CFRD screening practices, describe provider perceived barriers to screening, and identify strategies for improving screening. Methods: The surveys queried OGTT protocols, alternate screening strategies, and perceived barriers to screening. CF center characteristics and procedures for coordinating OGTTs were compared between centers achieving ≥50% versus <50% OGTT completion. Endocrinologists received additional questions regarding OGTT interpretation and management. Results: The survey response rate was 18% (51/290) from CF Centers and 63% (25/40) from Endocrinologists. The majority (57%) of CF centers utilized 2 OGTT timepoints (0,120 min). The majority (72%) of Endocrinologists utilized 3 timepoints (0,60,120 min). Four percent of CF centers and 8% of Endocrinologists utilized other timepoints. Forty-nine percent of CF centers reported ≥50% OGTT completion in the past year. Completion of ≥50% OGTT was 5 times more likely when patient reminders were consistently provided (p = 0.017). Both CF Centers and Endocrinologists employed alternative screening strategies including HbA1c (64%, 92%), fasting plasma glucose (49%, 67%), continuous glucose monitoring (30%, 58%), and home fingerstick monitoring (55%, 50%). Discussion: OGTT is the gold standard screening method for CFRD, but completion rates remain suboptimal, practice variation exists, and many providers utilize alternate screening strategies. Systematic reminders may improve completion rates. Studies to improve our approach to CFRD screening are urgently needed.

An update on methods for assessing bone quality and health in Cystic fibrosis.

With increasing life expectancy in people with Cystic fibrosis (CF), the focus of clinical care has shifted to management and prevention of non-pulmonary comorbidities. CF related bone disease, defined by low bone mineral density (BMD), is prevalent across all age groups and acknowledges the increased fractures rates that negatively impact lung function and quality of life. Dual energy X-ray absorptiometry (DXA) measurement of bone mineral content (BMC) and "areal" BMD (aBMD) is recommended for identifying and monitoring bone health in children and adults due to its low cost, low radiation exposure, and widespread availability. Recent studies in children and adolescents with chronic illness focus on adjustment of BMC and aBMD measurements for height due to the effects of short stature and delayed maturation on bone size. Expanded reference databases for alternate imaging sites such as the ultradistal radius and hip present opportunities for research and long-term monitoring. As the two-dimensional nature of DXA imposes limitations, we highlight other imaging modalities including peripheral quantitative computed tomography QCT (pQCT), magnetic resonance imaging, and quantitative ultrasound (QUS). These tools, while primarily used in a research setting, can impart information on true volumetric bone density and bone microarchitecture as well as contribute to fracture assessment and prediction. Due to the high morbidity and mortality associated with vertebral and hip fracture, we will present on vertebral fracture assessment (VFA) in both children and adults as well as applied analyses including hip structural analysis (HSA), trabecular bone score (TBS), and fracture risk assessment (FRAX) for high risk groups. Questions remain on the future clinical applicability and accessibility of these assessment and prediction tools, longitudinal monitoring through adolescence and adulthood, and how outcome measures may guide bone modifying therapies.

Spontaneous and iatrogenic hypoglycemia in cystic fibrosis.

Spontaneous episodes of hypoglycemia can occur in people with cystic fibrosis (CF) without diabetes, who are not on glucose lowering medications. Spontaneous hypoglycemia in CF could occur both in the fasting or postprandial state (reactive hypoglycemia). The pathophysiology of fasting hypoglycemia is thought to be related to malnutrition and increased energy expenditure in the setting of inflammation and acute infections. Reactive hypoglycemia is thought to be due to impaired first phase insulin release in response to a glucose load, followed by a delayed and extended second phase insulin secretion; ineffective counterregulatory response to dropping glucose levels may also play a role. The overall prevalence of spontaneous hypoglycemia varies from 7 to 69% as examined with oral glucose tolerance test (OGTT) or with continuous glucose monitoring (CGM) under free living conditions. Spontaneous hypoglycemia in CF is associated with worse lung function, higher hospitalization rates, and worse clinical status. In addition, patients with CF related diabetes on glucose-lowering therapies are at risk for iatrogenic hypoglycemia. In this article, we will review the pathophysiology, prevalence, risk factors, clinical implications, and management of spontaneous and iatrogenic hypoglycemia in patients with CF.

