Analysis of Butyrophilin-Mediated Activation of γδ T Cells from Human Spleen.

There is considerable interest in therapeutically engaging human γδ T cells. However, due to the unique TCRs of human γδ T cells, studies from animal models have provided limited directly applicable insights, and human γδ T cells from key immunological tissues remain poorly characterized. In this study, we investigated γδ T cells from human spleen tissue. Compared to blood, where Vδ2+Vγ9+ T cells are the dominant subset, splenic γδ T cells included a variety of TCR types, with Vδ1+ T cells typically being the most frequent. Intracellular cytokine staining revealed that IFN-γ was produced by a substantial fraction of splenic γδ T cells, IL-17A by a small fraction, and IL-4 was minimal. Primary splenic γδ T cells frequently expressed NKG2D (NK group 2 member D) and CD16, whereas expression of DNAM-1 (DNAX accessory molecule 1), CD28, PD-1, TIGIT, and CD94 varied according to subset, and there was generally little expression of natural cytotoxicity receptors, TIM-3, LAG-3, or killer Ig-like receptors. In vitro expansion was associated with marked changes in expression of these activating and inhibitory receptors. Analysis of functional responses of spleen-derived Vδ2+Vγ9+, Vδ1+Vγ9+, and Vδ1+Vγ9- T cell lines to recombinant butyrophilin BTN2A1 and BTN3A1 demonstrated that both Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells were capable of responding to the extracellular domain of BTN2A1, whereas the addition of BTN3A1 only markedly enhanced the responses of Vδ2+Vγ9+ T cells. Conversely, Vδ1+Vγ9+ T cells appeared more responsive than Vδ2+Vγ9+ T cells to TCR-independent NKG2D stimulation. Thus, despite shared recognition of BTN2A1, differential effects of BTN3A1 and coreceptors may segregate target cell responses of Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells.

Human CD4+ iNKT cell adoptive immunotherapy induces anti-tumour responses against CD1d-negative EBV-driven B lymphoma.

Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that are uniquely suitable as off-the-shelf cellular immunotherapies due to their lack of alloreactivity. Two major subpopulations of human iNKT cells have been delineated, a CD4- subset that has a TH1/cytolytic profile, and a CD4+ subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti-tumour effects is not known. Using live cell imaging, we found that CD4- iNKT cells limited growth of CD1d+ Epstein-Barr virus (EBV)-infected B-lymphoblastoid spheroids in vitro, whereas CD4+ iNKT cells showed little or no direct anti-tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV-driven human B cell lymphoma. We found that EBV-infected B cells down-regulated CD1d in vivo, and administering CD4- iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4+ iNKT cells. Immunotherapeutic CD4+ iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4+ iNKT cells also had adjuvant-like effects on monocyte-derived DCs and promoted antigen-dependent responses of human T cells in vitro. These results show that allogeneic CD4+ iNKT cellular immunotherapy leads to marked anti-tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen-specific T cells.

Cyclic loading failed to promote growth in a pig model of midfacial hypoplasia.

Yucatan miniature pigs, often used as large animal models in clinical research, are distinguished by a breed-specific midfacial hypoplasia with anterior crossbite. Although this deformity can be corrected by distraction osteogenesis, a less invasive method is desirable. We chose a mechanical cyclic stimulation protocol that has been successful in enhancing sutural growth in small animals and in a pilot study on standard pigs. Yucatan minipigs (n = 14) were obtained in pairs, with one of each pair randomly assigned to sham or loaded groups. All animals had loading implants installed on the right nasal and frontal bones and received labels for cell proliferation and mineral apposition. After a week of healing and under anesthesia, experimental animals received cyclic tensile loads (2.5 Hz, 30 min) delivered to the right nasofrontal suture daily for 5 days. Sutural strains were recorded at the final session for experimental animals. Sham animals received the same treatment except without loading or strain gauge placement. In contrast to pilot results on standard pigs, the treatment did not produce the expected sutural widening and increased growth. Although sutures were not fused and strains were in the normal range, the targeted right nasofrontal suture was narrowed rather than widened, with no statistically significant changes in sutural cell proliferation, mineral apposition, or vascularity. In general, Yucatan minipig sutures were more vascular than those of standard pigs and also tended to have more proliferating cells. In conclusion, either because the sutures themselves are abnormal or because of growth restrictions elsewhere in the skull, this cyclic loading protocol was unable to produce the desired response of sutural widening and growth. This treatment, effective in normal animals, did not improve naturally occurring midfacial hypoplasia in Yucatan minipigs.

