Longitudinal effects of affective distress on disease outcomes in rheumatoid arthritis: a meta-analysis and systematic review.

Patients with rheumatoid arthritis have higher rates of mental health conditions compared to the general population. It is believed that affective distress and rheumatoid arthritis have a bi-directional relationship. This review will examine the associations between affective distress and rheumatoid arthritis outcomes over time. Several disease outcomes are included covering disease activity, function, and disability to provide a broad picture of the various ways patients are impacted. A quality assessment was also conducted. There were 71 studies included in the review. Three measures (disease activity, disability, and mortality) had enough data to complete meta-analyses of odds ratios or hazard ratios. The outcomes included were disease activity, tender joint count, swollen joints, pain, physician global assessment, patient global assessment, physical disability, acute phase reactants, stiffness, fatigue, work disability, and mortality. Numerous measures were included for most of the outcomes due to the variability across studies of measures used. Patients with affective distress had lower rates of remission according to the DAS-28, greater disability, and higher mortality. All of the outcomes covered had studies with mixed results, but swollen joint count, tender joint count, patient global assessment, and physician global assessment had the strongest evidence that they were associated with mental health longitudinally. The relationships between affective distress and disease outcomes are complex and vary depending on the measures. Overall, the effects fade over time. It is important for clinicians to be aware of the differing manifestations of the relationship between affective distress and rheumatoid arthritis outcomes.

Discovery of Conformationally Constrained ALK2 Inhibitors.

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG.

Ongoing shielding behavior one year post COVID-19: results from a longitudinal study of patients with inflammatory arthritis.

Many patients with inflammatory arthritis (IA) were instructed to shield during the COVID-19 pandemic. Despite the ending of lockdowns and vaccination, large proportions of IA patients were continuing to shield when it is no longer needed. Given the detrimental effects of shielding on mental and physical health, understanding the rates and reasons for shielding is needed to help clinicians advise patients accordingly. This study was a 12-month prospective study following participants with IA during the COVID-19 pandemic. The proportions of IA patients shielding at each time point were calculated. Additionally, regressions and odds ratios for shielding were determined to assess medication type, mental health, and risk perception. While the extent of shielding fluctuated over the year of lockdowns, nearly all IA patients (93.5%) were still engaging in some shielding in 2021, with nearly half (43%) still shielding most or all of the time. Medications that were previously considered higher risk were not significantly associated with higher rates of shielding (OR = 1.60, p = 0.29), but greater symptoms of depression in June 2020 (OR = 1.07, p = 0.03) was both associated with increased the odds of shielding in June 2021. The high rates of IA patients continuing to shield in 2021 put more strain on patients and professionals as social isolation is linked with worsening mental and physical health, as well as greater difficulty with self-management. It is important for clinicians to be aware of this trend to ease the stress on patients.

Mental health, quality of life and self-management behaviours: online evaluation of inflammatory arthritis patients over 1 year of COVID-19 lockdowns.

Objective: Patients with inflammatory arthritis were especially vulnerable to the psychosocial and health impacts of coronavirus disease 2019 (COVID-19) and the lockdowns. This study investigated the impact of these changes on mental health, physical health and quality of life for inflammatory arthritis patients over 1 year following the initial lockdown in the UK. Methods: Three hundred and thirty-eight participants with inflammatory arthritis completed an ambidirectional study consisting of online questionnaires at four time points for 1 year. The questionnaires assessed demographic information, inflammatory arthritis condition, mental health, physical symptoms, self-management behaviours, COVID-19 status and impacts. Means, linear regressions and structural equation modelling for mediations were conducted over 12 months. Results: Physical health concerns peaked during June 2020, then declined, but did not return to baseline. Depression was associated with worse quality of life at baseline, as shown by the beta coefficient, (ß= 0.94, P < 0.01), September (ß = 0.92, P < 0.01), November (ß= 0.77, P < 0.01) and 1 year (ß = 0.77, P < 0.01). Likewise, anxiety was associated with worse quality of life at baseline (ß = 1.92, P < 0.01), September (ß = 2.06, P < 0.01), November (ß = 1.66, P = 0.03) and 1 year (ß = 1.51, P = 0.02). The association between depression and quality of life was mediated by physical activity (ß= 0.13, P < 0.01) at baseline. The association between anxiety and quality of life was also mediated by physical activity (ß = 0.25, P = 0.04) at baseline. Conclusion: Physical health continued to be worse 1 year later compared with before the COVID-19 lockdowns in patients with inflammatory arthritis. Mental health showed long-term effects on quality of life, with an impact for ≥12 months. Lastly, physical activity mediated between mental health and quality of life in the short term.