Body composition in individuals with cystic fibrosis.

Because nutritional status is intimately linked with pulmonary function and survival, nutrition has been at the mainstay of cystic fibrosis (CF) care. Body Mass Index (BMI) is traditionally used to define nutritional status because of the ease with which it can be calculated, but it has a number of limitations including its inability to differentiate fat mass (FM) from lean body mass (LBM), the latter thought to confer health advantage. A number of tools are available to quantify body composition including dual-energy x-ray absorptiometry (DXA), bioelectrical impedance, MRI, CT, air displacement plethysmography, and stable isotopes, and these have been used to varying degrees in studies of CF. In CF, LBM tends to be lower for a given BMI, particularly at lower BMI. In adults, lower fat-free mass (FFM) correlates with greater CF disease severity, lower pulmonary function and higher inflammatory markers. FFM is also positively associated with greater bone mineral density, while greater FM is associated with greater loss of lumbar spine bone mineral density over 2 years. In youth, LBM is positively associated with pulmonary function. The predictive value of body composition for functional and clinical outcomes and the role of improving LBM on these outcomes remain undefined. With improvements in BMI accompanying highly-effective modulator therapy, closer evaluations of body composition may inform risk for more traditional, non-CF adult outcomes in CF.

Proximal interphalangeal locking compression plate for pastern arthrodesis in horses.

BACKGROUND: Outcomes following proximal interphalangeal joint (PIPJ) arthrodesis by a variety of surgical methods are available. Reports detailing clinical outcomes following PIPJ arthrodesis utilising the proximal interphalangeal joint locking compression plate (PIP-LCP) and abaxial transarticular lag screws technique are limited. OBJECTIVES: To report survival, radiographic and clinical outcomes following PIPJ arthrodesis with PIP-LCP and abaxial transarticular lag screw fixation. STUDY DESIGN: Retrospective case series. METHODS: Medical records of all horses undergoing pastern arthrodesis from 2009 to 2018 were reviewed. Arthrodeses performed using a 3-hole, 4.5 mm narrow LCP, specifically designed for the proximal interphalangeal joint, were included. Patient details, presentation, radiographic findings, intraoperative and post-operative data, and complications were documented. Short- and long-term follow-up was available for 23 horses. RESULTS: Thirty PIPJ arthrodeses were performed in 29 horses meeting the criteria for inclusion. Twenty-eight horses (97%, 95% CI 83-100) survived to discharge. Twenty-three horses (79%, 95% CI 60%-92%) had successful outcomes including 12 of the 15 forelimb cases and 11 of the 13 hindlimb cases with available follow-up. Fifteen of 19 performance horses returned to athletic activity. Soundness in performance horses was recognised at less than 3 months in one case, 3 to 6 months in six cases, 6 to 12 months in five cases, and greater than 12 months in six cases. Complications included three implant infections, support limb laminitis (two horses), and fragmentation of the extensor process of the distal phalanx (one horse). MAIN LIMITATIONS: A retrospectively reviewed, small study population with a variety of breeds and disciplines. CONCLUSIONS: The PIP-LCP construct provides a very good prognosis for performance and an excellent prognosis for pasture soundness.

Mucopolysaccharidosis type I newborn screening: Importance of second tier testing for ethnically diverse populations.

Mucopolysaccharidosis type I (MPS I)/Hurler syndrome newborn screening was added to the recommended uniform screening panel (RUSP) in 2016. As states have added screening for MPS I, programs have reported increased rates of false positives. Reasons for false positive screens include carrier status, true false positive, late-onset/attenuated forms, and in about half of cases, pseudodeficiency alleles. These alleles have DNA variants that can cause falsely decreased enzyme activity on biochemical enzyme studies and have increased frequency in individuals of African American and African descent. We describe the District of Columbia (DC) experience with MPS I screening from December 2017 to February 2019. In the context of a review of the literature on newborn screening and family experiences and this DC-based experience, we offer potential solutions to address preliminary concerns regarding this screening. The impact of overrepresentation of screen positives in a minority group and unintentional creation of health disparities and community wariness regarding medical genetics evaluations must be considered to improve the newborn screen programs nationally and internationally.