Seizure control in women with epilepsy undergoing assisted reproductive technology.

The objective of this study was to determine seizure control in women with epilepsy (WWE) undergoing assisted reproductive technology (ART). Through retrospective chart review, WWE undergoing ART were identified. Demographics and details regarding epilepsy type, seizure control, and ART procedures were extracted. Seizure frequency prior to and during ART were compared. We identified 12 WWE, who underwent 29 embryo transfers, resulting in 16 pregnancies and 10 live births. Nine women were seizure-free at least 2 years before fertility treatment, including three with resolved epilepsy. Seven were on antiseizure medications throughout fertility treatment and pregnancy, with only one on polytherapy. Eleven (all with controlled epilepsy or epilepsy in remission) remained seizure-free throughout fertility treatment. One woman with drug-resistant epilepsy continued to have seizures throughout fertility treatment and pregnancy without an exacerbation of seizure frequency. There was no increased seizure frequency associated with fertility treatment and subsequent pregnancy in this small series of WWE. Although this study was statistically underpowered, our results provide some preliminary evidence that ART might not pose a threat to seizure control, but larger, confirmatory studies are necessary.

Seizure characteristics and outcomes in patients with neurological conditions related to high-risk paraneoplastic antibodies.

OBJECTIVE: Seizures are a common manifestation of paraneoplastic neurologic syndromes. The objective of this study was to describe the seizure characteristics and outcomes in patients with high-risk paraneoplastic autoantibodies (>70% cancer association) and to determine factors associated with ongoing seizures. METHODS: Patients from 2000 to 2020 with seizures and high-risk paraneoplastic autoantibodies were retrospectively identified. Factors associated with ongoing seizures at last follow-up were evaluated. RESULTS: Sixty patients were identified (34 males, median age at presentation = 52 years). ANNA1-IgG (Hu; n = 24, 39%), Ma2-IgG (n = 14, 23%), and CRMP5-IgG (CV2; n = 11, 18%) were the most common underlying antibodies. Seizures were the initial presenting symptom in 26 (43%), and malignancy was present in 38 (63%). Seizures persisted for >1 month in 83%, and 60% had ongoing seizures, with almost all patients (55/60, 92%) still being on antiseizure medications at last follow-up a median of 25 months after seizure onset. Ongoing seizures at last follow-up were associated with Ma2-IgG or ANNA1-IgG compared to other antibodies (p = .04), highest seizure frequency being at least daily (p = .0002), seizures on electroencephalogram (EEG; p = .03), and imaging evidence of limbic encephalitis (LE; p = .03). Death occurred in 48% throughout the course of follow-up, with a higher mortality in patients with LE than in those without LE (p = .04). Of 31 surviving patients at last follow-up, 55% continued to have intermittent seizures. SIGNIFICANCE: Seizures in the setting of high-risk paraneoplastic antibodies are frequently resistant to treatment. Ongoing seizures are associated with ANNA1-IgG and Ma2-IgG, high seizure frequency, and EEG and imaging abnormalities. Although a subset of patients may respond to immunotherapy and achieve seizure freedom, poor outcomes are frequently encountered. Death was more common among patients with LE.

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis. METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM. RESULTS: There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic-clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug-resistant epilepsy. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.

Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: There are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome). METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM. RESULTS: There was a strong consensus for valproic acid as the first-line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel-blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research.

Drug-resistant temporal lobe epilepsy with temporal encephaloceles: How far to resect.