The impact of consecutive COVID-19 lockdowns in England on mental wellbeing in people with inflammatory arthritis.

BACKGROUND: During the first UK COVID-19 lockdown, studies identified over half of inflammatory arthritis (IA) patients in the UK reported a worsening of emotional distress. Given the prolonged nature of the pandemic, and the strict 'shielding' restrictions imposed on 'extremely clinically vulnerable' populations, it is likely that the implementation of the second lockdown period in England, during November 2020, may also have had a negative impact on the mental health of IA patients. The aim of this study was to qualitatively explore the impact of consecutive lockdown periods on mental wellbeing in people with IA. METHODS: Nine IA patients took part in semi-structured telephone interviews at both baseline (June/July 2020) and follow-up (November 2020). The interview schedule, which was developed and piloted with a Patient Research Partner, explored patient experiences and mental health impacts of the COVID-19 lockdown periods. Interviews were analysed using inductive thematic analysis. RESULTS: Five males and four females, with rheumatoid arthritis, psoriatic arthritis, or spondylarthritis, aged between 24-79 years (mean = 49.9, SD = 20.9) were included in the sample. Four main themes impacting on mental wellbeing were identified from the data: (1) Pandemic fatigue versus pandemic acclimatisation, (2) Social interaction and isolation, (3) Clarity of information, (4) Seasonal changes. CONCLUSION: The first two COVID-19 lockdown periods in England had an ongoing impact on the mental health of patients with IA. Healthcare professionals, in conjunction with government support, should ensure that adequate information and mental health resources are available to support IA patients during periods of ongoing restrictions, whilst also continuing to encourage behaviours which promote good mental health and wellbeing.

The impact of COVID-19 on clinical care, self-management and mental health of patients with inflammatory arthritis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) lockdown and ongoing restrictions in the UK affected access to clinical care, self-management and mental health for many patients with inflammatory arthritis. The aim of this study was to determine the impact of lockdown on inflammatory arthritis clinical care, self-management, disease outcomes and mental health. METHODS: In total, 338 people with inflammatory arthritis participated in a prospective study, completing a series of online questionnaires. The questionnaires assessed demographics, inflammatory arthritis condition and management, clinical care, quality of life and mental health. Visual analogue scales (VASs) were completed at each assessment. Linear regression, controlling for confounders, was conducted to determine factors associated with physical and mental health outcomes. RESULTS: More than half of participants reported worsening VAS by >10 points for patient global assessment (PGA), pain, fatigue and emotional distress during the initial lockdown. Changes in clinical care were associated with worse PGA (b = 8.95, P = 0.01), pain (b = 7.13, P = 0.05), fatigue (b = 17.01, P < 0.01) and emotional distress (b = 12.78, P < 0.01). Emotional distress and depression were also associated with worse outcomes in PGA, pain and fatigue, whereas loneliness was not. In contrast, physical activity seemed to mitigate these effects. Loneliness did not show any associations with outcomes. Over time, these effects decreased or disappeared. CONCLUSION: Changes to clinical care owing to lockdown were associated with worse disease outcomes in patients with inflammatory arthritis. There has also been a clear impact on mental health, with possibly complex relationships between mental health and psychosocial factors. Physical activity emerged as a key influence on disease outcomes and mental health.

