Farm animal exposure, respiratory illnesses, and nasal cell gene expression.

BACKGROUND: Farm exposures in early life reduce the risks for childhood allergic diseases and asthma. There is less information about how farm exposures relate to respiratory illnesses and mucosal immune development. OBJECTIVE: We hypothesized that children raised in farm environments have a lower incidence of respiratory illnesses over the first 2 years of life than nonfarm children. We also analyzed whether farm exposures or respiratory illnesses were related to patterns of nasal cell gene expression. METHODS: The Wisconsin Infant Study Cohort included farm (n = 156) and nonfarm (n = 155) families with children followed to age 2 years. Parents reported prenatal farm and other environmental exposures. Illness frequency and severity were assessed using illness diaries and periodic surveys. Nasopharyngeal cell gene expression in a subset of 64 children at age 2 years was compared to farm exposure and respiratory illness history. RESULTS: Farm versus nonfarm children had nominally lower rates of respiratory illnesses (rate ratio 0.82 [95% CI, 0.69, 0.97]) with a stepwise reduction in illness rates in children exposed to 0, 1, or ≥2 animal species, but these trends were nonsignificant in a multivariable model. Farm exposures and preceding respiratory illnesses were positively related to nasal cell gene signatures for mononuclear cells and innate and antimicrobial responses. CONCLUSIONS: Maternal and infant exposure to farms and farm animals was associated with nonsignificant trends for reduced respiratory illnesses. Nasal cell gene expression in a subset of children suggests that farm exposures and respiratory illnesses in early life are associated with distinct patterns of mucosal immune expression.

The Impact of D2 Versus D1 Lymphadenectomy in Siewert II Gastroesophageal Junction (GEJ) Cancer.

BACKGROUND: Although multiple treatment options exist for gastroesophageal junction (GEJ) cancer, surgery remains the mainstay for potential cure. Extended nodal dissection with a D2 lymphadenectomy (LAD) remains controversial for Siewert II GEJ cancer. Although D2 LAD may lead to a greater lymph node harvest, its effect on survival remains elusive. The authors hypothesized that additional D2 dissection in Siewert II GEJ cancer does not lead to increased survival. METHODS: This study reviewed Siewert II patients who received a D1 or D2 LAD in addition to minimally invasive esophagectomy (MIE) after receiving neoadjuvant chemoradiation or perioperative chemotherapy (2012-2022). The patients were followed for up to 5 years. The outcomes measured were survival, number of nodes sampled, and operative time. The association between D1 or D2 LAD and overall survival was analyzed with Kaplan-Meier methods and a multivariable Cox regression model. RESULTS: Among 155 patients, 74 % underwent D1 and 26 % underwent D2 LAD. The patients with D2 had more than 15 lymph nodes harvested more frequently than those who had D1 (83 % vs 48 %; p < 0.001), with no difference in positive nodes (2.8 ± 5.2 vs 2.1 ± 4.2; p = 0.4). The patients with D2 LAD had a longer median operative time than those who with D1 LAD (362 vs 244 min; p < 0.001). In Kaplan-Meier and multivariable Cox regression models, overall survival did not differ significantly between the patients undergoing D2 and those who had D1 (adjusted hazard ratio [aHR], 0.52; 95 % confidence interval [CI], 0.25-1.00; p = 0.067). CONCLUSIONS: Little consensus exists regarding the optimal lymph node harvest for GEJ cancers. In Siewert II cancer, D2 LAD may not be mandatory and may lead to increased operative morbidity with no significant difference in survival.

Initial Experience With Single-Port Robotic Right Colectomies: Results of an Investigator-Initiated Investigational Device Exemption Study Using a Novel Single-Port Robotic Platform.

