Clinical outcomes of children and adolescents with sickle cell disease and COVID-19 infection: A year in review at a metropolitan tertiary pediatric hospital.

Background: COVID-19 was declared a global pandemic in March 2020. Early reports were primarily in adults, and sickle cell disease (SCD) was classified as a risk factor for severe COVID-19 disease. However, there are a limited number of primarily multi-center studies reporting on the clinical course of pediatric patients with SCD and COVID-19. Methods: We conducted an observational study of all patients with SCD diagnosed with COVID-19 at our institution between March 31, 2020, and February 12, 2021. Demographic and clinical characteristics of this group were collected by retrospective chart review. Results: A total of 55 patients were studied, including 38 children and 17 adolescents. Demographics, acute COVID-19 clinical presentation, respiratory support, laboratory findings, healthcare utilization, and SCD modifying therapies were comparable between the children and adolescents. Seventy-three percent (N = 40) of all patients required emergency department care or hospitalization. While 47% (N = 26) were hospitalized, only 5% (N = 3) of all patients required intensive care unit admission. Patients frequently had concurrent vaso-occlusive pain crisis (VOC) (N = 17, 43%) and acute chest syndrome (ACS) (N = 14, 35%). Those with ACS or an oxygen requirement had significantly higher white blood cell count, lower nadir hemoglobin, and higher D-dimers, supporting a pro-inflammatory and coagulopathic picture. Non-hospitalized patients were more likely to be on hydroxyurea than hospitalized patients (79 vs. 50%, p = 0.023). Conclusion: Children and adolescent patients with SCD and acute COVID-19 often present with ACS and VOC pain requiring hospital-level care. Hydroxyurea treatment appears to be protective. We observed no mortality despite variable morbidity.

Optimising the screening for haemoglobinopathies in pregnancy planning.

Haemoglobinopathies are among the most common inherited disorders around the world. In the United States the diagnosis of haemoglobinopathy or a carrier state is made by universal newborn screening. However, many individuals of childbearing age do not know they are a haemoglobinopathy carrier. Screening for common haemoglobinopathies is generally offered as a part of pregnancy planning so that prospective parents can be counselled regarding the risk of having a child with a haemoglobinopathy. Multiple tests exist to screen patients for presence of haemoglobinopathy carrier or disease state; however, it is crucial to order and interpret the results correctly to appropriately counsel couples. In this case series, we describe clinical scenarios where prospective parents were surprised to unexpectedly have a child with sickle cell disease, a haemoglobinopathy that causes severe clinical complications. Through these cases we demonstrate that deficiencies in testing can occur at different levels which may lead to incorrect estimation of the risk of having a child affected by a haemoglobinopathy. Consultation with a haematologist, laboratory medicine specialist, or genetic counsellor should be considered to select the appropriate test and interpret its results.

Telemedicine in sickle cell disease: Patient, parent, and provider perspectives.

INTRODUCTION: Patients with sickle cell disease (SCD) need frequent health maintenance visits and may face barriers accessing care. Telemedicine, during COVID pandemic, has provided a unique model of care to improve access; however, potential barriers and satisfaction with its use in SCD have not been fully evaluated. OBJECTIVE: To determine caregiver, patient, and healthcare provider (HCP) perspectives and satisfaction with telemedicine in healthcare delivery. METHODS: We surveyed patients with SCD, caregivers, and HCP, who participated in at least one telemedicine visit from March 2020 to June 2021, using the Telemedicine Usability Questionnaire (TUQ). We also accessed and compared the Press Ganey surveys completed by families who completed a telemedicine or in-person visit. Data were summarized using descriptive statistics. The internal reliability of TUQ was assessed using Cronbach's coefficient alpha. Press Ganey data comparing satisfaction with telemedicine versus in-person visits were analyzed by Mann-Whiney U test. RESULTS: Fifty-two patients/caregivers and 10 HCP completed the survey. Patients/caregivers rated satisfaction "excellent" in the five areas (Usefulness, Ease of use, Effectiveness, Reliability and Satisfaction). HCP rated Usefulness, Ease of use, Effectiveness, Satisfaction as "good," and Reliability as "excellent." Press Ganey scores for satisfaction with care for telemedicine and in-person visits were not statistically different (p > .05). DISCUSSION: We found high satisfaction for caregivers and patients as well as HCP in the delivery of clinical services via telemedicine for SCD. We suggest that telemedicine is a viable option for this population and may help overcome the barriers SCD families often face accessing care.