Intraoperative Cytology for Video-Assisted Thoracic Surgery: A Quality Improvement Analysis.

BACKGROUND: Frozen section is a standard of care procedure during thoracic surgery when an immediate diagnosis is needed. An alternative procedure is intraoperative cytology. Video-assisted thoracic surgery is currently widely used for thoracic surgical procedures. The aim of this study was to assess intraoperative cytology together with frozen section for accuracy, turnaround time, and total response time during video-assisted thoracic surgery. METHODS: We included patients having video-assisted thoracic surgery between August 2018 and February 2019 at our institution. A cytopathologist and a surgical pathologist independently performed intraoperative cytology and frozen sections, respectively. Final histologic diagnosis was the reference standard. Intraoperative cytology, frozen section turnaround, and total response times were analyzed. RESULTS: A total of 52 specimens from 27 patients were included. The intraoperative cytology correlated with final histology in 98% of cases. Frozen section correlated with final histology in 100% of cases. Intraoperative cytology turnaround and total response times were equal (mean, 4.35 minutes; range, 2-15 minutes). Mean frozen section turnaround and response times were 26.2 minutes (range, 9-61 minutes) and 36.7 minutes (range, 16-90 minutes), respectively. We found a statistically significant difference between intraoperative cytology and frozen section turnaround time and total response times (P < .001). CONCLUSIONS: This study highlights that intraoperative cytology could be as accurate as frozen section and considerably faster during video-assisted thoracic surgery (P < .001). Total response time could potentially be used as a quality metric for video-assisted thoracic surgery.

The impact of COVID-19 on self-management behaviours and healthcare access for people with inflammatory arthritis.

BACKGROUND: Inflammatory arthritis (IA) patients have been identified as at greater risk of severe illness from COVID-19. It is likely that lockdown restrictions (enforced by the UK government in response to the COVID-19 pandemic) and subsequent changes made to healthcare provision could impact patients' abilities to effectively manage their condition. The aim of this study was to qualitatively explore the impact of COVID-19 on self-management behaviours and healthcare access for people with IA. METHODS: Semi-structured interviews were conducted with 21 IA patients in June-July 2020, with nine follow-up interviews in November 2020. Interview schedules were developed with a Patient Research Partner and explored participants' experiences of the COVID-19 pandemic. Interviews were conducted via telephone and analysed using inductive thematic analysis. RESULTS: Participants were aged between 24 and 79 years (mean = 50.1, SD = 15.8), largely female (71%) and White British (86%). Four initial themes were identified: (1) Impact of COVID-19 on medication adherence, (2) Impact of COVID-19 on physical activity, (3) Impact of COVID-19 on diet, and (4) Impact of COVID-19 on healthcare access and delivery. Subthemes focused on positive and negative changes made to these areas, as well as behaviours which remained consistent. Follow-up interviews highlighted differences in participants' experiences during the two lockdown periods. CONCLUSION: COVID-19 has affected patients' abilities to manage their IA. Healthcare professionals need to recognise the ongoing impact of COVID-19 on patient self-management and healthcare access to ensure that adequate understanding and support is available to patients who may have inadequate disease control as a result.

Relationships Between Daily Device Use and Early Communication Outcomes in Young Children With Cochlear Implants.