PURPOSE: This study sought to evaluate the impact of surgical extent on seizure outcome in drug-resistant temporal lobe epilepsy (DR-TLE) with temporal encephaloceles (TE). METHODS: This was a single-institution retrospective study of patients who underwent surgery for DR-TLE with TE between January 2008 and December 2020. The impact of surgical extent on seizure outcome was evaluated. In a subset with dominant DR-TLE, the impact of surgical extent on neuropsychometric outcome was evaluated. RESULTS: Thirty-four patients were identified (female, 56%; median age at surgery, 43 years). TE were frequently overlooked on initial magnetic resonance imaging (MRI), with encephaloceles only detected after repeat or expert re-review of MRI, additional multi-modal imaging, or intra-operatively in 31 (91%). Sixteen (47%) underwent limited resections, including encephalocele resection only (n = 5) and encephalocele resection with more extensive temporal corticectomy sparing the amygdala and hippocampus (n = 11). The remainder (n = 18, 53%) underwent standard anterior temporal lobectomy and amygdalohippocampectomy (ATLAH). Limited resection was performed more frequently on the left (12/17 vs. 4/17, p = 0.015). Twenty-seven patients (79%) had a favourable outcome (Engel I/II), and 17 (50%) were seizure-free at the last follow-up (median seizure-free survival of 27.3 months). There was no statistically significant difference in seizure-free outcomes between limited resection and ATLAH. In dominant DR-TLE, verbal memory decline was more likely after ATLAH than limited resection (3/4 vs. 0/9, p = 0.014). CONCLUSION: Expert re-review of imaging and multi-modal advanced imaging improved TE identification. There was no statistical difference in seizure-free outcomes based on surgical extent. Preservation of verbal memory supports limited resection in dominant temporal cases.

Harm reduction in undergraduate and graduate medical education: a systematic scoping review.

BACKGROUND: Substance use increasingly contributes to early morbidity and mortality, which necessitates greater preparation of the healthcare workforce to mitigate its harm. The purpose of this systematic scoping review is to: 1) review published curricula on harm reduction for substance use implemented by undergraduate (UME) and graduate medical education (GME) in the United States and Canada, 2) develop a framework to describe a comprehensive approach to harm reduction medical education, and 3) propose additional content topics for future consideration. METHODS: PubMed, Scopus, ERIC: Education Resources Information Center (Ovid), and MedEdPORTAL were searched. Studies included any English language curricula about harm reduction within UME or GME in the United States or Canada from 1993 until Nov 22, 2021. Two authors independently reviewed and screened records for data extraction. Data were analyzed on trainee population, curricula objectives, format, content, and evaluation. RESULTS: Twenty-three articles describing 19 distinct educational programs across the United States were included in the final sample, most of which created their own curricula (n = 17). Data on educational content were categorized by content and approach. Most programs (85%) focused on introductory substance use knowledge and skills without an understanding of harm reduction principles. Based on our synthesis of the educational content in these curricula, we iteratively developed a Harm Reduction Educational Spectrum (HRES) framework to describe curricula and identified 17 discrete content topics grouped into 6 themes based on their reliance on harm reduction principles. CONCLUSIONS: Harm reduction is under-represented in published medical curricula. Because the drug supply market changes rapidly, the content of medical curricula may be quickly outmoded thus curricula that include foundational knowledge of harm reduction principles may be more enduring. Students should be grounded in harm reduction principles to develop the advanced skills necessary to reduce the physical harm associated with drugs while still simultaneously recognizing the possibility of patients' ongoing substance use. We present the Harm Reduction Educational Spectrum as a new framework to guide future healthcare workforce development and to ultimately provide the highest-quality care for patients who use drugs.

Moral Distress in the Time of COVID-19: Occupational Therapists' Perspectives.

The conditions of COVID-19 have caused moral distress in healthcare workers. Occupational therapists have had to adapt to these unknown times to best treat their clients. The purpose of this study was to explore the experience of moral distress in occupational therapists during the time of COVID-19. Eighteen occupational therapists were included who worked in a variety of settings. Investigators conducted semi-structured interviews to explore experience with moral distress (distress felt when confronting an ethical problem) during the time of COVID-19. The data were analyzed using a hermeneutical phenomenological approach to generate themes regarding the experience of moral distress. Investigators identified themes of occupational therapists' experiences during the COVID-19 pandemic. These themes included: Experiences of moral distress, capturing participants' encounters with morally distressing issues; effects of moral distress, exploring the impact of COVID-19 experiences on participants' well-being and quality of life; and managing moral distress, addressing ways in which occupational therapists tried to mitigate moral distress throughout the pandemic. This study brings awareness to the experience of occupational therapists during the pandemic and explores implications for preparing occupational therapists for future occurrences of moral distress.

The Roseoloviruses Downregulate the Protein Tyrosine Phosphatase PTPRC (CD45).