BACKGROUND: Minimally invasive surgical techniques have been widely adopted in colorectal surgery. New technological breakthroughs have led to even less invasive alternatives like single-port surgery, but this has been hindered by technical challenges such as the collision of robotic arms within a limited space. The Intuitive da Vinci Single-Port robotic platform is a novel system that overcomes some of these challenges. IMPACT OF INNOVATION: This study aimed to assess the safety and feasibility of the Intuitive da Vinci Single-Port robotic platform in right segmental colectomies among adult patients. These findings may set the stage for more widespread use of single-port robotic surgery. TECHNOLOGY, MATERIALS, AND METHODS: The Intuitive da Vinci Single-Port robot is a system designed specifically for single-port robotic surgery. This platform enables flexible port location and efficient internal and external range of motion using a single C-shaped arm. In the present study, right colectomies were performed in adult patients using this platform between May 2022 and November 2022, and they were compared to right colectomies in adult patients performed using the standard multiport platform between January 2019 and December 2022. The main outcome measure was safety and quality event rates. PRELIMINARY RESULTS: Of 30 patients, 16.7% of patients (n = 5) underwent single-port robotic right colectomy and 83.3% (n = 25) underwent multiport right colectomy. In the single-port group, 40% of patients (n = 2) developed a safety/quality event (postoperative portal vein thrombosis and excessive postoperative pain). In the multiport group, 32% of patients (n = 8) developed 1 safety/quality event and 8% (n = 2) had more than 1 event. CONCLUSIONS AND FUTURE DIRECTIONS: This preliminary study, one of the first Food and Drug Administration-approved, investigator-initiated uses of this platform in colorectal surgeries, shows that this platform is a safe and feasible option for right colectomies. On preliminary evaluation, it appears comparable in terms of relevant safety/quality events to the multiport platform. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT05321134.

Human nucleolar protein 7 (NOL7) is required for early pre-rRNA accumulation and pre-18S rRNA processing.

The main components of the essential cellular process of eukaryotic ribosome biogenesis are highly conserved from yeast to humans. Among these, the U3 Associated Proteins (UTPs) are a small subunit processome subcomplex that coordinate the first two steps of ribosome biogenesis in transcription and pre-18S processing. While we have identified the human counterparts of most of the yeast Utps, the homologs of yeast Utp9 and Bud21 (Utp16) have remained elusive. In this study, we find that NOL7 is the likely ortholog of Bud21. Previously described as a tumour suppressor through regulation of antiangiogenic transcripts, we now show that NOL7 is required for early pre-rRNA accumulation and pre-18S rRNA processing in human cells. These roles lead to decreased protein synthesis and induction of the nucleolar stress response upon NOL7 depletion. Beyond Bud21's nonessential role in yeast, we establish human NOL7 as an essential UTP that is necessary to maintain both early pre-rRNA levels and processing.

Exploring the complexity and spectrum of racial/ethnic disparities in colon cancer management.

BACKGROUND: Colorectal cancer is a leading cause of morbidity and mortality across U.S. racial/ethnic groups. Existing studies often focus on a particular race/ethnicity or single domain within the care continuum. Granular exploration of disparities among different racial/ethnic groups across the entire colon cancer care continuum is needed. We aimed to characterize differences in colon cancer outcomes by race/ethnicity across each stage of the care continuum. METHODS: We used the 2010-2017 National Cancer Database to examine differences in outcomes by race/ethnicity across six domains: clinical stage at presentation; timing of surgery; access to minimally invasive surgery; post-operative outcomes; utilization of chemotherapy; and cumulative incidence of death. Analysis was via multivariable logistic or median regression, with select demographics, hospital factors, and treatment details as covariates. RESULTS: 326,003 patients (49.6% female, 24.0% non-White, including 12.7% Black, 6.1% Hispanic/Spanish, 1.3% East Asian, 0.9% Southeast Asian, 0.4% South Asian, 0.3% AIAE, and 0.2% NHOPI) met inclusion criteria. Relative to non-Hispanic White patients: Southeast Asian (OR 1.39, p < 0.01), Hispanic/Spanish (OR 1.11 p < 0.01), and Black (OR 1.09, p < 0.01) patients had increased odds of presenting with advanced clinical stage. Southeast Asian (OR 1.37, p < 0.01), East Asian (OR 1.27, p = 0.05), Hispanic/Spanish (OR 1.05 p = 0.02), and Black (OR 1.05, p < 0.01) patients had increased odds of advanced pathologic stage. Black patients had increased odds of experiencing a surgical delay (OR 1.33, p < 0.01); receiving non-robotic surgery (OR 1.12, p < 0.01); having post-surgical complications (OR 1.29, p < 0.01); initiating chemotherapy more than 90 days post-surgery (OR 1.24, p < 0.01); and omitting chemotherapy altogether (OR 1.12, p = 0.05). Black patients had significantly higher cumulative incidence of death at every pathologic stage relative to non-Hispanic White patients when adjusting for non-modifiable patient factors (p < 0.05, all stages), but these differences were no longer statistically significant when also adjusting for modifiable factors such as insurance status and income. CONCLUSIONS: Non-White patients disproportionately experience advanced stage at presentation. Disparities for Black patients are seen across the entire colon cancer care continuum. Targeted interventions may be appropriate for some groups; however, major system-level transformation is needed to address disparities experienced by Black patients.