OBJECTIVES: Children with significant hearing loss can gain access to sound via a cochlear implant (CI), but they must wear the device to reap the communication benefits of the device. That is, poor daily device use may result in underdeveloped perceptual and language skills in children and adolescents using CIs. This retrospective study focuses on the relationship between daily CI use and communication performance (auditory skills, speech recognition, expressive and receptive language) in young children, with the hypothesis that greater daily device use coincides with better communication outcomes. DESIGN: The authors conducted a clinical chart review of patients with CIs younger than 5 years old who used at least 1 CI speech processor with datalogging technology. Participants (n = 65) had a mean chronologic age of 3.5 years, mean implantation age of 1.9 years, and mean device experience of 1.6 years. Approximately one quarter of participants had additional disabilities. Daily device use (i.e., datalogging information), child characteristics (e.g., age at CI), and assessments of communication skills (i.e., parent questionnaires, speech recognition tests, standardized language assessments) were obtained from each child's records. The investigators performed correlational analyses to examine relationships between communication outcomes and daily device use, and they employed group comparisons and correlations to identify child characteristics that were significantly associated with daily device use (p < 0.05, corrections for family-wise error). RESULTS: Young children with CIs used their device, on average, 6.7 hr/d, with 63% below full-time use (<8 hr/d). Children without additional disabilities who wore their CI more hours per day had significantly better auditory, speech recognition, and language skills. A significant correlation also emerged between daily device use and early auditory skills in young CI users with additional disabilities, though relationships were more complicated for this subsample. Longer daily device use significantly correlated with younger age at CI and longer device experience. Differences in device use occurred in regards to absence versus presence of additional disabilities, bilateral versus unilateral device configuration, sign versus spoken language, and private versus government-assisted insurance. CONCLUSIONS: The strong relationship between daily device use and early communication suggests clinicians and parents should focus on increasing the number of hours per day young children wear their CIs to enhance auditory and language outcomes. However, intervention strategies must consider barriers to consistent device use and goals of the family to efficiently and effectively support families of young children with CIs who struggle with inconsistent device use.

Optimising rapid on-site evaluation-assisted endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes: The real-time cytopathology intervention process.

INTRODUCTION: Lymph node sampling by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the state of art procedure for staging the mediastinum and hilar regions in lung cancer patients. Our experience of implementing the real-time cytopathology intervention (RTCI) process for intraoperative EBUS-TBNAs is presented. This study is aimed to describe in detail the RTCI process for EBUS-TBNAs, and assess its utility and diagnostic yield before and after its implementation in parallel to conventional rapid on-site evaluation (c-ROSE). METHODS: A retrospective review of all EBUS-TBNAs between July 2016 and July 2017 at the University of Rochester Medical Center was performed. Final diagnoses, patient clinical data, and number of non-diagnostic samples (NDS) were reviewed. The numbers of NDS obtained from EBUS-TBNAs with no cytology assistance (NCA), with RTCI and with c-ROSE were analysed. RESULTS: Non-diagnostic lymph node samples were found in 20 out of 116 (17%), three out of 114 (2.6%) and 33 out of 286 (11.5%) cases with NCA, RTCI and c-ROSE, respectively. Application of statistical analysis revealed significant difference in the NDS between the groups of cases in the operating room with NCA and RTCI (P = .005). The different settings and variables between the cases performed using RTCI in the operating room and those assisted with c-ROSE in the bronchoscopy suite preclude legitimate comparison. CONCLUSION: Our results indicate that the use of RTCI could yield a significantly low proportion of NDS when assisting EBUS-TBNA of mediastinal and hilar lymph node for lung cancer patients enhancing the diagnostic efficiency of the procedure.

Urinary tract cytology: a cytologic-histopathologic correlation with The Paris System, an institutional study.

INTRODUCTION: Urothelial carcinoma (UC) requires lifelong monitoring, commonly through urinary cytology and cystoscopy. Urine cytology has a relatively high sensitivity for detecting high-grade urothelial carcinoma (HGUC); however, its sensitivity for low-grade urothelial neoplasm (LGUN) is significantly lower with wide interobserver variability. The Paris System (TPS) was proposed to create standardized diagnostic categories with defined cytomorphologic criteria. We attempt to evaluate diagnostic efficacy of identifying UC using TPS through cytologic-histologic correlation. MATERIALS AND METHODS: A retrospective search identified 170 cases of urine cytology cases with concurrent biopsies collected during a 2-year time period at University of Rochester Medical Center. Patient age, sex, smoking history, prior malignancy diagnoses, cystoscopy findings, specimen collection method, UroVysion results, and 1-year follow-up of surgical pathology cases were included. RESULTS: Cytologic-histologic correlation was identified in 59% of cases, with 18% true positives and 41% true negatives. Discordant results were identified in 41% of cases; of these, 4% were false positives, 11% false negatives, 12% potential sampling bias, and 14% were low-grade urothelial carcinoma (LGUC). The analysis of this 2-year study finds a positive predictive value of urine cytology for HGUC to be 81%, a negative predictive value of 79%, a sensitivity of 61%, a specificity of 91%, and an accuracy of 79%. CONCLUSIONS: Our results support TPS's ability to improve the reliability and accuracy of interpretations in urine cytology for HGUC. Nevertheless, additional studies are essential to improve the diagnostic accuracy of LGUN, and urine adequacy, in order to improve patient care and early detection, while identifying potential sampling bias.

