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Age-structured population models require reliable estimates of cohort-specific survival rates, yet vital rates of younger age classes are often difficult to estimate because of the logistical challenges of monitoring young animals. As part of a study of sandhill cranes Antigone canadensis in the zone of contact between breeding distributions of the Eastern Population and Midcontinent Population in Minnesota, we monitored first summer survival of 34 sandhill cranes (hereafter colts) by using very-high-frequency and global positioning system–global system for mobile communications transmitters. We estimated daily survival probabilities from 19 to 120 d posthatch by using a generalized linear model accounting for interval censoring, resulting in an estimated period survival rate of 0.52 (90% CI, 0.36–0.71) over summer (100 d). Estimated daily probabilities of survival increased as colts became older and fledged (at 70–75 d posthatch), when they presumably became less vulnerable to predation. Causes of mortality were mostly unknown aside from one case of a collision with a vehicle. There is a scarcity of published colt survival rate estimates for sandhill cranes, and what is available varies widely by study site. Region-specific sandhill crane colt survival rate estimates can inform future management efforts and inform population dynamics research and overall natural history knowledge of sandhill cranes.

OBJECTIVE: Regulatory and payment changes associated with COVID-19 facilitated wide-spread use of telehealth within pediatric primary care starting in March 2020. Given prior quality concerns about antibiotic management for children during telemedicine visits outside of primary care, we sought to examine acute respiratory tract infection (ARTI) visit volume and antibiotic management for children via telemedicine integrated within pediatric primary care. METHODS: Using electronic health record data from 47 practices within a large pediatric primary care network, we identified visits for ARTI from April to September 2020. For these visits, we categorized antibiotic management consistent with clinical guidelines as guideline concordant. We compared telemedicine and in-person visit guideline-concordant antibiotic management, diagnoses, and antibiotic prescribing using chi-square tests and examined trends over time using descriptive statistics. Antibiotic stewardship during the study period included learning collaborative videoconferences and sharing of clinic and clinician-level metrics through an interactive dashboard. RESULTS: During the 6-month period, 8332 ARTI visits were identified, with 3003 (36%) via telemedicine. Guideline-concordant antibiotic management occurred in 92.5% of telemedicine visits compared to 90.7% of in-person office visits (P = .004). Telemedicine ARTI visits receiving diagnoses of acute otitis media or streptococcal pharyngitis declined from peak of 52% (May) to 7% (September). Guideline-concordant antibiotic management of sinusitis and viral ARTI during telemedicine visits increased from 88% (April) to 97% (September). CONCLUSION: With active antibiotic stewardship, pediatricians practicing within certified medical homes consistently delivered highly guideline-concordant care for ARTIs to their patient population via telemedicine integrated into primary care.

Background: We have demonstrated that TBX18 suffices to reprogram postnatal ventricular cardiomyocytes (CMs) to induced pacemaker cells. Cell-cell interactions and cell-extracellular matrix (ECM) are important regulators of microtissue organization and assembly. Here, we sought to gain a finer understanding of self-organization and assembly of pacemaker microtissue with myocytes and non-myocytes driven by TBX18. Methods: 2D monolayer of neonatal rat ventricular myocytes (NRVMs) were transduced with Adeno- GFP and Adeno-TBX18 in vitro model. AAV9-TBX18 was delivered via tail vein injection of Hcn4 (+/eGFP) transgenic mice to track the induced pacemaker myocytes. Result: TBX18-NRVMs showed more compact nodal-like aggregates with a higher density of CMs and surrounded by nonmyocytes. The number of alpha smooth muscle actin (αSMA) + myofibroblasts producing specific ECM and facilitating cell motility was increased by 190% in TBX18-NRVMs as well. Systemic delivery of AAV9-TBX18 via tail vein of mice created aggregation of de novo Hcn4+ induced pacemaker myocytes (iPMs) surrounded by αSMA+ myofibroblasts in vivo. Then, we treated pre-plated neonatal rat ventricular cells (NRVCs, including CMs and nonmyocytes) to explore the potential role of cell-cell communication and cell-ECM interaction in the formation of nodal-like aggregates through scRNA-seq. The data indicated that TBX18+ CM (28.6% % of all CMs) and TBX18-negative CMs (71.4% of all CMs) presented highly consistent transcriptomic profiles at day 3. No significant difference in Hcn4 transcript levels and the ratio of iPMs (defined as Hcn4+, Gja1 low , Nkx2.5 low , Tnni3 high , Actn2 high CM) was observed between them, as well as other pacemaker genes, suggesting cross-communication between them. Despite of TBX18+ fibroblasts (FBs) accounting for only 5% of all FBs, a higher proportion of activated myofibroblasts (39.3% vs. 25.4%) and lower proportion of quiescent FBs were observed in TBX18-NRVCs compared to control. Enrichment analysis revealed that TBX18-CMs lost ventricular specific electrical coupling and sarcomere organization (down-regulated Gja1, Cdh2, Irx3 ), but reconstructed hemidesmosome assembly and cell-ECM interaction enriched in sinoatrial node myocytes (Upregulated Lamc1, Itgb1, Plec, Des, Actn1, and Acta2 ) and activated Tgfβ signaling. Furthermore, treatment with gap junction inhibitor palmitoleic acid as well as Tgfβ receptor inhibitor A83-01 significantly suppressed the activation of quiescent fibroblasts to αSMA+ myofibroblasts and the formation of nodal-like aggregation of TBX18-NRVMs. Conclusion: TBX18 drives self-organization and nodal-like assembly of pacemaker microtissue with myocytes and non-myocytes through cell-cell communication of gap junction and Tgfβ signal.

Implantable cardiac pacemaker devices are generally effective for patients with symptomatic bradyarrhythmia. However, device-dependent cardiac pacing is far from ideal and often inadequate, particularly for pediatric patients who need to go through invasive revision of the indwelling hardware. Biological pacemakers have been proposed as device-free alternatives to the current treatment, but sustained, unwavering biological pacing beyond days after the biologic delivery has not been demonstrated. We have previously demonstrated that re-expression of an embryonic transcription factor, TBX18, could reprogram ventricular cardiomyocytes into induced pacemaker myocytes (iPMs). Here, we report that exogenous expression of TBX18 per se leads to severe fibrosis in situ, impairing the iPMs’ ability to pace together. Acute fibrosis is accompanied with proliferation and activation of cardiac fibroblasts via Tgfβ-Smad2/3 pathway. Small molecule inhibition of Tgfβ signaling mitigated the interstitial remodeling, independent from TBX18-induced iPM reprogramming at the single-cell level. Direct and focal gene transfer of TBX18 into the left ventricular myocardium created ventricular pacing in a rat model of chronic atrioventricular block, but such activity began to wane in a week. In contrast, a combination therapy consisting of TBX18 gene transfer and Tgfβ inhibition enabled sustained biological pacing beyond the four-week study period. Our data demonstrate that inhibition of Tgfβ signaling suffices to achieve durable cardiac pacing by TBX18-induced biological pacemakers.