Like all herpesviruses, the roseoloviruses (HHV6A, -6B, and -7) establish lifelong infection within their host, requiring these viruses to evade host antiviral responses. One common host-evasion strategy is the downregulation of host-encoded, surface-expressed glycoproteins. Roseoloviruses have been shown to evade the host immune response by downregulating NK-activating ligands, class I MHC, and the TCR/CD3 complex. To more globally identify glycoproteins that are differentially expressed on the surface of HHV6A-infected cells, we performed cell surface capture of N-linked glycoproteins present on the surface of T cells infected with HHV6A, and compared these to proteins present on the surface of uninfected T cells. We found that the protein tyrosine phosphatase CD45 is downregulated in T cells infected with HHV6A. We also demonstrated that CD45 is similarly downregulated in cells infected with HHV7. CD45 is essential for signaling through the T cell receptor and, as such, is necessary for developing a fully functional immune response. Interestingly, the closely related betaherpesviruses human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) have also separately evolved unique mechanisms to target CD45. While HCMV and MCMV target CD45 signaling and trafficking, HHV6A acts to downregulate CD45 transcripts. IMPORTANCE Human herpesviruses-6 and -7 infect essentially 100% of the world's population before the age of 5 and then remain latent or persistent in their host throughout life. As such, these viruses are among the most pervasive and stealthy of all viruses. Host immune cells rely on the presence of surface-expressed proteins to identify and target virus-infected cells. Here, we investigated the changes that occur to proteins expressed on the cell surface of T cells after infection with human herpesvirus-6A. We discovered that HHV-6A infection results in a reduction of CD45 on the surface of infected T cells and impaired activation in response to T cell receptor stimulation.

Burnout and Commitment to Primary Care: Lessons From the Early Impacts of COVID-19 on the Workplace Stress of Primary Care Practice Teams.

PURPOSE: The COVID-19 pandemic has dramatically affected all areas of health care. Primary care practices are on the front lines for patients seeking health care during this period. Understanding clinical and administrative staff members' strategies for managing the broad-ranging changes to primary care service delivery is important for the support of workforce well-being, burnout, and commitment to primary care. METHODS: Thirty-three staff members from 8 practices within a single health care system completed short, semistructured interviews from May 11, 2020 to July 20, 2020. Interviews were coded using a combination of conventional and directed content analysis. RESULTS: Themes emerged from the data that mapped onto the Job Demands-Control-Social Support model. Participants reported that every aspect of primary care service delivery needed to be adapted for COVID-19, which increased their job demands significantly. Several also described pride in their development of new skills, and in most interviews, they expressed that the experience brought staff together. Staff engaged in active cognitive reframing of events during the interviews as they coped with increased workplace stress. However, as the pandemic changed from an acute stress event to a chronic stressor, staff were more likely to indicate signs of burnout. CONCLUSIONS: Primary care teams absorbed tremendous burdens during COVID-19 but also found that some stress was offset by increased support from management and colleagues, belief in their own necessity, and new development opportunities. Considering high prepandemic strain levels, the ability of primary care teams to persist under these conditions might erode as the crisis becomes an enduring challenge.

Inborn errors of immunity manifesting as atopic disorders.

Inborn errors of immunity are traditionally best known for enhancing susceptibility to infections. However, allergic inflammation, among other types of immune dysregulation, occurs frequently in patients with inborn errors of immunity. As such, the term primary atopic disorders (PADs) was recently coined to describe the group of heritable monogenic allergic disorders. It is becoming increasingly important for clinicians to recognize that allergic diseases such as food allergy, atopic dermatitis, and allergic asthma are expressions of misdirected immunity, and in patients who present with severe, early-onset, or coexisting allergic conditions, these can be indications of an underlying PAD. Identifying monogenic allergic disease through next-generation sequencing can dramatically improve outcomes by allowing the use of precision-based therapy targeting the patient's underlying molecular defect. It is therefore imperative that clinicians recognize PADs to be able to provide informed therapeutic options and improve patient outcomes. Here, we summarize the clinical features commonly seen with each of the currently known PADs, identify clinical warning signs that warrant assessment for PADs, and lastly, discuss the benefits of timely diagnosis and management of these conditions.

High diagnosis rate for nonimmune hydrops fetalis with prenatal clinical exome from the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) Study.

PURPOSE: Nonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic etiologies. We explored incremental diagnostic yield of testing with prenatal exome sequencing (ES) for NIHF following a negative standard NIHF workup. METHODS: Participants enrolled into the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study met a strict definition of NIHF and had negative standard-of-care workup. Clinical trio ES from fetal samples and parental blood was performed at a CLIA-certified reference laboratory with clinical reports returned by geneticists and genetic counselors. Negative exomes were reanalyzed with information from subsequent ultrasounds and records. RESULTS: Twenty-two fetal exomes reported 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases comprised seven de novodominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, and RRAS2), three musculoskeletal disorders (RYR1, AMER1, and BICD2), two metabolic disorders (sialidosis and multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1). CONCLUSION: The etiology of NIHF predicts postnatal prognosis and recurrence risk in future pregnancies. ES provides high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup.