Use of rheumatoid arthritis impact of disease (RAID) in routine care; identification of DAS28 remission and unmet patient-reported outcomes.

OBJECTIVE: The aim was to assess how the patient-reported outcome RA impact of disease (RAID) relates to DAS28 categories in routine care, its utility in identifying patients in DAS28 remission (RDAS) or low disease activity (LDAS) and the burden of unmet patient-reported needs in those achieving RDAS/LDAS. METHODS: DAS28 and RAID scores were collected from patients with established RA attending for routine review. The relationship between RAID and DAS28 was assessed with univariate pairwise correlation and mixed-effects linear regression analyses. RAID <2 was defined as a patient-acceptable state. RESULTS: One hundred and ninety-eight patients were assessed, with 220 observations, using DAS28-CRP categories: 47.5% RDAS, 14.1% LDAS, 31.8% moderate DAS (MDAS) and 6.6% high DAS (HDAS). Both patient visual analog scale score and tender joint count exhibited a high statistical association with RAID using linear regression (P < 0.0001). The mean RAID score per DAS28-CRP category was RDAS 1.84, LDAS 4.78, MDAS 5.60 and HDAS 7.68, with a statistically significant increase in RAID per unit increase in DAS-CRP or DAS28-ESR on linear regression (P < 0.001). Of 66 patients with RAID <2, 64 (97%) were in RDAS and 65 (98.5%) in RDAS/LDAS. Of 134 patients in RDAS/LDAS, RAID was ≥2 in 69 (51.5%), with fatigue and sleep being the worst-scoring domains. CONCLUSION: RAID functions well as a patient-reported outcome in routine care. Patients with RAID <2 have a high likelihood of being in RDAS/LDAS and, if pre-screened, could avoid a clinic visit. Analysis of RAID domains provides individualized targets for holistic care in RA management, with fatigue and sleep problems dominating unmet needs in those in RDAS/LDAS.

Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity.

DEAD-box helicase 3, X-linked (DDX3X) regulates the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated antiviral response, but can also be a host factor contributing to the replication of viruses of significance to human health, such as human immunodeficiency virus type 1 (HIV-1). These roles are mediated in part through its ability to actively shuttle between the nucleus and the cytoplasm to modulate gene expression, although the trafficking mechanisms, and impact thereof on immune signaling and viral infection, are incompletely defined. We confirm that DDX3X nuclear export is mediated by the nuclear transporter exportin-1/CRM1, dependent on an N-terminal, leucine-rich nuclear export signal (NES) and the monomeric guanine nucleotide binding protein Ran in activated GTP-bound form. Transcriptome profiling and ELISA show that exportin-1-dependent export of DDX3X to the cytoplasm strongly impacts IFN-ß production and the upregulation of immune genes in response to infection. That this is key to DDX3X's antiviral role was indicated by enhanced infection by human parainfluenza virus-3 (hPIV-3)/elevated virus production when the DDX3X NES was inactivated. Our results highlight a link between nucleocytoplasmic distribution of DDX3X and its role in antiviral immunity, with strong relevance to hPIV-3, as well as other viruses such as HIV-1.

Regional cortical thickness and neuroticism across the lifespan.