Acupuncture as an Adjunctive Treatment for Pain in Hospitalized Children With Sickle Cell Disease.

CONTEXT: Acute episodes of pain associated with sickle cell disease (SCD) account for over 100,000 hospitalizations and expenses of nearly one billion dollars annually in the U.S. New treatment approaches are needed as the current opioid based therapy is often inadequate in controlling pain, resulting in prolonged inpatient stays, and high rates of readmission. OBJECTIVES: To evaluate acceptability of acupuncture as an adjunctive therapy and explore the impact of acupuncture on pain related outcomes in a population of youth with SCD hospitalized for management of acute pain. METHODS: This IRB approved single center study recruited youth with SCD (9-20 years) who were hospitalized for management of acute pain into either the acupuncture group or controls. Both groups also received standard pain management therapies. RESULTS: Participants in the acupuncture (n = 19) and control (n = 10) group were comparable in clinical characteristics. Acupuncture had an acceptability rate of over 66% and was tolerated well without any side effects. Acupuncture was associated with reduction in pain scores (6.84-5.51; P < 0.0001). Acupuncture group demonstrated a trend toward lower length of stay and readmission rates, but these were not statistically significant. Opioid use was not different between the groups. Treatment Evaluation Inventory survey showed high rates of satisfaction with acupuncture. CONCLUSION: Acupuncture was broadly accepted and well-tolerated in our study population. Acupuncture treatment was associated with a statistically significant and clinically meaningful reduction in pain scores immediately following the treatments, and a trend towards a reduction in length of stay and readmission for pain.

Integrative holistic approaches for children, adolescents, and young adults with sickle cell disease: A single center experience.

CONTEXT: Painful vaso-occlusive crises (VOCs) associated with sickle cell disease (SCD) are the most common cause of morbidity, hospitalizations, and poor quality of life. Additional symptoms such as sleep disturbances, fatigue, and stress are also common. Non-traditional approaches are often used by families, but concerns remain that patients may forgo standard of care effective therapies in favor of dangerous unproven alternatives. OBJECTIVES: To describe a single center experience related to a multidisciplinary integrative medicine clinic within the division of hematology dedicated to children and young adults with SCD. METHODS: The Sickle Cell Integrative Clinic at Children's National Hospital services patients with SCD. The main goal of this clinic is to provide access to non-pharmacologic interventions, and to manage patients' symptoms in a holistic manner along with standard of care management of SCD. This IRB approved study evaluated experiences of both patients and parents who attended this clinic. RESULTS: Thirty-seven unique patients attended this clinic over 2 years and 31 participated in the study. After attending the SCD integrative clinic, the majority of patients reported integrative therapies to be an acceptable way of treating pain and believed these to be effective. Overall, the vast majority (88 %) of patients reported having a positive experience with the therapies offered in the clinic. None of the patients experienced any adverse events related to integrative therapies provided in the clinic. CONCLUSION: Our experience suggests that encouraging conversations and offering safe and potentially effective integrative therapies alongside conventional SCD therapies under medical guidance allows patients to have an open discussion about their beliefs and treatment goals, improves patient satisfaction and can improve outcomes.

An intracochlear DP-gram: Proof of principle in noise-damaged rabbits.