IntroductionThere are unmet mental health needs of depressed adolescents and young adults (AYAs) across the USA. Behavioural technology adequately integrated into clinical care delivery has potential to improve care access and efficiency. This multisite randomised controlled trial evaluates how a coach-enhanced digital cognitive behavioural intervention (dCBI) enhances usual care for depressed AYAs in paediatric practices with minority enriched samples.Methods and analysisParticipants (n=750) ages 16–22 who meet threshold criteria for depressive severity (Patient Health Questionnaire-9; PHQ-9 score 10-24) will be recruited through paediatric practices across three academic institutions (Boston, Pittsburgh and San Diego). Participants will be randomised to 12 weeks of dCBI+treatment as usual (TAU) (n=450) or TAU alone (n=300) in outpatient paediatric practices. Assessments will be completed at baseline, 6 weeks and 12 weeks with the primary outcome being improvement in clinician-rated and self-reported depressive severity (Children’s Depression Rating Scale—Revised and PHQ-9) and secondary outcomes being self-reported suicidal ideation (item 9 on PHQ-9), anxiety severity (Generalised Anxiety Disorder), general quality of life (Satisfaction with Life Scale) and general functioning (Children’s Global Assessment Scale). The study design is an intent-to-treat mixed effects regression with group, and covariates nested within the sites.Ethics and disseminationAll participants or their parent/guardian (under 18 years or unemancipated) will give informed consent to a study team member. All data are expected to be collected over 18 months. The Institutional Review Board (IRB) is a board at each institution in the United States that reviews and monitors research involving human subjects. IRB approval from the University of Pittsburgh was obtained on 30 November 2021 (STUDY21080150), from the University of California San Diego’s Human Research Protection Program IRB on 14 July 2022 (802047), and from the Boston Children’s Hospital IRB on 25 October 2022 (P00040987). Full study results are planned to be published within 2 years of initial study recruitment (October 2024). Dissemination of findings will occur in peer-reviewed journals, professional conferences and through reports to participating entities and stakeholders.Trial registration numberNCT05159713; ClinicalTrials.gov

Sufficient primary stability through interference fit is required for bone ingrowth and subsequent long-term fixation of cementless knee replacement implants, and can be evaluated in experimental testing. In this study, primary stability of a novel posterior-stabilized (PS) femoral component (Attune PS) and a contemporary PS component (Triathlon PS) were analyzed, and compared to previous outcomes of cruciate-retaining (CR) implants. Potential bone ingrowth was evaluated by measuring micromotions over the implant-bone interface in six cadaveric femur pairs under two loading conditions using digital image correlation, for a paired comparison of the PS implants. Push-off forces required to achieve implant removal under high-flexion were determined as a measure of implant fixation. Achieved interference fit was determined by reconstructing the implant positions through use of separate implant and resected bone geometries. Lower overall micromotions and a higher average push-off force were measured in the Attune PS implant, indicating increased initial fixation compared to the Triathlon PS design. Interference fit was significantly higher for the Attune PS and was related to lower gait micromotions in Triathlon and overall PS groups. Based on reported clinical results and the comparison with available CR implant results, both PS implants are expected to provide sufficient initial clinical stability.

Background Most pediatric studies of asthma and COVID‐19 to date have been ecological, which offer limited insight. We evaluated the association between asthma and COVID‐19 at an individual level. Methods Using data from prospective clinical registries, we conducted a nested case‐control study comparing three groups: children with COVID‐19 and underlying asthma (“A+C” cases); children with COVID‐19 without underlying disease (“C+” controls); and children with asthma without COVID‐19 (“A+” controls). Results The cohort included 142 A+C cases, 1110 C+ controls, and 140 A+ controls. A+C cases were more likely than C+ controls to present with dyspnea and wheezing, to receive pharmacologic treatment including systemic steroids (all p

Each heartbeat that pumps blood throughout the body is initiated by an electrical impulse generated in the sinoatrial node (SAN). However, a number of disease conditions can hamper the ability of the SAN′s pacemaker cells to generate consistent action potentials and maintain an orderly conduction path, leading to arrhythmias. For symptomatic patients, current treatments rely on implantation of an electronic pacing device. However, complications inherent to the indwelling hardware give pause to categorical use of device therapy for a subset of populations, including pediatric patients or those with temporary pacing needs. Cellular-based biological pacemakers, derived in vitro or in situ, could function as a therapeutic alternative to current electronic pacemakers. Understanding how biological pacemakers measure up to the SAN would facilitate defining and demonstrating its advantages over current treatments. In this review, we discuss recent approaches to creating biological pacemakers and delineate design criteria to guide future progress based on insights from basic biology of the SAN. We emphasize the need for long-term efficacy in vivo via maintenance of relevant proteins, source-sink balance, a niche reflective of the native SAN microenvironment, and chronotropic competence. With a focus on such criteria, combined with delivery methods tailored for disease indications, clinical implementation will be attainable.

BackgroundMost pediatric studies of asthma and COVID-19 to date have been ecological, which offer limited insight. We evaluated the association between asthma and COVID-19 at an individual level.MethodsUsing data from prospective clinical registries, we conducted a nested case-control study comparing three groups: children with COVID-19 and underlying asthma (“A+C” cases); children with COVID-19 without underlying disease (“C+” controls); and children with asthma without COVID-19 (“A+” controls).ResultsThe cohort included 142 A+C cases, 1110 C+ controls, and 140 A+ controls. A+C cases were more likely than C+ controls to present with dyspnea and wheezing, to receive pharmacologic treatment including systemic steroids (all pConclusionsIn our cohort, asthma was a risk factor for hospitalization in children with COVID-19, but not for worse COVID-19 outcomes. SARS-CoV-2 does not seem to be a strong trigger for pediatric asthma exacerbations. Asthma severity was not associated with higher risk of COVID-19.Key messagesIn this pediatric cohort, asthma was a risk factor for hospitalization in children with COVID-19, but not for worse COVID-19 outcomes. Baseline asthma severity was not associated with higher risk of COVID-19, and SARS-CoV-2 did not seem to be a strong trigger for pediatric asthma exacerbations.