Neuroticism is associated with greater reactivity to stress and lifetime psychopathology. In the present study we examined the association between neuroticism and regional and total cortical thickness (CT) across the lifespan, accounting for gender. We also assessed interactions among these factors. 450 subjects between 19 and 80 years were included. Participants completed the International Personality Item Pool and a structural MRI scan. Total CT and the mean values of CT in five regions of interest were examined. We also investigated the interaction effect among age, gender and neuroticism on CT. There was no significant association between neuroticism and regional/total CT. A significant interaction between neuroticism, age, and gender on the thickness of the anterior cingulate was found. Women high in neuroticism showed a thinner anterior cingulate cortex than women low in neuroticism, with increasing age. In contrast, men high in neuroticism had a thicker anterior cingulate cortex compared to men low in neuroticism, with increasing age. Overall, high neuroticism was associated with differential cortical thickness in the anterior cingulate among men and women with increasing age.

Clinical outcomes following cochlear implantation in children with inner ear anomalies.

OBJECTIVE: A significant proportion of children with congenital hearing loss who are candidates for cochlear implants (CIs) may have inner ear malformations (IEMs). Surgical and speech outcomes following CI in these children have not been widely reported. METHODS: The charts of children who were evaluated for a CI between 1/1/1986 and 12/31/2014 at a university-based tertiary level pediatric cochlear implant center were reviewed. Principal inclusion criteria included (i) age 1-18 years, (ii) history of bilateral severe to profound sensorineural hearing loss, and (iii) limited benefit from binaural amplification. Exclusion criteria included (i) underlying diagnosis of neurodevelopmental disorder and (ii) lack of follow up for speech assessment if a CI was performed. The following outcome measures were reviewed: (i) imaging findings with magnetic resonance imaging or high resolution computed tomography, (ii) intraoperative complications, and (iii) speech perception categorized as the ability to perceive closed set, open set, or none. RESULTS: The prevalence of IEMs was 27% (102 of 381), of which 79% were bilateral. Cochlear dysplasia accounted for 30% (40 of 136) of the anomalies. Seventy-eight of the 102 patients received a CI (78%). Surgery was noted to be challenging in 24% (19 of 78), with a perilymphatic gusher being the most common intraoperative finding. Cochlear dysplasia, vestibular dysplasia and cochlear nerve hypoplasia were associated with poor speech perception (open OR closed set speech recognition scores, 0-23%), although the outcomes in children with enlarged vestibular aqueduct were similar to those of children with normal inner ear anatomy (65%). CONCLUSIONS: Cochlear implantation is safe in children with IEMs. However, the speech perception outcomes are notably below those of patients with normal anatomy, with the exception of when an enlarged vestibular aqueduct is present.

The Impact of Postmeningitic Labyrinthitis Ossificans on Speech Performance After Pediatric Cochlear Implantation.

OBJECTIVE: 1) To characterize pediatric cochlear implant performance in patients with hearing loss secondary to bacterial meningitis. 2) To evaluate performance differences in patients with and without labyrinthitis ossificans (LO). STUDY DESIGN: Retrospective case review. SETTING: A large university-based multidisciplinary cochlear implant program. PATIENTS: Forty-nine patients with hearing loss from bacterial meningitis who received cochlear implants from 1991 to 2011. Thirty-nine patients had adequate data for analysis. INTERVENTION: Cochlear implantation with postoperative performance evaluation. MAIN OUTCOME MEASURE(S): Speech perception category (SPC). RESULTS: Nineteen (48.7%) patients had intraoperative evidence of LO. Fourteen patients (70.0%) without LO compared with seven (36.8%) with LO developed open-set speech after implantation. There was a trend toward better postimplant SPC outcomes in patients without LO that did not reach statistical significance (p = 0.17). The presence of LO negatively correlated with classroom placement (p < 0.05). Analysis of each group individually demonstrated statistically significant improvement in pre- versus postimplant SPC outcomes (p < 0.001). CONCLUSION: The presence of LO may negatively affect performance in pediatric patients receiving a cochlear implant for hearing loss secondary to bacterial meningitis.