Distortion-product otoacoustic emissions (DPOAEs) can be used to assess cochlear damage and are often evaluated by generating a DP-gram in which 2f1-f2 DPOAE levels are plotted as a function of the higher-frequency primary at f2. DPOAEs are derived from the reverse propagation of distortion-product (DP) wavelets from their intracochlear sites of generation to emerge as measurable acoustic signals in the outer ear canal. However, at least, some of these same wavelets also propagate within the cochlea in the normal forward direction to the DP-frequency (fdp) place, where they appear as intracochlear distortion products (iDPs). Depending on several factors, especially, the extent to which DP wavelets add or cancel with each other in phase, one might expect iDPs to differ from DPOAEs in their ability to map the frequency pattern of cochlear damage. In the present study, the behavior of 2f1-f2 iDPs was inferred by interacting a probe tone (f3) with the iDP of interest to produce a 'secondary' DPOAE (i.e., DPOAE2ry), which was then used to infer the level of 2f1-f2 iDPs as a function of the f2-test frequency, thus, constituting a newly developed iDP-gram. To determine the feasibility of and potential applications for the iDP-gram procedure, noise-induced cochlear damage was assessed in two 'test' rabbits, one of which exhibited a well-defined punctate loss in their DP-gram, while the other exhibited a broader V-shaped loss. To validate the iDP-gram procedure, standard DP-grams were simultaneously collected and compared to their iDP-gram counterparts. Cochlear damage was independently assessed using auditory brainstem responses (ABRs) describing threshold-shift patterns to which both DP-gram types could be compared. Each DP-gram variety, to some extent, was able to detect a punctate loss in one rabbit and a broader V-shaped loss in the other. For the punctate-loss subject, the standard DP-gram showed a more generalized loss across test frequencies, while iDP-grams showed several localized notches superimposed on the generalized-loss pattern. In general, for the V-shaped loss pattern, both DP-gram types performed very well at detecting the large loss, with the lower primary-tone levels being most sensitive. At the narrow primary-tone ratios of f2/f1=1.05, standard DP-grams were unable to detect either loss pattern, while for the punctate loss, they paradoxically showed enhancement. Notably, the simultaneously collected iDP-grams performed favorably at the narrow-ratio setting, which is consistent with the notion that DPs travelling toward the 2f1-f2 fdp place are not subject to the cancellation of wavelets typical for narrow primary-ratio conditions that can confound measures of DPs moving towards the ear canal to emerge as DPOAEs.

Acupuncture for pain management in children with sickle cell disease.

Pain associated with sickle cell disease (SCD) is frequently treated with opioids which have many side effects. There is a need for adjuvant non-opioid therapies that can improve pain control. Acupuncture, an integrative approach, has been shown to be useful in non-SCD pain conditions but has been used to a very limited extent in SCD. In this report we present a single academic pediatric center experience showing acceptability, feasibility and improved pain experience with adjuvant acupuncture therapy in children with SCD and suggest that acupuncture should be explored as a treatment option for managing pain in SCD.

Comprehensive Infant Clinic for Sickle Cell Disease: Outcomes and Parental Perspective.

INTRODUCTION: Comprehensive care for children with sickle cell disease (SCD) includes penicillin prophylaxis, pneumococcal immunization, hydroxyurea therapy, and transcranial Doppler screening for stroke prevention. Along with caregiver education, these strategies have been shown to be effective in reducing early morbidity and mortality in this population. The subspecialty Infant Sickle Cell Clinic was initiated to improve access, education, patient outcomes, and family satisfaction. METHOD: Telephone surveys were conducted with parents to assess satisfaction with the Infant Sickle Cell Clinic, compliance with guidelines, and comfort level with managing their child's SCD. RESULTS: This quality improvement project reported high levels of parent satisfaction and improved outcomes with the proposed approach but also presents areas for improvement. DISCUSSION: Our report presents a unique model of providing care to families with infants newly diagnosed with SCD. The group format serves as a useful model to allow families an interactive educational session with guest speakers.

Views of parents of children with sickle cell disease on pre-implantation genetic diagnosis.

Pre-implantation genetic diagnosis (PGD) is an option for parents who have a child with sickle cell disease (SCD) to have another child without SCD. We conducted a survey of 19 parents with at least one child with SCD to investigate views on PGD. Before education, 44% of parents were aware of PGD. All parents rated PGD education as important. All parents considering another child also reported interest in using PGD if insurance covered its costs. Parents who have a child with SCD appear to be interested in PGD and educational tools informing this group about PGD should be developed.