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biology and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP). We characterized the reliability and stability of LEAP, its relationship to the field potential, and its efficacy for quantifying AP morphology of human induced pluripotent stem cell derived and primary rodent cardiomyocytes. Rise time, action potential duration, beat period, and triangulation were used to quantify compound responses and AP morphology changes induced by genetic modification. LEAP is the first high throughput, non-invasive, label-free, stable method to capture AP morphology from an intact cardiomyocyte syncytium. LEAP can accelerate our understanding of stem cell models, while improving the automation and accuracy of drug testing.

Objective The study aimed to evaluate an integrated electronic questionnaire system implementation in outpatient community pediatric practices on workflow, completion rates, and recorded scores. Methods We evaluated the implementation and outcomes of an integrated electronic questionnaire system at 45 community pediatric practices that used standardized questionnaires to screen for autism, depression, and substance use and to measure asthma control. Electronic health record (EHR) data for all well child visits were extracted for the 3 months before and after implementation. We used statistical process control charts to evaluate questionnaire completion rates and Chi-square tests to evaluate screening completion and positive screening rates. The collection and entry of questionnaire information was observed and timed. Results EHR data included 107,120 encounters across 45 practices that showed significant and sustained improvement in completion rates for all questionnaires. The rate of recorded concerning questionnaires decreased for asthma control (19.3 vs. 12.8%, p Discussion Electronic questionnaire administration saved staff time and patient time. We report overall improvement in questionnaire completion rates, with notable variation in improvement in completion across practices and in change in concerning recorded result rates across measures. Conclusion Conversion of four standard paper questionnaires to an integrated electronic system reduces patient and staff time while increasing completion rates when well integrated into routine care.

Contains fulltext : 251094.pdf (Publisher’s version ) (Open Access) Periprosthetic bone loss is an important factor in tibial implant failure mechanisms in total knee arthroplasty (TKA). The purpose of this study was to validate computational postoperative bone response using longitudinal clinical DEXA densities. Computational remodeling outcome over a population was obtained by incorporating the strain-adaptive remodeling theory in finite element (FE) simulations of 26 different tibiae. Physiological loading conditions were applied, and bone mineral density (BMD) in three different regions of interest (ROIs) was considered over a postoperative time of 15 years. BMD outcome was compared directly to previously reported clinical BMD data of a comparable TKA cohort. Similar trends between computational and clinical bone remodeling over time were observed in the two proximal ROIs, with most rapid bone loss taking place in the initial months after TKA and BMD starting to level in the following years. The extent of absolute proximal BMD change was underestimated in the FE population compared with the clinical subject group, which might be the result of significantly higher initial clinical baseline BMD values. Large differences in remodeling response were found in the distal ROI, in which resorption was measured clinically, but a large BMD increase was predicted by the FE models. Multiple computational limitations, related to the FE mesh, loading conditions, and strain-adaptive algorithm, likely contributed to the extensive local bone formation. Further research incorporating subject-specific comparisons using follow-up CT scans and more extensive physiological knee loading is recommended to optimize bone remodeling more distal to the tibial baseplate.

Introduction: Cardiac pacing can be created by myocardial delivery of TBX18. However, evidence for overt fibrosis at the injection site and the use of viral vectors impede clinical translation of this concept. We hypothesized that non-viral gene transfer of TBX18 combined with prevention of fibrosis with a Tgfβ inhibitor enables durable ventricular pacing in the porcine model of CAVB. Methods: All pigs underwent transvenous RF ablation of the AV node to achieve complete heart block on day-1. The pigs were implanted with a backup pacemaker (VVI=50 bpm) and with osmotic pumps designed to release A83-01, an inhibitor of Tgfβ receptors. Synthetic mRNA encoding either TBX18 (n=7) or GFP (n=2) in saline was injected in the high interventricular septum with a NOGA-MYOSTAR™ catheter. Continuous and ambulatory ECG, blood pressure (BP) and activity were recorded for the 4-week study period with telemetry. Results: The control pigs were dependent on backup pacing throughout 4 weeks with retrograde conduction from the RV apex. In contrast, TBX18 injected pigs showed higher heart rate (HR) compared to control (4-week mean HR of 58±7 vs 52±7, p p p p =0.164), indicating superior hemodynamic measures. Radiopaque agent-enabled, real-time fluoroscopic visualization revealed that the injected biologic spread beyond the intended delivery site in 2 of 7 TBX18 pigs. The mean and max. HR of the 2 pigs were slower than the other five TBX18 pigs, suggesting that conventional imaging can be leveraged to identify redosing criteria, and minimize non-responders. No increase in spontaneous or induced arrhythmias was observed in TBX18 pigs compared to control. Conclusions: mRNA delivery of TBX18 combined with Tgfβ inhibition achieved durable septal pacing for 4 weeks in a porcine model chronic heart block, demonstrating therapeutic efficacy with greater safety profiles.

Introduction: Adenoviral gene delivery of transcription factor, TBX18, has been proven to reprogram ordinary cardiomyocytes to pacemaker cells, and provide ventricular pacing in the rodent and porcine heart. Yet host innate immune response to recombinant viral therapies remains a hurdle to overcome for successful translation. Somatic cell reprogramming does not require persistent expression of the reprogramming factors after arriving at the final cell fate. We hypothesized that brief expression of synthetic TBX18 mRNA suffices to convert chamber cardiomyocytes to induced pacemaker cells, thus obviating issues inherent to adenoviral gene therapy. Methods: Synthetic mRNAs were in vitro transcribed as previously described. Neonatal rat ventricular myocytes (NRVMs) were used as an in vitro platform to test pacemaker reprogramming by TBX18 mRNA. GFP or fLuc encoded mRNA was used as controls in all experiments. Results: Three days after synthetic TBX18 mRNA transfection, Hcn4 transcript level increased >6-fold compared to control. After two weeks, genes enriched in the pacemaker tissue, e.g., Shox2, Hcn4, and Tbx3, continued to be expressed higher in TBX18-NRVMs compared to control by >4.2-fold. The level of endogenously expressed, rat Tbx18 increased by 50% in NRVMs transfected with synthetic human TBX18 mRNA, which point to long-term reprogramming. To identify and lineage-trace reprogrammed pacemaker cells in real time, we cultured ventricular cardiomyoytes from transgenic mouse line Hcn4 ( GFP/+ ) , in which de novo pacemaker cells expressing Hcn4 contain eGFP fluorescence. Twelve days after synthetic mRNA or adenoviral gene transfer of TBX18 or GFP control, a significantly higher number of Hcn4 ( GFP/+ ) cells were observed in both mRNA and adenoviral TBX18-treated wells compared to their respective controls. TBX18 mRNA-transfected NRVM monolayers exhibited >2-fold slower conduction velocities compared to fLuc-transfected myocytes. In line with slow conduction velocity in the induced pacemaker myocytes, expression of ventricular gap junction protein, Cx43, decreased significantly compared to control. Conclusions: Together, the data indicate durable nodal pacemaker cell reprogramming with transient expression of synthetic TBX18 mRNA.