Paired Box 9 (PAX9), the RNA polymerase II transcription factor, regulates human ribosome biogenesis and craniofacial development.

Dysregulation of ribosome production can lead to a number of developmental disorders called ribosomopathies. Despite the ubiquitous requirement for these cellular machines used in protein synthesis, ribosomopathies manifest in a tissue-specific manner, with many affecting the development of the face. Here we reveal yet another connection between craniofacial development and making ribosomes through the protein Paired Box 9 (PAX9). PAX9 functions as an RNA Polymerase II transcription factor to regulate the expression of proteins required for craniofacial and tooth development in humans. We now expand this function of PAX9 by demonstrating that PAX9 acts outside of the cell nucleolus to regulate the levels of proteins critical for building the small subunit of the ribosome. This function of PAX9 is conserved to the organism Xenopus tropicalis, an established model for human ribosomopathies. Depletion of pax9 leads to craniofacial defects due to abnormalities in neural crest development, a result consistent with that found for depletion of other ribosome biogenesis factors. This work highlights an unexpected layer of how the making of ribosomes is regulated in human cells and during embryonic development.

Ribosomopathies: Old Concepts, New Controversies.

Ribosomopathies are a diverse subset of diseases caused by reduced expression of, or mutations in, factors necessary for making ribosomes, the protein translation machinery in the cell. Despite the ubiquitous need for ribosomes in all cell types, ribosomopathies manifest with tissue-specific defects and sometimes increased cancer susceptibility, but few treatments target the underlying cause. By highlighting new research in the field, we review current hypotheses for the basis of this tissue specificity. Based on new work, we broaden our understanding of the role of ribosome biogenesis in diverse tissue types throughout embryonic development. We also pose the question of whether previously described human conditions such as aging can be at least partially attributed to defects in making ribosomes.

Greater trochanter morphology and association with patient demographics, surgical factors, and post-operative stem position: a retrospective assessment of 150 cementless THRs in 135 dogs.