Comparing Distortion Product Otoacoustic Emissions to Intracochlear Distortion Products Inferred from a Noninvasive Assay.

The behavior of intracochlear distortion products (iDPs) was inferred by interacting a probe tone (f3) with the iDP of interest to produce a "secondary" distortion product otoacoustic emission termed DPOAE(2ry). Measures of the DPOAE(2ry) were then used to deduce the properties of the iDP. This approach was used in alert rabbits and anesthetized gerbils to compare ear-canal 2f1-f2 and 2f2-f1 DPOAE f2/f1 ratio functions, level/phase (L/P) maps, and interference-response areas (IRAs) to their simultaneously collected DPOAE(2ry) counterparts. These same measures were also collected in a human volunteer to demonstrate similarities with their laboratory animal counterparts and their potential applicability to humans. Results showed that DPOAEs and inferred iDPs evidenced distinct behaviors and properties. That is, DPOAE ratio functions elicited by low-level primaries peaked around an f2/f1 = 1.21 or 1.25, depending on species, while the corresponding inferred iDP ratio functions peaked at f2/f1 ratios of ~1. Additionally, L/P maps showed rapid phase variation with DPOAE frequency (fdp) for the narrow-ratio 2f1-f2 and all 2f2-f1 DPOAEs, while the corresponding DPOAE(2ry) measures evidenced relatively constant phases. Common features of narrow-ratio DPOAE IRAs, such as large enhancements for interference tones (ITs) presented above f2, were not present in DPOAE(2ry) IRAs. Finally, based on prior experiments in gerbils, the behavior of the iDP directly measured in intracochlear pressure was compared to the iDP inferred from the DPOAE(2ry) and found to be similar. Together, these findings are consistent with the notion that under certain conditions, ear-canal DPOAEs provide poor representations of iDPs and thus support a "beamforming" hypothesis. According to this concept, distributed emission components directed toward the ear canal from the f2 and basal to f2 regions can be of differing phases and thus cancel, while these same components directed toward fdp add in phase.

Influence of sound-conditioning on noise-induced susceptibility of distortion-product otoacoustic emissions.

Cochlear damage caused by loud sounds can be attenuated by "sound-conditioning" methods. The amount of adaptation for distortion product otoacoustic emissions (DPOAEs) measured in alert rabbits previously predicted an ear's susceptibility to a subsequent noise exposure. The present study investigated if sound-conditioning influenced the robustness of such DPOAE adaptation, and if such conditioning elicited more protection by increasing the amount of DPOAE adaptation. Toward this end, rabbits were divided into two study groups: (1) experimental animals exposed to a sound-conditioning protocol, and (2) unconditioned control animals. After base-line measures, all rabbits were exposed to an overstimulation paradigm consisting of an octave band noise, and then re-assessed 3 weeks post-exposure to determine permanent changes in DPOAEs. A major result was that prior sound-conditioning protected reductions in DPOAE levels by an average of 10-15 dB. However, DPOAE adaptation decreased with sound-conditioning, so that such conditioning was no longer related to noise-induced reductions in DPOAEs. Together, these findings suggest that sound-conditioning affected neural pathways other than those that likely mediate DPOAE adaptation (e.g., medial olivocochlear efferent and/or middle-ear muscle reflexes).

Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial.

Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial. This study provides a prospective, randomized, double-blinded, placebo-controlled clinical trial investigating the safety profile and the efficacy of NAC to prevent hearing loss in a military population after weapons training. Of the 566 total study subjects, 277 received NAC while 289 were given placebo. The null hypothesis for the rate of STS was not rejected based on the measured results. While no significant differences were found for the primary outcome, rate of threshold shifts, the right ear threshold shift rate difference did approach significance (p = 0.0562). No significant difference was found in the second primary outcome, percentage of subjects experiencing an adverse event between placebo and NAC groups (26.7% and 27.4%, respectively, p = 0.4465). Results for the secondary outcome, STS rate in the trigger hand ear, did show a significant difference (34.98% for placebo-treated, 27.14% for NAC-treated, p-value = 0.0288). Additionally, post-hoc analysis showed significant differences in threshold shift rates when handedness was taken into account. While the secondary outcomes and post-hoc analysis suggest that NAC treatment is superior to the placebo, the present study design failed to confirm this. The lack of significant differences in overall hearing loss between the treatment and placebo groups may be due to a number of factors, including suboptimal dosing, premature post-exposure audiograms, or differences in risk between ears or subjects. Based on secondary outcomes and post hoc analyses however, further studies seem warranted and are needed to clarify dose response and the factors that may have played a role in the observed results.