BACKGROUND Telehealth, the delivery of health care through telecommunication technology, has potential to address multiple health system concerns. Despite this potential, only 15% of pediatric primary care clinicians reported using telemedicine as of 2016, with the majority identifying inadequate payment for these services as the largest barrier to their adoption. The COVID-19 pandemic led to rapid changes in payment and regulations surrounding telehealth, enabling its integration into primary care pediatrics. OBJECTIVE Due to limited use of telemedicine in primary care pediatrics prior to the COVID-19 pandemic, much is unknown about the role of telemedicine in pediatric primary care. To address this gap in knowledge, we examined the association between practice-level telemedicine use within a large pediatric primary care network and practice characteristics, telemedicine visit diagnoses, in-person visit volumes, child-level variations in telemedicine use, and clinician attitudes toward telemedicine. METHODS We analyzed electronic health record data from 45 primary care practices and administered a clinician survey to practice clinicians. Practices were stratified into tertiles based on rates of telemedicine use (low, intermediate, high) per 1000 patients per week during a two-week period (April 19 to May 2, 2020). By practice tertile, we compared (1) practice characteristics, (2) telemedicine visit diagnoses, (3) rates of in-person visits to the office, urgent care, and the emergency department, (4) child-level variation in telemedicine use, and (5) clinician attitudes toward telemedicine across these practices. RESULTS Across pediatric primary care practices, telemedicine visit rates ranged from 5 to 23 telemedicine visits per 1000 patients per week. Across all tertiles, the most frequent telemedicine visit diagnoses were mental health (28%-36% of visits) and dermatologic (15%-28%). Compared to low telemedicine use practices, high telemedicine use practices had fewer in-person office visits (10 vs 16 visits per 1000 patients per week, P=.005) but more total encounters overall (in-office and telemedicine: 28 vs 22 visits per 1000 patients per week, P=.006). Telemedicine use varied with child age, race and ethnicity, and recent preventive care; however, no significant interactions existed between these characteristics and practice-level telemedicine use. Finally, clinician attitudes regarding the usability and impact of telemedicine did not vary significantly across tertiles. CONCLUSIONS Across a network of pediatric practices, we identified significant practice-level variation in telemedicine use, with increased use associated with more varied telemedicine diagnoses, fewer in-person office visits, and increased overall primary care encounter volume. Thus, in the context of the pandemic, when underutilization of primary care was prevalent, higher practice-level telemedicine use supported pediatric primary care encounter volume closer to usual rates. Child-level telemedicine use differed by child age, race and ethnicity, and recent preventive care, building upon prior concerns about differences in access to telemedicine. However, increased practice-level use of telemedicine services was not associated with reduced or increased differences in use, suggesting that further work is needed to promote equitable access to primary care telemedicine.

The use of genetic testing to identify individuals with hereditary cancer syndromes has been widely adopted by clinicians for management of inherited cancer risk. The objective of this study was to develop and validate a 34-gene inherited cancer predisposition panel using targeted capture-based next-generation sequencing (NGS). The panel incorporates genes underlying well-characterized cancer syndromes, such as BRCA1 and BRCA2 (BRCA1/2), along with more recently discovered genes associated with increased cancer risk. We performed a validation study on 133 unique specimens, including 33 with known variant status; known variants included single nucleotide variants (SNVs) and small insertions and deletions (Indels), as well as copy-number variants (CNVs). The analytical validation study achieved 100% sensitivity and specificity for SNVs and small Indels, with 100% sensitivity and 98.0% specificity for CNVs using in-house developed CNV flagging algorithm. We employed a microarray comparative genomic hybridization (aCGH) method for all specimens that the algorithm flags as CNV-positive for confirmation. In combination with aCGH confirmation, CNV detection specificity improved to 100%. We additionally report results of the first 500 consecutive specimens submitted for clinical testing with the 34-gene panel, identifying 53 deleterious variants in 13 genes in 49 individuals. Half of the detected pathogenic/likely pathogenic variants were found in BRCA1 (23%), BRCA2 (23%), or the Lynch syndrome-associated genes PMS2 (4%) and MLH1 (2%). The other half were detected in 9 other genes: MUTYH (17%), CHEK2 (15%), ATM (4%), PALB2 (4%), BARD1 (2%), CDH1 (2%), CDKN2A (2%), RAD51C (2%), and RET (2%). Our validation studies and initial clinical data demonstrate that a 34-gene inherited cancer predisposition panel can provide clinically significant information for cancer risk assessment.

OBJECTIVES: Incomplete subspecialty referrals, whether unscheduled or unattended, represent unmet patient needs and an opportunity to improve patient safety and experiences. Our objectives were to describe the rates of appointment scheduling and visit attendance after pediatric subspecialty referral and to examine patient and systems factors associated with scheduled referrals and attended appointments. METHODS: We conducted a retrospective review of referrals within a network of 52 primary and urgent care sites from November 2016 to October 2017. We included referrals for children ≤17 years old referred to medical or surgical subspecialists. We examined patient and health systems factors associated with (1) appointment scheduling and (2) visit attendance. RESULTS: Of 20 466 referrals, 13 261 (65%) resulted in an appointment scheduled within 90 days and 10 514 (51%) resulted in a visit attended within 90 days. In adjusted analyses, referral to surgical subspecialists was associated with an increased likelihood of appointment scheduling but a decreased likelihood of visit attendance. Compared with appointments scheduled within 7 days, appointments with intervals from referral to scheduled appointment exceeding 7 days were associated with decreasing likelihood of visit attendance (adjusted odds ratio 8–14 days 0.48; 95% confidence interval 0.37–0.61). Patient factors associated with decreased likelihood of both appointment scheduling and visit attendance included African American race, public insurance, and lower zip code median income. CONCLUSIONS: Patient and system factors were associated with variation in appointment scheduling and visit attendance. Decreased interval to appointment was significantly associated with visit attendance. These factors represent targets for interventions to improve referral completion.