BACKGROUND: Total hip replacement (THR) in the gold standard surgical treatment for the canine hip. While it has been shown that greater trochanter morphology affects post-operative cementless stem position in humans, trochanter morphology and the effect on cementless stem position has not been extensively evaluated in dogs. The objective of this study was to classify greater trochanter morphology and identify potential associations between trochanter morphology and patient demographics, femoral canal geometry, surgical time, technique modifications, and post-operative stem position in client-owned dogs undergoing cementless THR. RESULTS: In this retrospective study, medical records and radiographs of 135 dogs undergoing 150 cementless total hip replacements from 2013 to 2020 were included. Trochanters were classified in the frontal plane using an ordinal grading system adapted from human THR. A Grade I trochanter denoted a trochanter positioned lateral to the periosteal surface of the lateral femoral cortex, whereas a Grade IV trochanter denoted a trochanter positioned medial to the anatomic axis of the femur. Associations between trochanter grade and other variables were examined using ANOVA, Kruskall-Wallis, or chi-squared tests. Significance was assumed at P ≤ .05. Trochanters were classified as follows: Grade I (44/150, 29.3%), Grade II (56/150, 37.4%), Grade III (44/150, 29.3%), Grade IV (6/150, 4.0%). Grade IV trochanters had lower anatomic lateral distal femoral angle (aLDFA; 91.0 ± 6.2°), angle of inclination (117.7 ± 10.5°), and canal flare index (1.53 ± 0.27). When compared to all groups, Grade IV trochanters were associated with longer surgical times (Grade IV: 227.0 ± 34.2 min; all grades: 183.2 ± 32.9 min) and technique modifications (Grade IV: 83.3%; all grades: 18%). Grade I trochanters had stems placed in valgus (- 1.8 ± 2.33°), whereas Grade II (0.52 ± 2.36°), III (0.77 ± 2.58°), and IV (0.67 ± 2.73°) trochanters exhibited varus stems. Depth of stem insertion was greater (11.2 ± 4.2 mm) for Grade IV trochanters. CONCLUSIONS: Trochanter grade was associated with post-operative stem alignment and translation in the frontal plane. Grade IV trochanters were associated with altered femoral geometry, increased surgical time, technique modifications, and stem insertion depth. Pre-operative greater trochanter classification may prove useful in identifying cases requiring prolonged surgical times or technique modifications.

Determination of anatomic level of myelomeningocele by prenatal ultrasound.

PURPOSE: Ultrasound is the primary method for prenatal identification of myelomeningocele and is critical to prognostication and treatment planning. No study has considered the degree of inaccuracy of prenatal US lesion level estimates and anatomic lesion level on postnatal imaging using the weighted kappa coefficient (κw), nor the impact of maternal BMI on agreement. We examined the accuracy of prenatal ultrasound lesion level estimation in a cohort of patients with myelomeningocele using κw and determined whether BMI influenced accuracy. METHODS: The study is a retrospective review including patients born 2011-2019 who had prenatal imaging and primary myelomeningocele closure at a single institution. Lesion levels from prenatal ultrasound and postnatal imaging studies were analyzed for agreement at exact level, within 1 level, and within 2 levels using κw. Maternal BMI was examined for correlation with accuracy. RESULTS: Fifty-seven patients met inclusion criteria. Mean BMI was 31.2. There was no association between maternal BMI and agreement at any level. Lesion level on prenatal ultrasound agreed with postnatal imaging to the exact level in 13 (22.8%) cases, within 1 level in 38 (66.7%) cases, and within 2 levels in 50 (87.7%) cases. Weighted kappa showed moderate agreement at exact level (κw = 0.494) and substantial agreement within 1 (κw = 0.761) and 2 levels (κw = 0.902). CONCLUSION: Weighted kappa adds confidence for clinical decision making by accounting for accuracy. Prenatal ultrasound is a reliable and accurate method of determining lesion level with near-perfect agreement to postnatal imaging within 2 spinal levels. Maternal BMI may not influence lesion level determination after initial diagnosis.

The effect of a smoke-evacuation unit on ultrafine particle concentrations in the operating room during approach to the proximal tibia for tibial plateau-leveling osteotomy surgery in dogs.