Adaptation of distortion product otoacoustic emissions predicts susceptibility to acoustic over-exposure in alert rabbits.

A noninvasive test was developed in rabbits based on fast adaptation measures for 2f1-f2 distortion-product otoacoustic emissions (DPOAEs). The goal was to evaluate the effective reflex activation, i.e., "functional strength," of both the descending medial olivocochlear efferent reflex (MOC-R) and the middle-ear muscle reflex (MEM-R) through sound activation. Classically, it is assumed that both reflexes contribute toward protecting the inner ear from cochlear damage caused by noise exposure. The DP-gram method described here evaluated the MOC-R effect on DPOAE levels over a two-octave (oct) frequency range. To estimate the related activation of the middle-ear muscles (MEMs), the MEM-R was measured by monitoring the level of the f1-primary tone throughout its duration. Following baseline measures, rabbits were subjected to noise over-exposure. A main finding was that the measured adaptive activity was highly variable between rabbits but less so between the ears of the same animal. Also, together, the MOC-R and MEM-R tests showed that, on average, DPOAE adaptation consisted of a combined contribution from both systems. Despite this shared involvement, the amount of DPOAE adaptation measured for a particular animal's ear predicted that ear's subsequent susceptibility to the noise over-exposure for alert but not for deeply anesthetized rabbits.

Time-domain demonstration of distributed distortion-product otoacoustic emission components.

Distortion-product otoacoustic emissions (DPOAEs) were measured in rabbits as time waveforms by employing a phase-rotation technique to cancel all components in the final average, except the 2f1-f2 DPOAE. Subsequent filtering allowed the DPOAE waveform to be clearly visualized in the time domain. In most conditions, f2 was turned off for 6 ms, which produced a gap so that the DPOAE was no longer generated. These procedures allowed the DPOAE onset as well as the decay during the gap to be observed in the time domain. DPOAEs were collected with L1 = L2 = 65-dB sound pressure level primary-tone levels for f2/f1 ratios from 1.25 to 1.01 in 0.02 steps. Findings included the appearance of complex onsets and decays for the DPOAE time waveforms as the f2/f1 ratio was decreased and the DPOAE level was reduced. These complexities were unaffected by interference tones (ITs) near the DPOAE frequency place (fdp), but could be removed by ITs presented above f2, which also increased DPOAE levels. Similar outcomes were observed when DPOAEs were measured at a sharp notch in the DPOAE level as a function of the f2 primary tone frequency, i.e., DP-gram. Both findings were consistent with the hypothesis that the DPOAE-ratio function, and some notches in the DP-gram, are caused by interactions of distributed DPOAE components with unique phases.

Neurodevelopmental deficits among infants and toddlers with sickle cell disease.