Complete atrioventricular block (CAVB) is a life-threatening arrhythmia. A small animal model of chronic CAVB that properly reflects clinical indices of bradycardia would accelerate the understanding of disease progression and pathophysiology, and the development of therapeutic strategies. We sought to develop a surgical model of CAVB in adult rats, which could recapitulate structural remodeling and arrhythmogenicity expected in chronic CAVB. Upon right thoracotomy, we delivered electrosurgical energy subepicardially via a thin needle into the atrioventricular node (AVN) region of adult rats to create complete AV block. The chronic CAVB animals developed dilated and hypertrophied ventricles with preserved systolic functions due to compensatory hemodynamic remodeling. Ventricular tachyarrhythmias, which are difficult to induce in the healthy rodent heart, could be induced upon programmed electrical stimulation in chronic CAVB rats and worsened when combined with β-adrenergic stimulation. Focal somatic gene transfer of TBX18 to the left ventricular apex in the CAVB rats resulted in ectopic ventricular beats within days, achieving a de novo ventricular rate faster than the slow atrioventricular (AV) junctional escape rhythm observed in control CAVB animals. The model offers new opportunities to test therapeutic approaches to treat chronic and severe CAVB which have previously only been testable in large animal models.

Background Telehealth, the delivery of health care through telecommunication technology, has potential to address multiple health system concerns. Despite this potential, only 15% of pediatric primary care clinicians reported using telemedicine as of 2016, with the majority identifying inadequate payment for these services as the largest barrier to their adoption. The COVID-19 pandemic led to rapid changes in payment and regulations surrounding telehealth, enabling its integration into primary care pediatrics. Objective Due to limited use of telemedicine in primary care pediatrics prior to the COVID-19 pandemic, much is unknown about the role of telemedicine in pediatric primary care. To address this gap in knowledge, we examined the association between practice-level telemedicine use within a large pediatric primary care network and practice characteristics, telemedicine visit diagnoses, in-person visit volumes, child-level variations in telemedicine use, and clinician attitudes toward telemedicine. Methods We analyzed electronic health record data from 45 primary care practices and administered a clinician survey to practice clinicians. Practices were stratified into tertiles based on rates of telemedicine use (low, intermediate, high) per 1000 patients per week during a two-week period (April 19 to May 2, 2020). By practice tertile, we compared (1) practice characteristics, (2) telemedicine visit diagnoses, (3) rates of in-person visits to the office, urgent care, and the emergency department, (4) child-level variation in telemedicine use, and (5) clinician attitudes toward telemedicine across these practices. Results Across pediatric primary care practices, telemedicine visit rates ranged from 5 to 23 telemedicine visits per 1000 patients per week. Across all tertiles, the most frequent telemedicine visit diagnoses were mental health (28%-36% of visits) and dermatologic (15%-28%). Compared to low telemedicine use practices, high telemedicine use practices had fewer in-person office visits (10 vs 16 visits per 1000 patients per week, P=.005) but more total encounters overall (in-office and telemedicine: 28 vs 22 visits per 1000 patients per week, P=.006). Telemedicine use varied with child age, race and ethnicity, and recent preventive care; however, no significant interactions existed between these characteristics and practice-level telemedicine use. Finally, clinician attitudes regarding the usability and impact of telemedicine did not vary significantly across tertiles. Conclusions Across a network of pediatric practices, we identified significant practice-level variation in telemedicine use, with increased use associated with more varied telemedicine diagnoses, fewer in-person office visits, and increased overall primary care encounter volume. Thus, in the context of the pandemic, when underutilization of primary care was prevalent, higher practice-level telemedicine use supported pediatric primary care encounter volume closer to usual rates. Child-level telemedicine use differed by child age, race and ethnicity, and recent preventive care, building upon prior concerns about differences in access to telemedicine. However, increased practice-level use of telemedicine services was not associated with reduced or increased differences in use, suggesting that further work is needed to promote equitable access to primary care telemedicine.

Experimental testing of orthopaedic implants requires simplifications concerning load application and activities being analyzed. This computational study investigated how these simplifications affect micromotions at the bone-implant interface of an uncemented femoral knee implant. As a basis, validated in vivo loads of the stance phase of gait and a deep knee bend were adopted. Eventually, three configurations were considered: (i) simulation of the complete loading cycle; (ii) inclusion of only tibiofemoral loads (ignoring patellofemoral loads); and (iii) applying only a single peak tibiofemoral force. For all loading conditions the largest micromotions found at the proximal anterior flange. Without the patellofemoral force, peak micromotions increased 6% and 22% for gait and deep knee bend, respectively. By applying a single peak tibiofemoral force micromotions were overestimated. However, the peak micromotions corresponded to the maximum tibiofemoral force, and strong micromotion correlations were found between a complete loading cycle and a single peak load (R2 = 0.73 and R2 = 0.89 for gait and deep knee bend, respectively). Deep knee bend resulted in larger micromotions than gait. Our study suggests that a simplified peak force can be used to assess the stability of cementless femoral components. For more robust testing, implants should be subjected to different loading modes.

Periprosthetic bone loss is an important factor in tibial implant failure mechanisms in total knee arthroplasty (TKA). The purpose of this study was to determine the effect of postoperative knee alignment and population variation on tibial bone remodeling, to assess long-term stability of a knee replacement. Strain-adaptive finite element (FE) remodeling simulations were conducted following kinematic and mechanical alignment of a cemented fixed-bearing implant after TKA; kinematic TKA alignment was assumed to be more consistent with the preoperative varus alignment, while mechanical alignment was defined according to the neutral mechanical axes. To account for the effect of tibial variation on the outcome, bone remodeling was considered over a population of 47 subjects. Bone mineral density (BMD) was analyzed over three regions of interest (ROIs); medial, lateral and distal. The two proximal ROIs showed an average decrease in BMD in both alignments after two years. Greater overall proximal bone loss was found in the mechanical postoperative knees in comparison with kinematically aligned implants. Bone resorption was also concentrated more medially in mechanical alignment: increased medial ROI bone loss was found in every subject compared to kinematic alignment; while in the lateral ROI, higher regional two-year BMD was found in 39 of the 47 cases (82.9%) following mechanical alignment. Two distinct remodeling pathways were identified over both alignments, based on the variance in density change over the population; displaying predominant bone apposition either around the distal tip of the keel or at the lateral cortex. This study demonstrates that correction of native varus alignment to neutral mechanical alignment leads to an increase in medial bone resorption. Large variation between specimens illustrates the benefit of population-based FE analyses over single model studies.