Cost-effective and scalable DNA extraction method from dried blood spots.

BACKGROUND: Dried blood spot (DBS) samples have been widely used in newborn screening (NBS) for the early identification of disease to facilitate the presymptomatic treatment of congenital diseases in newborns. As molecular genetics knowledge and technology progresses, there is an increased demand on NBS programs for molecular testing and a need to establish reliable, low-cost methods to perform those analyses. Here we report a flexible, cost-efficient, high-throughput DNA extraction method from DBS adaptable to small- and large-scale screening settings. METHODS: Genomic DNA (g.DNA) was extracted from single 3-mm diameter DBS by the sequential use of red cell lysis, detergent-alkaline, and acid-neutralizing buffers routinely used in whole blood and plant tissue DNA extractions. We performed PCR amplification of several genomic regions using standard PCR conditions and detection methods (agarose gel, melting-curve analysis, TaqMan-based assays). Amplicons were confirmed by BigDye® Terminator cycle sequencing and compared with reference sequences. RESULTS: High-quality g.DNA was extracted from hundreds of DBS, as proven by mutation detection of several human genes on multiple platforms. Manual and automated extraction protocols were validated. Quantification of g.DNA by Oligreen® fluorescent nucleic acid stain demonstrated a normal population distribution closely corresponding with white blood cell counts detected in newborn populations. CONCLUSIONS: High-quality, amplifiable g.DNA is extractable from DBSs. Our method is adaptable, reliable, and scalable to low- and high-throughput NBS at low cost ($0.10/sample). This method is routinely used for molecular testing in the New York State NBS program.

Cochlear implantation in children with cochlear nerve absence or deficiency.

OBJECTIVE: To evaluate speech perception after cochlear implantation in children with cochlear nerve absence or deficiency. METHODS: A retrospective case review was performed to identify children who underwent cochlear implantation with cochlear nerve absence or deficiency. The cochlear nerve was evaluated by high-resolution three-dimensional T2-weighted fast spin echo MR in the oblique sagittal and axial planes. A deficient cochlear nerve was defined as a cochlear nerve that is smaller in diameter when compared with the adjacent facial nerve in the midportion of the internal auditory canal. The cochlear nerve was considered absent if there was no imaging evidence of a cochlear nerve. Speech awareness threshold and the speech perception category score were used to measure speech perception after cochlear implantation. RESULTS: Seven children who underwent cochlear implantation in an ear without imaging evidence of a cochlear nerve were identified. One child developed early closed-set speech recognition. The other 6 children developed only speech detection or pattern perception. Two children underwent cochlear implantation with a deficient cochlear nerve. One developed consistent closed-set word recognition and the other developed early closed-set word recognition. The mean follow-up time for all patients was 3.8 years (range, 1.1-7.1 yr). CONCLUSION: Cochlear nerve deficiency is not an uncommon cause for profound sensorineural hearing loss and presents a challenge in the decision-making process regarding whether to proceed with a cochlear implant. Children with a deficient but visible cochlear nerve on magnetic resonance image can expect to show some speech understanding after cochlear implantation; however, these children do not develop speech understanding to the level of implanted children with normal cochlear nerves. Children with an absent cochlear nerve determined by magnetic resonance imaging can be expected to have limited postimplantation sound and speech awareness.

P1 latency as a biomarker for central auditory development in children with hearing impairment.

We used the latency of the P1 cortical auditory-evoked potential (CAEP) as a biomarker for the development of central auditory pathways in three children who received intervention through hearing aids and/or cochlear implants. Our goal was to examine the clinical feasibility of using the latency of the P1 CAEP as an objective tool to evaluate whether acoustic amplification for hearing-impaired children has provided sufficient stimulation for normal development of central auditory pathways. If clinicians have such a marker, then they can more confidently make a decision about whether to provide a child with a cochlear implant following an appropriate hearing-aid trial. Using the same marker, clinicians will also be able to monitor the maturation of central auditory pathways once electrical stimulation is initiated.