OBJECTIVE: To evaluate the effectiveness of a smoke-evacuation unit on reducing ultrafine particle concentration in the operating room (OR) during the approach to the proximal tibia for tibial plateau-leveling osteotomy (TPLO). STUDY DESIGN: Prospective, randomized, controlled clinical trial. SAMPLE POPULATION: Twenty-nine client-owned dogs undergoing unilateral TPLO at a single institution were assigned to either smoke-evacuator groups (SE; n = 15) or non-smoke-evacuator groups (NSE; n = 14). METHODS: Dogs were randomly assigned to the SE group or the NSE group. An airborne particle measuring device measured and recorded baseline and intraoperative particles per cm3 (ppc) during the approach to the proximal tibia during which electrosurgery was used to provide hemostasis, dissect subcutis, transect and elevate fascia. The mean ppc, maximum ppc, and baseline ppc were compared between groups. Mean ppc was also compared to the baseline ppc within each group. RESULTS: During surgery, mean ppc (1352) and maximum ppc (62 450) for the NSE group were higher in than mean ppc (763) and maximum ppc (10 100) for the SE group (P < .0001, P < .0001, respectively). Mean ppc was higher in both SE (mean ppc = 763; P < .0001) and NSE (mean ppc = 1352; P = .0001) than their respective baseline ppc (213 and 240). CONCLUSION: The use of a smoke evacuator decreased particle concentrations 56.4% during the approach to the proximal tibia. Performing the approach to the proximal tibia resulted in higher particle concentrations than the baseline, regardless of smoke-evacuator use. CLINICAL SIGNIFICANCE: Surgeons should be aware of smoke produced by electrosurgery, potential health consequences, and methods of smoke mitigation (smoke evacuation).

Responsibilities and capabilities of health engagement professionals (HEPs): Perspectives from HEPs and health consumers in Australia.

BACKGROUND: In Australia, the National Safety and Quality Health Service Standards (2012) stipulates that partnering with health consumers to improve health-care experiences is one of the criteria health-care organizations are assessed and accredited against. This standard has given rise to a role: health engagement professionals (HEPs). While there are no standard requirements for recruitment into this role, this study contributes to much needed research into understanding their responsibilities and capabilities, and their contributions to engagement outcomes. METHODS: Using a qualitative, interpretive approach, 16 HEPs and 15 health consumer representatives (who have experiences of interacting with HEPs) participated in an in-depth phone interview in December 2019. We explored (a) the purposes of the role, (b) the responsibilities and work activities and (c) the capabilities required to carry out the responsibilities. RESULTS: Health engagement professionals are specialists in designing engagement mechanisms for health-care organizations to co-design health services with health consumers. They facilitate partnerships between health-care organizations and health consumers. They play significant roles in listening to, facilitating understanding amongst different stakeholder groups (eg hospital management, health-care workers and health consumers) and navigating the bureaucratic structures to influence outcomes. Four major responsibilities (advocacy, education, facilitation and administration) and four categories of capabilities (relational, communication, professional and personal) were identified. CONCLUSION: A list of job responsibilities and desired capabilities of HEPs is provided to help health-care organizations better understand the requirements for the role. This would help them decide how applicants to these roles would meet the requirements (eg experience of navigating bureaucratic systems).

Morphometric measurements to predict meniscal size in skeletally mature dogs for meniscal transplantation.

OBJECTIVE: To determine a relationship between morphometric measurements (MM) and meniscal dimensions (MD) in the dog. STUDY DESIGN: Cadaveric study. ANIMALS: Eighteen mixed-breed canine cadavers (22.35 ± 4.06 kg); 36 each of medial and lateral menisci. METHODS: The following MM were obtained in duplicate: height at scapula, withers, pelvis, rump, and greater trochanter; chest circumference; pelvic circumference; length from occiput to the base of the tail; hock to stifle length (HS); body weight; body condition score; and body fat percentage (BF%). Stifles were disarticulated, and digital photographs of in situ menisci were used to obtain meniscal measurements in duplicate. Morphometric parameters were compared with MD via Pearson correlation (r). A correlation of r ≥ 0.65 was considered strong. RESULTS: The strongest correlation was noted between HS and MD, with r = 0.85 for lateral meniscal width, r = 0.77 for medial meniscal length, and r = 0.76 for medial meniscal width. Lateral meniscal length had the strongest correlation with height at rump (HRu) (r = 0.73). Body weight correlated strongly with meniscal width and fairly with meniscal length. Body condition score and BF% correlated weakly with MD. CONCLUSION: Hock to stifle length was an easily obtainable variable and was proportional to MD. CLINICAL SIGNIFICANCE: Hock to stifle length may be considered by tissue banks and veterinary surgeons as a quick and cost effective screening tool for appropriate meniscal sizing in dogs.