Retinoic acid plays a pivotal role during the heart development. The mammalian heart is formed from cardiac progenitors in the first and second heart fields (FHF and SHF). FHF progenitors populate the left ventricle and the atria; SHF progenitors populate the right ventricle, outflow tract and parts of the atria. Loss of retinoic acid signaling leads to depletion of FHF progenitors and compensatory increase in SHF progenitors. Here we hypothesized that mimicking the in vivo retinoic acid signaling during human pluripotent stem cell differentiation could lead to FHF cardiomyocytes.Human pluripotent stem cells were differentiated to cardiac lineage by treatment with Activin A, BMP4 and bFGF (control) for the first three days (d0-3). This lead to >70% Brachyury+ mesodermal cells, and >90% of Brachyury+ cells became cTnT+ cardiac myocytes. Retinoic acid signaling activated with exogenous RA (1μM) from d5-8 (RA protocol). This RA protocol was compared to another protocol in which d5-8 retinoic acid activation was followed by initial inhibition with a pan-retinoic acid (RiRA protocol). At d14, both RA and RiRA cardiomyocytes expressed higher transcript and protein levels of the FHF markers, NKX2.5, TBX5and HCN4, but lower levels of the SHF markers, ISL1, MEF2c, FGF8/10, compared to control. RiRA cardiomyocytes showed highest expression of ventricular markers, IRX4 and HRT2 , lowest expression of an atrial specific marker CoupTFII, which were mirrored in RA cardiomyocytes. In line with their atrial/ventricular-specific gene expression profile, RA cardiomyocytes demonstrated higher beating rates, higher maximum shortening velocity, faster conduction velocity, higher atrial specific ANP secretion and higher sensitivity to atrial-selective sodium blocker, ranolazine compared to control. In contrast, RiRA cardiomyocytes generated higher force but shorter action potential duration compared to control.Taken together, the data demonstrate temporal regulation of retinoic acid signaling can not only accurately recapitulate ventricular to atrial cardiomyocyte differentiation by delineating FHF vs. SHF lineages.

The spontaneous formation of coacervate microdroplet-laden photo-crosslinked hydrogels derived from the simple mixing of oxidized, methacrylated alginate (OMA) and methacrylated gelatin (GelMA) enables simultaneous creation of drug-laden microdroplets and encapsulation of stem cells in photopolymerized coacervate hydrogels under physiological conditions. This can be utilized as a novel platform for in situ formation of localized, sustained bioactive molecule delivery to encapsulate stem cells for therapeutic applications.

Item does not contain fulltext To achieve long-lasting fixation of cementless implants, an adequate primary stability is required. We aimed to compare primary stability of a new cementless femoral knee component (Attune(R)) against a conventional implant (LCS(R)) under different loading conditions. Six pairs of femora were prepared following the normal surgical procedure. Calibrated CT-scans and 3D-optical scans of the bones were obtained to measure bone mineral density (BMD) and cut accuracy, respectively. Micromotions were measured in nine regions of interest at the bone-implant interface using digital image correlation. The reconstructions were subjected to the implant-specific's peak tibiofemoral load of gait and a deep knee bend loading profiles. Afterwards, the implants were pushed-off at a flexion angle of 150 degrees . Micromotions of Attune were significantly lower than LCS under both loading conditions (P

e18526 Background: Molecular profiling can help diagnose, classify, and guide treatment of myeloid neoplasms. Next generation sequencing (NGS) is a powerful platform that can facilitate identification of actionable genetic alterations in multiple genes simultaneously. To serve clinical management needs, we developed and validated a NGS panel for 47 genes associated with diagnostic, prognostic, and/or therapeutic utilities for each of the subclasses of myeloid neoplasms: acute myeloid leukemia (AML, 42 genes), myelodysplastic syndrome (MDS, 36 genes), and myeloproliferative neoplasms (MPN, 26 genes). Methods: A total of 154 unique de-identified specimens were analyzed. Intra- and inter-assay precision studies were performed by standard laboratory practice. Single nucleotide variations (SNVs), insertions/deletions (indels), and FLT3 partial tandem duplications (PTD) were assessed for the entire coding regions of 23 genes and targeted exons of 24 genes. Target regions were captured by hybridization with complementary biotinylated DNA baits, and NGS was performed on an Illumina NextSeq500 instrument. Sequence reads obtained were analyzed using a bioinformatics pipeline that was developed in-house. At least 500 unique reads with base quality (Q) ≥20 (99% confidence) were required for coverage QC, except targets on X chromosome for male specimens, which required 250 unique reads. Results: On average, each sample generated 13.2 million reads, 100% (SD = 0.2%) mapped reads to the reference sequence, 61.7% (SD = 8.8%) on-target reads, and 1,952 (SD = 873) mean coverage. Data using ≥Q20 unique coverage of all target regions across all validation samples demonstrated that all target regions, even in the extreme end of GC spectrum (range: 12%-87%), met coverage requirements. Intra- and inter-assay precision studies, using 7 and 21 specimens, respectively, resulted in 100% concordance among replicates. An accuracy study of 131 unique specimens (a subset of the 154 specimens) yielded in 99.6% (755/758, 95% CI: 99.4%-100%) concordance for variants with allele frequencies ≥5% in comparison to other molecular methods including Sanger sequencing. No reportable variants were detected from any normal specimens (n = 17). Conclusions: We developed and validated a NGS panel for 47 genes with diagnostic, prognostic, and/or therapeutic utilities for each of the subclasses of myeloid neoplasms: AML (42 genes), MDS (36 genes), and MPN (26 genes). This panel will allow simultaneous analysis of the 47 genes with high sensitivity and specificity and may help manage clinical needs.

Recent data indicates that DJ-1 plays a role in the cellular response to stress. Here, we aimed to examine the underlying molecular mechanisms mediating the actions of DJ-1 in the heart following myocardial ischemia-reperfusion (I/R) injury. In response to I/R injury, DJ-1 KO mice displayed increased areas of infarction and worsened left ventricular function when compared to WT mice, confirming a protective role for DJ-1 in the heart. In an effort to evaluate the potential mechanism(s) responsible for the increased injury in DJ-1 KO mice, we focused on SUMOylation, a post-translational modification process that regulates various aspects of protein function. DJ-1 KO hearts after I/R injury were found to display enhanced accumulation of SUMO-1 modified proteins and reduced SUMO-2/3 modified proteins. Further analysis, revealed that the protein expression of the de-SUMOylation enzyme SENP1 was reduced, whereas the expression of SENP5 was enhanced in DJ-1 KO hearts after I/R injury. Finally, DJ-1 KO hearts were found to display enhanced SUMO-1 modification of dynamin-related protein 1, excessive mitochondrial fission, and dysfunctional mitochondria. Our data demonstrates that the activation of DJ-1 in response to myocardial I/R injury protects the heart by regulating the SUMOylation status of Drp1 and attenuating excessive mitochondrial fission.