Musicogenic epilepsy: Expanding the spectrum of glutamic acid decarboxylase 65 neurological autoimmunity.

The objective of this study was to describe serological association of musicogenic epilepsy and to evaluate clinical features and outcomes of seropositive cases. Through retrospective chart review, musicogenic epilepsy patients were identified. Among 16 musicogenic epilepsy patients, nine underwent autoantibody evaluations and all had high-titer glutamic acid decarboxylase 65-immunoglobulin G (GAD65-IgG; >20 nmol·L-1 , serum, normal ≤ .02 nmol·L-1 , eight women). Median GAD65-IgG serum titer was 294 nmol·L-1 (20.3-3005 nmol·L-1 ), and median cerebrospinal fluid titer (n = 4) was 14.7 nmol·L-1 . All patients had temporal lobe epilepsy, and bitemporal epileptiform abnormalities were common. Right temporal lobe seizures were most frequently captured when seizures were induced by music on electroencephalogram (3/4; 75%). Intravenous (IV) methylprednisolone and/or IV Ig (IVIG) was utilized in four patients, with one having greater than 50% reduction. Rituximab (n = 2) and mycophenolate (n = 1) were ineffective. Two patients underwent right temporal lobe resections but continued to have seizures. Vagus nerve stimulation was effective at reducing seizures in one patient by 50%, and an additional patient was seizure-free by avoiding provoking music. Right temporal lobe epilepsy was more common among patients with musicogenic epilepsy when compared to nonmusicogenic GAD65 epilepsies (n = 71, 89% vs. 47%, p = .03). GAD65-IgG should be tested in patients with musicogenic epilepsy, given implications for management and screening for comorbid autoimmune conditions.

A qualitative analysis of third-year medical students' reflection essays regarding the impact of COVID-19 on their education.

BACKGROUND: The COVID-19 pandemic fundamentally changed every aspect of healthcare delivery and training. Few studies have reported on the impact of these changes on the experiences, skill development, and career expectations of medical students. METHOD: Using 59 responses to a short reflection essay prompt, 3rd year medical students in Philadelphia described how the COVID-19 pandemic affected their education in mid-2020. Using conventional content analysis, six main themes were identified across 14 codes. RESULTS: Students reported concerns regarding their decreased clinical skill training and specialty exposure on their career development due to the loss of in-person experience during their family medicine clerkship. A small number felt very let down and exploited by the continued high cost of tuition while missing clinical interactions. However, many students also expressed professional pride and derived meaning from limited patient and mentorship opportunities. Many students developed a new sense of purpose and a call to become stronger public health and patient advocates. CONCLUSIONS: The medical field will need to adapt to support medical students adversely impacted by the COVID-19 pandemic, from an educational and mental health standpoint. However, there are encouraging signs that this may also galvanize many students to engage in leadership roles in their communities, to become more empathetic and thoughtful physicians, and to redesign healthcare in the future to better meet the needs of their most vulnerable patients.

Tau deposition in young adults with drug-resistant focal epilepsy.

OBJECTIVE: To evaluate the presence of tau deposition and pathologic features of chronic traumatic encephalopathy (CTE) in young adult patients treated with focal cortical resections for drug-resistant epilepsy. METHODS: Sixty consecutive patients who had undergone surgical treatment for drug-resistant focal epilepsy between 18 and 45 years of age were identified (2010-2017). Medical records were reviewed to determine clinical factors, including history of head trauma, age at seizure onset, age at surgical resection, seizure type(s) and frequency, imaging findings, and surgical outcome. All formalin-fixed, paraffin-embedded blocks from the surgical specimens from each subject were sectioned and stained with hematoxylin and eosin and antibodies to tau (Thermo Fisher Scientific Clone AT8), and examined blindly for tau pathology, including lesions characteristic of CTE. RESULTS: The median age at resection was 29.5 years (range = 19-45). A history of head trauma was reported in 19 patients. Although none of the patients had pathological findings characteristic of CTE, 23 patients (38%) demonstrated tau-immunoreactive lesions, including neurites, neurofibrillary pretangles, neurofibrillary tangles, subpial tau, and/or glial tau. In 4 of the 23 patients (7% of the cohort; 17% of those with tau pathology), substantial tau burden was identified. Three of these 4 patients had no significant history of head trauma; 1 patient had multiple sports-related concussions. No specific clinical factors correlated with the presence of tau pathology. SIGNIFICANCE: Tau-immunoreactive lesions were found in 38% of 60 patients who underwent a focal cortical resection for drug-resistant focal epilepsy. Diagnostic features of CTE were not detected in any patient; however, the pathological evaluation for CTE was limited to a surgical specimen. The prominent and excessive tau deposition in 23 patients (38%) is abnormal in this age group and warrants further investigation.