Effect of sedation or general anesthesia on elbow goniometry and thoracic limb circumference measurements in dogs with naturally occurring elbow osteoarthritis.

OBJECTIVE: To evaluate the effect of sedation or general anesthesia (GA) on elbow goniometry and thoracic limb circumference (TLC) measurements in dogs with elbow osteoarthritis (OA). STUDY DESIGN: Prospective study. ANIMALS: Twenty-four client-owned dogs with radiographically confirmed elbow OA. METHODS: Elbow goniometry and TLC measurements were made before and after either sedation or GA by using a hand-held goniometer and spring tension measuring tape, respectively. Observers were not allowed to review their pre-sedation or pre-GA measurements at the time of obtaining measurements on dogs under sedation or GA. Mixed analysis of variance models were used to compare elbow goniometry and TLC measurements before and after sedation or GA. RESULTS: Eleven and thirteen dogs were included in the sedation and GA groups, respectively. Mean elbow flexion decreased by 5° and 3° and mean elbow extension increased by 6° and 2° under sedation and GA, respectively. Total range of motion increased by 11° under sedation and by 5° under GA. Each of these changes was statistically significant (P < .05) except elbow extension under GA (P = .129). Sedation and GA did not influence TLC measurements (P > .05). CONCLUSION: Sedation or GA led to slight and similar increase in elbow flexion and extension but did not influence TLC measurements in dogs with elbow OA. CLINICAL SIGNIFICANCE: Sedation or GA can cause slight alterations to goniometric measurements in canine elbows with OA. The protocols used in this study for sedation and GA seem interchangeably acceptable for goniometry and TLC measurements in dogs with elbow OA.

Influence of orthopedic examination on lameness scores and interobserver and intraobserver agreement in dogs with naturally occurring elbow osteoarthritis.

OBJECTIVE: To determine the influence of orthopedic examination on numerical rating score (NRS) and visual analog score (VAS) when scoring lameness in dogs with elbow osteoarthritis (OA) and to evaluate interobserver and intraobserver agreement in NRS and VAS on the basis of video-graphic gait analysis. DESIGN: Prospective blinded study. ANIMALS: Eighteen client-owned dogs with radiographically confirmed elbow OA. METHODS: Videos were obtained for all dogs at a walk and at a trot both prior to and immediately after orthopedic examination. All videos were randomly sequenced. Six observers, unaware of the timing of the video, independently assigned both NRS and VAS twice, with at least a 2-week interval. Scores were evaluated with mixed analysis of variance, and the agreement among observers was accessed by intraclass correlation coefficient (ICC). RESULTS: No difference was detected between NRS and VAS at walk or at trot before and after orthopedic examination. Numeric rating score and VAS at walk were lower than those at trot before an orthopedic examination by scores of 0.17 (P = .0018) and 3.54 (P = .0019), respectively. The ICC for both scores for all observers was >0.9. CONCLUSION: An orthopedic examination did not exacerbate the NRS and the VAS for dogs with elbow OA. Interobserver and intraobserver agreement was high for both lameness scores. CLINICAL SIGNIFICANCE: Lameness may be scored after gait evaluation in dogs with elbow OA irrespective of the timing of a comprehensive orthopedic examination.

Effect of tibial rotation on the tibial plateau angle measurement in dogs: An ex vivo study.