Three-dimensional (3D) multicellular spheroids of human adipose tissue-derived stem cells (hASCs) are an attractive system for basic science studies and tissue engineering applications, as they can resemble cellular condensations present in developmental and healing processes. The purpose of this study was to engineer a hydrogel-based microwell platform by capitalizing on the differential swelling behavior of micropatterned dual-crosslinked oxidized, methacrylated alginate (OMA)/multi-arm polyethylene glycol (PEG) hydrogels for rapid formation of uniform multicellular hASC spheroids with controllable size and evaluation of the capacity of the system to be used to drive osteogenic differentiation of the spheroids. By changing the micropattern size, the size of the hydrogel microwells was easily controllable. Microwell-seeded hASCs generated spheroids of relatively uniform size and high cell viability. hASC spheroids exhibited rapid mineralization in osteogenic media, which was faster than that of conventional two-dimensionally cultured hASCs. This new hydrogel microwell system has great potential for controlled multicellular spheroid formation and defined signal presentation from the hydrogel material to the cell aggregates to regulate tissue formation.

Several targeted therapies have been approved for treatment of solid tumors. Identification of gene mutations that indicate response to these therapies is rapidly progressing. A 34-gene next-generation sequencing (NGS) panel, developed and validated by us, was evaluated to detect additional mutations in community-based cancer specimens initially sent to our reference laboratory for routine molecular testing. Consecutive de-identified clinical specimens (n = 121) from melanoma cases (n = 31), lung cancer cases (n = 27), colorectal cancer cases (n = 33), and breast cancer cases (n = 30) were profiled by NGS, and the results were compared with routine molecular testing. Upon initial mutation testing, 20 % (24/121) were positive. NGS detected ≥1 additional mutation not identified by routine testing in 74 % of specimens (90/121). Of the specimens with additional mutations, 16 harbored mutations in National Comprehensive Cancer Network guideline genes. These various additional mutations were in gene regions not routinely covered, in genes not routinely tested, and/or present at low allele frequencies. Moreover, NGS yielded no false negatives. Overall, NGS detected mutations in 59 % of the genes (20/34) included in the panel, 75 % of which (15/20) were detected in multiple tumor types. Mutations in TP53 were found in 51 % of tumors tested (62/121). Mutations in at least one other (non-TP53) gene present in the panel were detected in 64 % of cases (77/121). This assay provides improved breadth and sensitivity for profiling clinically relevant genes in these prevalent solid tumor types.

62-year-old female presented to the ambulatory clinic with progressive shortness of breath over the course of approximately 1 year. She denied cough, fever, chills, chest pain, hemoptysis, or orthopnea. Approximately 1 year before presentation, she was admitted to the hospital for abdominal pain, distention, and early satiety. At that time she was diagnosed with chronic idiopathic myelofi brosis after bone marrow biopsy. She responded well on hydroxyurea and eventually discharged home. She also denied any occupational or environmental exposures prior to presentation.

Papillary thyroid carcinoma with metastasis to the frontal skull is extremely rare. We report a case of unsuspected papillary thyroid carcinoma with frontal skull metastasis. The patient was a 62-year-old African American woman with presentation of a 4-cm firm, painless, immobile, ill-defined mass at the right forehead. Ultrasound and computer tonography detected a hypervascular and osteolytic tumor involving the skull and overlying skin. Fine-needle aspiration was performed followed by surgical biopsy. Cytologic examination revealed the presence of hypercellular and bloody material. The neoplasm showed glandular features and was composed of clusters of round to oval cells with pinkish squamoid cytoplasm, oval nuclei and inconspicuous nucleoli on smears and sections of cell block. With immunocytochemical stain, the neoplastic cells were positive for pancytokeratin and vimentin and focally positive for EMA, while they were negative for S100, HMB45, Melan-A, CD34, GFAP, CD10, LCA, RCC and CD138. The diagnosis was a metastatic carcinoma. Clinical follow up with surgical biopsy was recommended. Surgical biopsy demonstrated histological and cytological features of papillary thyroid carcinoma including prominent papillae, nuclear overlapping, grooves, and intranuclear pseudoinclusions. Thus, a diagnosis of metastatic papillary thyroid carcinoma was rendered. Though skull metastasis of thyroid carcinoma is rare, it should be considered in the differential diagnosis when a skull mass lesion is encountered. Diagn. Cytopathol. 2009. © 2009 Wiley-Liss, Inc.

Experimental testing of orthopaedic implants requires simplifications concerning load application and activities being analyzed. This computational study investigated how these simplifications affect micromotions at the bone-implant interface of an uncemented femoral knee implant. As a basis, validated in vivo loads of the stance phase of gait and a deep knee bend were adopted. Eventually, three configurations were considered: (i) simulation of the complete loading cycle; (ii) inclusion of only tibiofemoral loads (ignoring patellofemoral loads); and (iii) applying only a single peak tibiofemoral force. For all loading conditions the largest micromotions found at the proximal anterior flange. Without the patellofemoral force, peak micromotions increased 6% and 22% for gait and deep knee bend, respectively. By applying a single peak tibiofemoral force micromotions were overestimated. However, the peak micromotions corresponded to the maximum tibiofemoral force, and strong micromotion correlations were found between a complete loading cycle and a single peak load (R(2) = 0.73 and R(2) = 0.89 for gait and deep knee bend, respectively). Deep knee bend resulted in larger micromotions than gait. Our study suggests that a simplified peak force can be used to assess the stability of cementless femoral components. For more robust testing, implants should be subjected to different loading modes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:812-819, 2016.