Distal limb pathologic conditions in horses treated with sleeve-style digital cryotherapy (285 cases).

Digital cryotherapy (DC) is frequently used as laminitis prophylaxis for horses. While DC with ice-water slurries is reported to be safe for up to 48 h, the safety of sleeve-style digital cryotherapy (SSDC) with ice in direct contact with the distal limb has not been evaluated. Our objective was to determine the incidence of distal limb pathologic conditions (DLPC) among horses treated with SSDC. A retrospective study of cases from 2011 to 2015 identified 285 horses treated with SSDC for a minimum of 12 h. Data collected from medical records included demographic, treatment, diagnostic, and SSDC treatment parameters. Bivariate statistics and a generalized linear regression model were created to evaluate risk factors associated with increased incidence of DLPC. Among horses treated with SSDC, 7% had tissue injury of the distal limb. Increasing duration of SSDC was associated with increased incidence of DLPC. Lesions observed included dermatitis, cellulitis, alopecia, coronitis, tissue necrosis, and distal limb edema. These lesions were similar to frostbite, non-freezing cold injury, and prolonged water immersion injuries seen in other species. While the incidence of DLPC was low, the authors recommend that horses undergoing SSDC with ice in direct contact with the skin should be monitored closely for injury when prolonged cryotherapy is clinically indicated. Further studies to improve safety, efficacy, and convenience of alternative methods of DC for horses are warranted.

Equine mesenchymal stromal cells from different tissue sources display comparable immune-related gene expression profiles in response to interferon gamma (IFN)-γ.

Mesenchymal stromal cells (MSC) have the therapeutic potential to decrease inflammation due to their immunomodulatory properties. They can be isolated from various tissue sources such as bone marrow, adipose tissue, and blood, but it is unknown how the tissue source of origin affects the responses of MSC to inflammatory stimuli. Here, we conceptually addressed this question by evaluating the immune-related gene expression profiles of equine MSC from different tissue sources in response to interferon gamma (IFN-γ) stimulation, with the goal to determine if there is a preferable MSC source for clinical application in an inflammatory environment. The salient findings from this initial study were that the baseline expression of all immune related genes analyzed, with the exception of prostaglandin-endoperoxide synthase 2 (PTGS2), was variable in MSC depending on tissue source. Following IFN-γ stimulation, however, gene expression profiles became more similar across all tissue sources, suggesting that MSC from different sources will likely respond similarly in an inflammatory environment when used clinically.

Precursor-to-product ratios reflect biochemical phenotype in congenital adrenal hyperplasia.

Precursor-to-product ratios in steroid hormone metabolism may accurately reflect enzymatic activity and production of metabolites relative to their disappearance. The purpose of this study was to explore the use of direct precursor-to-product steroid ratios to discriminate between infants with congenital adrenal hyperplasia (CAH) due to 21- α -hydroxylase deficiency and infants with no disorder, thus characterizing the biochemical phenotype in CAH. Deidentified dried blood spot samples from confirmed CAH cases identified by newborn screen (CAH-positive, N = 8) and from cases with no disorder (CAH-negative, N = 10) were obtained from the California State Newborn Screening Program. Samples (∼6.25 mm circular spots) underwent methanol and water extraction (9:1 ratio). Deuterated steroids served as isotope internal standards. 17-α-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), androstenedione (A4) and cortisol (F) concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the 17-OHP/S, 17-OHP/A4, and S/F ratios were calculated. The mean 17-OHP and A4 concentrations in samples from CAH cases were significantly increased when compared to cases with no disorder (p = 0.003 for both). 17-OHP/S and 17-OHP/A4 ratios were also significantly elevated in CAH cases (p = 0.007 and p < 0.001, respectively). In contrast, S and F concentrations and the S/F ratio were similar between the two groups. In CAH, the elevated 17-OHP/S ratio is a biomarker of diminished 21-α-hydroxylase activity, and the elevated 17-OHP/A4 ratio is a biomarker of adrenal androgen excess via increased 17,20-lyase activity. The similar S/F ratio indicates that the rate of production via 11-ß-hydroxylase and disappearance of F is maintained in CAH.