OBJECTIVE: To determine the effect of tibial rotation on radiographic tibial plateau angle (TPA) measurement in normal and cranial cruciate ligament (CrCL)-deficient stifles. STUDY DESIGN: Cadaveric study. SAMPLE POPULATION: Five pairs of canine cadaver hind limbs with no stifle osteoarthritis. METHODS: Mediolateral radiographs of each specimen were obtained at 0°, 10°, 20°, and 30° of internal and external rotation of the tibia with both intact and transected CrCL. Two Kirschner wires were placed at the cranial and caudal landmarks of the tibial plateau, and the 0° views were imaged again, representing the anatomic TPA. Five observers measured the TPA twice on all images. Measurements were compared by using a mixed-model ANOVA. Intraobserver and interobserver variability were evaluated by using the coefficient of variation. RESULTS: Tibial plateau angle did not differ among the anatomic, CrCL-intact, and CrCL-deficient 0° views or between the CrCL-intact and CrCL-deficient views at the various tibial rotations. The only difference detected was between CrCL-intact stifles radiographed at 0° and external rotation (range, 1.16°-1.6°; P = .016, P = .001, and P < .001). Tibial rotation, CrCL transection, and their interaction all failed to influence intraobserver and interobserver variability (P > .05). CONCLUSION: In CrCL-deficient stifles, tibial rotation of up to 30° internally and externally did not result in clinically relevant changes in TPA measurements. CLINICAL SIGNIFICANCE: The TPA can be successfully measured with up to 30° of internal and external tibial rotation in CrCL-deficient stifles with no osteoarthritic changes.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Visual evoked potentials detect cortical processing deficits in Rett syndrome.

OBJECTIVE: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X-linked MECP2 gene and characterized by developmental regression during the first few years of life. The objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative biomarker to monitor brain function in RTT. METHODS: We recorded pattern-reversal VEPs in Mecp2 heterozygous female mice and 34 girls with RTT. The amplitudes and latencies of VEP waveform components were quantified, and were related to disease stage, clinical severity, and MECP2 mutation type in patients. Visual acuity was also assessed in both mice and patients by modulating the spatial frequency of the stimuli. RESULTS: Mecp2 heterozygous female mice and RTT patients exhibited a similar decrease in VEP amplitude that was most striking in the later stages of the disorder. RTT patients also displayed a slower recovery from the principal peak of the VEP response that was impacted by MECP2 mutation type. When the spatial frequency of the stimulus was increased, both patients and mice displayed a deficit in discriminating smaller patterns, indicating lower visual spatial acuity in RTT. INTERPRETATION: VEP is a method that can be used to assess brain function across species and in children with severe disabilities like RTT. Our findings support the introduction of standardized VEP analysis in clinical and research settings to probe the neurobiological mechanism underlying functional impairment and to longitudinally monitor progression of the disorder and response to treatment.

Student challenges during third-year perioperative clerkships through the lens of faculty and residents: A qualitative study.

PURPOSE: Studies of medical students suggest they often find the transition from the pre-clinical curriculum to clinical rotations particularly challenging during perioperative clerkships. Educators could add a new perspective into students' clerkship experiences and potential interventions to improve them. The purpose of this study was to examine the educator perspective on students' experiences in perioperative clerkships. The findings could inform potential curricular interventions to facilitate student transition from a didactic environment into perioperative clerkships. METHODS: Semi-structured qualitative interviews were conducted with 16 faculty and residents in the departments of anaesthesia, obstetrics and gynaecology (OBGYN), and general surgery across multiple clinical teaching sites at one institution. Interview questions explored their perceptions of the challenges students face during their transition into perioperative clerkships and probed thoughts on curriculum interventions they believed would be the most beneficial. Interviews were recorded, transcribed and analysed thematically. FINDINGS: Three themes were identified. Faculty and residents perceive that student experiences on perioperative clerkships are shaped by (1) students' ability to adapt to the specialty and operating room norms on these clerkships, (2) students' understanding of how they can meaningfully contribute to the clinical team, and (3) dedicated teaching time constraints. Interventions were suggested to address educator expectations and student gaps, such as implementing a pre-clerkship orientation across anaesthesia, general surgery and OBGYN. CONCLUSIONS: To facilitate the medical student transition to perioperative clerkships, interventions should aid students in adapting to clerkship norms for these specialties and clarifying their role and expectations within the care team.