Molecular profiling of tumor mutations has expedited molecular targeted therapy for cancer patients. Additionally, tumor mutation load and DNA microsatellite instability (MSI) status can help predict patient’s response to immunotherapy. We analytically validated a gene test targeting clinically actionable cancer mutations of all 4 major types: single nucleotide variations (SNVs); insertion/deletions (INDELs); whole gene copy number variations (CNVs); and structural rearrangements (translocations) as well as the MSI status. This test interrogates all coding exons from 49 core cancer genes, introns for a subset of genes selected for detection of prevalent gene rearrangements, and the TERT (telomerase reverse transcriptase) promoter region. MSI status is determined from a set of 5 intronic mono-nucleotide repeats collectively associated with microsatellite instability. Targeted DNA regions are captured by in-solution hybridization with complementary biotinylated RNA baits and sequenced on the Illumina NextSeq®500 platform. Paired formalin-fixed, paraffin-embedded (FFPE) tumor samples and whole blood samples are analyzed simultaneously for the detection of SNV, INDEL, CNV, translocation and MSI status. FFPE samples can also be analyzed alone if the whole blood sample is not available, eliminating the reporting of MSI status. A minimum of 50 ng FFPE DNA and 100 ng of whole blood DNA are required for this test. A total of 123 FFPE, 2 FFPE FNA samples, 19 paired FFPE and whole blood paired samples covering lung cancer, colorectal cancer, melanoma and breast cancer were included in this validation study. Analytical validation of assay performance demonstrated that, on average, 700-fold read depth was achieved across all targeted regions with >95% of these regions covered by a minimum of 300 unique reads. Analytical sensitivity was ≥5% mutation frequency for SNV and INDEL and ≥20% for translocation and CNV. Thirty-eight unique variants were confirmed between this test and orthogonal methodologies: 22 SNVs, 6 INDELs, 5 translocations, and 5 CNV. Fifty-eight out of 59 (98% concordance) paired FFPE/blood samples achieved the same MSI status result with this targeted sequencing approach compared to the reference National Comprehensive Cancer Network (NCCN) Bethesda PCR test. MSI-positive samples, on average, were determined to have 5-fold higher mutation count compared to MSI-negative samples, consistent with the previously reported higher mutation burden. In conclusion, we have developed and analytically validated a core cancer gene test employing NGS technology with demonstrated high analytical sensitivity and specificity. Coupled with clinical interpretation, this test will facilitate clinical decision-making for molecular targeted therapy and immunotherapy. Citation Format: Lin Ma, Michael Hua, Steven Rivera, Anna Gerasimova, Quoclinh Nguyen, Sirisha Sunkara, Robert Lagier, Alla Smolgovsky, David Wolfson, Jared F. Taylor, Frederick Racke, Charles Strom, Andrew Grupe, Joseph Catanese, Feras Hantash. Validation of a clinically actionable cancer core gene test for solid tumors facilitating targeted molecular therapy and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5356. doi:10.1158/1538-7445.AM2017-5356

We evaluated performance characteristics of a laboratory-developed, non-invasive prenatal screening (NIPS) assay for fetal aneuploidies. This assay employs massively parallel shotgun sequencing with full automation. GC sequencing bias correction and statistical smoothing were performed to enhance discrimination of affected and unaffected pregnancies. Maternal plasma samples from pregnancies with known aneuploidy status were used for assay development, verification, and validation. Assay verification studies using 2,085 known samples (1873 unaffected, 69 trisomy 21, 20 trisomy 18, 17 trisomy 13) demonstrated complete discrimination between autosomal trisomy (Z scores >8) and unaffected (Z scores

The aim of this study was to investigate the accuracy of imprint cytology (IC) of breast core biopsy under ultrasound guidance and to assess the value of a rapid on-site preliminary diagnosis of breast lesions. A total of 437 breast core needle biopsies under ultrasound guidance with touch imprint cytology, histology, and final diagnosis were reviewed. These cases were collected from archived files at our institution. Of 437 core biopsies, IC classified 241 (55%) as benign; 22 (5%) as probably benign; 28 (6%) as probably malignant; 107 (25%) as malignant; and 39 (9%) as inadequate for IC diagnosis. Histological classifications for the 437 cases were: 285 (65%) benign; 132 (30%) malignant; 16 (4%) atypical hyperplasia; and 4 (1%) inadequate specimen. The overall sensitivity and specificity indices of IC were 95% and 96%, respectively, for benign and probably benign lesions vs malignant and probably malignant breast lesions. The overall positive and negative predictive values were 91% and 97%, respectively. The overall accuracy was 95% (379 of 398 cases, excluding specimens inadequate for IC diagnosis). IC of ultrasound-guided core needle biopsy provides a rapid and reliable preliminary diagnosis for breast lesions; it also serves as a means to verify the adequacy of biopsy specimens and to optimize the biopsy procedure. Use of IC may reduce anxiety in patients with benign lesions and expedite the diagnosis and assessment of treatment options in patients with breast cancer.

✓There is a well-recognized association between dysontogenetic tumors of the spinal cord (including teratomas and enterogenous cysts) and dysraphic congenital spinal malformations. The authors present a case of an adult with an intramedullary mature teratoma (IMMT) at the level of C1–2 of the cord associated with dysraphic congenital spinal malformations. Intramedullary mature teratomas of the cervical region of the spinal cord are very rare in adults; only four such lesions have been reported, two of which involved upper cervical segments. Despite the potentially critical location of the tumor, monitored microsurgery resulted in complete removal of the tumor with an intact surrounding capsule, associated fibrous tract, and ellipse of skin with a central dimple. There was an excellent postoperative neurological outcome. The clinical features, imaging studies, treatment options, postoperative outcome, and plausible pathological correlations of IMMTs are discussed.

An experimental and theoretical investigation of the regenerative capabilities of electrooptic (E/O) and all-optical (A/O) interferometric wavelength converters is presented. We show that both the E/O and A/O regeneration scheme exhibit a 5-dB noise suppression capability. Furthermore, we demonstrate that by cascading two A/O-converters after an erbium-doped fiber amplifier (EDFA), the performance is further improved resulting in a total noise suppression of 8 dB. Our detailed model, which accounts for the redistribution of a signal in the converters, shows good agreement with the experiments and predicts a significant increase in the number of EDFAs that can be cascaded with interferometric wavelength converters in the link.

A detailed theoretical investigation of the input power dynamic range for gain-clamped semiconductor optical amplifier (GC-SOA) gates at 10 Gb/s is presented. We show that although the gain is clamped, the dynamic changes of the carrier distribution in the GC-SOA causes pattern effects on a time scale given by the relaxation frequency of the GC-SOA. Combined with a higher noise figure compared to a conventional SOA, this results in a dynamic range only /spl sim/0.5 dB better than for an optimized SOA gate.

In this paper, we describe a monolithically integrated tunable optical packet forwarding chip in InP. The chip consists of a differential Mach-Zehnder Interferometer SOA tunable 40 Gbps wavelength converter integrated with an electro-refractive modulator for 10 Gbps label modulation. Error free performance and dynamic forwarding of asynchronous variable length packets is reported.