Elite firefighter/first responder mindsets and outcome coping efficacy.

The present study examined coping strategies used by firefighters, the relationship between appraisals and coping strategies used, and the relationship between transitional coping strategies used and outcome coping efficacy for mental preparedness. Firefighter coping strategies of problem focused coping and seeking social support were found to have positive significant relationships to outcome coping efficacy, after transitioning from one critical incident to a second. The coping strategies of blamed self wishful thinking, and avoidance appear to have a negative significant relationship to outcome coping efficacy. Additionally, the appraisals of challenge and positive reappraisal to meet the challenge appear to have a positive significant relationship to problem focused coping and seeking social support. These findings on outcome coping efficacy may be of help to firefighters for rehabilitative efforts after traumatic incidents when used in the Peer Support Review intervention model.

Impact of a teaching rotation on residents' attitudes toward teaching: a 5-year study.

BACKGROUND: Residents play a tremendous role in educating medical students and other residents during their training. Many residency programs have thus instituted formal instruction on teaching. This 5-year study was conducted to quantitatively evaluate the impact of a teaching rotation on residents' attitudes towards teaching. METHODS: Residents participated in a 1-month teaching rotation, which included didactic sessions as well as protected time to practice their teaching skills. Before and after the rotation, residents anonymously filled out surveys regarding their attitudes towards teaching. Data were collected from 73 residents from July 2004 to September 2009. The data were analyzed using a 2-tailed t-test with independent variables and a 1-way ANOVA followed by a posttest. RESULTS: Four categories showed significant improvement, including feeling prepared to teach (P < .0001), having confidence in their teaching ability (P < .0001), being aware of their expectations as a teacher (P < .0001), and feeling that their anxiety about teaching was at a healthy level (P = .0037). There was an increase in the level of enthusiasm, but the P value did not reach a significant range (P = .12). The level of enthusiasm started high and was significantly higher on the pretest than every other tested category (P < .0001). Footnote c to Table 2 should read: P value as calculated using the Mann-Whitney U test [corrected]. CONCLUSIONS: Residents are enthusiastic about teaching, and their level of enthusiasm remains high following a teaching rotation. Residents feel more prepared to teach, more confident in their teaching ability, more aware of their expectations as a teacher, and less anxious about teaching following a formal teaching rotation.

Compassionate-use oxaliplatin with bolus 5-fluorouracil/leucovorin in heavily pretreated patients with advanced colorectal cancer.

OBJECTIVES: The efficacy of a concomitant oxaliplatin/bolus 5-fluorouracil/leucovorin regimen in 123 heavily pretreated patients with advanced colorectal cancer was evaluated. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and radiographically progressive cancer which failed to respond to between two and five prior treatment modalities were consented and enrolled. METHODS: Patients received oxaliplatin on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-fluorouracil/leucovorin was administered on day 1 of weeks 1 through 6. RESULTS: Grade 3 to 4 toxicities were as follows: diarrhea 30%; vomiting 11%; hematologic < 3%; peripheral neuropathy 2.5%. Of the 101 patients evaluable for response, 7% achieved a partial response (median duration 4.25 mo), 1 patient achieved a minor response (7 mo), and 31% had stable disease (median duration 6.08 mo). The median time to progression was 3.6 months. CONCLUSION: This regimen in heavily pretreated patients with disseminated colorectal cancer is of modest benefit, often at the expense of considerable gastrointestinal toxicity. It appears that the use of oxaliplatin/bolus 5-fluorouracil/leucovorin is more toxic than oxaliplatin/infusional 5-fluorouracil and possibly less effective.