OBJECTIVE: Neurodevelopmental deficits are among the serious complications of sickle cell disease (SCD). However, few studies have prospectively evaluated neurodevelopmental deficits in very young children with SCD. We analyzed baseline neurodevelopmental data from a cohort of 80 infants and toddlers with SCD to identify primary disease-related events and sociodemographic risk factors associated with early developmental delay. METHODS: This is an analysis of baseline date of a 4-year mixed, cross-sectional/longitudinal study. Full-term children at age 3.5 years or younger with SCD (any genotype) were eligible. Neurodevelopmental evaluations (Bayley II) were conducted at ages 9, 15, 21, 30, and 40 months. Demographics, hematologic variables, and medical events were obtained. RESULTS: Significant neurodevelopmental deficits were evident: 17.5% scoring >2SD below the mean on Bayley Mental Index or Motor Index. Odds ratio of significant developmental delay was >9 times more likely among those who had experienced vaso-occlusive pain episodes, after controlling for socioeconomic status (SES), gender, pneumonia/acute chest syndrome, and hemoglobin concentration. Male gender was also a risk factor for developmental delay. CONCLUSIONS: Early cognitive and motor delays were present in young children with SCD, with higher prevalence among those who had experienced pain crises. Increased vulnerability of male gender is consistent with other at-risk populations but has not been previously addressed in SCD research. Furthermore, these delays are not sufficiently explained by lower SES. Significant developmental delay in children with SCD may go unrecognized by primary care practices, medical specialty clinics, or parents. The importance of routine neurodevelopmental assessment for children with chronic medical conditions is clear.

Ectopic pregnancy after hysterectomy: a case report.

BACKGROUND: Ectopic pregnancy after hysterectomy is an unusual diagnosis that may lead to significant morbidity, especially when diagnosis is not timely. CASE: A 41-year-old woman presenting with abdominal pain and vaginal bleeding 5 years after a vaginal hysterectomy was found to have a tubal ectopic pregnancy, which required emergent surgical intervention. CONCLUSION: Ectopic pregnancy after hysterectomy represents a challenging diagnosis because it is counter-intuitive and very uncommon. The diagnosis of posthys-terectomy ectopic pregnancy, though exceptionally rare, should be considered for women presenting with abdominal pain after hysterectomy.

Characterizing distortion-product otoacoustic emission components across four species.

Distortion-product otoacoustic emissions (DPOAEs) were measured as level/phase (L/P) maps in humans, rabbits, chinchillas, and rats with and without an interference tone (IT) placed either near the 2f(1)-f(2) DPOAE frequency place (f(dp)) or at one-third of an octave above the f(2) primary tone (1/3-oct IT). Vector differences between with and without IT conditions were computed to derive a residual composed of the DPOAE components removed by the IT. In humans, a DPOAE component could be extracted with the expected steep phase gradient indicative of reflection emissions by ITs near f(dp). In the laboratory species, ITs near f(dp) failed to produce any conclusive evidence for reflection components. For all species, 1/3-oct ITs extracted large DPOAE components presumably generated at or basal to the IT-frequency place that exhibited both distortion- and reflection-like phase properties. Together, these findings suggested that basal distortion components could assume reflection-like phase behavior when the assumptions of cochlear-scaling symmetry, the basis for shallow phase gradients for constant f(2)/f(1) ratio sweeps, are violated. The present results contradict the common belief that DPOAE components associated with steep or shallow phase slopes are unique signatures for reflection emissions arising from f(dp) or distortion emissions generated near f(2), respectively.

Noise-induced changes in gene expression in the cochleae of mice differing in their susceptibility to noise damage.

The molecular mechanisms underlying the vast differences between individuals in their susceptibility to noise-induced hearing loss (NIHL) are unknown. The present study demonstrated that the effects of noise over-exposure on the expression of molecules likely to be important in the development of NIHL differ among inbred mouse strains having distinct susceptibilities to NIHL including B6 (B6.CAST) and 129 (129X1/SvJ and 129S1/SvImJ) mice. The noise-exposure protocol produced a loss of 40 dB in hearing sensitivity in susceptible B6 mice, but no loss for the two resistant 129 substrains. Analysis of gene expression in the membranous labyrinth 6 h following noise exposure revealed upregulation of transcription factors in both the susceptible and resistant strains. However, a significant induction of genes involved in cell-survival pathways such as the heat shock proteins HSP70 and HSP40, growth arrest and DNA-damage-inducible protein 45ß (GADD45ß), and CDK-interacting protein 1 (p21(Cip1)) was detected only in the resistant mice. Moreover, in 129 mice significant upregulation of HSP70, GADD45ß, and p21(Cip1) was confirmed at the protein level. Since the functions of these proteins include roles in potent anti-apoptotic cellular pathways, their upregulation may contribute to protection from NIHL in the resistant 129 mice.