Parent Engagement Correlates With Parent and Preterm Infant Oxytocin Release During Skin-to-Skin Contact.

BACKGROUND: Preterm infants remain increasingly neurodevelopmentally disadvantaged. Parental touch, especially during skin-to-skin contact (SSC), has potential to reduce adverse consequences. PURPOSE: To examine relationships between parental engagement and salivary oxytocin and cortisol levels for parents participating in SSC intervention. METHODS: A randomized crossover design study was conducted in a neonatal intensive care unit; 28 stable preterm infants, mothers, and fathers participated. Parental engagement was measured using the Parental Risk Evaluation Engagement Model Instrument (PREEMI) prior to hospital discharge. Saliva samples for oxytocin and cortisol levels were collected 15-minute pre-SSC, 60-minute during-SSC, and 45-minute post-SSC. RESULTS: Data were analyzed using Pearson's correlation to measure relationships between parental engagement composite scores and salivary oxytocin and cortisol levels. A significant negative correlation between paternal engagement and paternal oxytocin levels (r = -0.43; P = .03) and a significant negative correlation between infant oxytocin levels and maternal engagement (r = -0.54; P = .004) were present. Adjusted linear regression models demonstrated that as infant oxytocin levels increased during SSC, maternal engagement scores significantly decreased at discharge (ß = -.04; P = .01). Linear regression, adjusting for infant oxytocin and cortisol levels, showed that as paternal oxytocin levels increased, there was a significant decrease in paternal engagement (ß = -.16; P = .03) and as paternal cortisol levels increased, there was a significant decrease in paternal engagement (ß = -68.97; P =.05). IMPLICATIONS FOR PRACTICE: Significant relationships exist between parental engagement and salivary oxytocin and cortisol levels. Defining parent engagement facilitates identification of parent risks and needs for intervention to optimize preterm outcomes. IMPLICATIONS FOR RESEARCH: The PREEMI can serve as a standardized instrument to examine parent engagement.

Dose-response Relationship Between Donor Human Milk, Mother's Own Milk, Preterm Formula, and Neonatal Growth Outcomes.

BACKGROUND: A dose-response relationship between proportions of donor human milk (DHM) intake and in-neonatal intensive care unit (in-NICU) growth rates, if any, remains poorly defined. Objective was to evaluate interrelationships between percentages of DHM, mother's own milk (MOM), and preterm formula (PF) intake and neonatal growth parameters at 36 weeks postmenstrual age or NICU discharge. METHODS: Infants eligible for this single-center retrospective study were inborn at ≤32 weeks gestation or ≤1800 g, stayed in the NICU for ≥7 days, and received enteral nutrition consisting of human milk fortified with Enfamil human milk fortifier acidified liquid. Study exposures were defined as 10% increments in the total volumetric proportions of infant diet provided as MOM, DHM, or PF. Outcomes were growth parameters at 36 weeks postmenstrual age or NICU discharge. Multivariable linear regression modeled the adjusted additive effect of infant diet on individual growth parameters. RESULTS: A total of 314 infants records were eligible for analysis. Using MOM as reference, the adjusted mean growth velocity for weight significantly decreased by 0.17 g ·â€Škg ·â€Šday for every 10% increase in DHM intake, but did not vary with PF intake. The adjusted mean change in weight z score significantly decreased with increasing proportion of DHM intake but significantly improved with increasing PF intake. The adjusted mean head circumference velocity was significantly decreased by 0.01 cm/wk for every 10% increase in DHM intake, in reference to MOM, but did not vary with PF intake. Neither proportion of DHM nor PF intake was associated with length velocity. CONCLUSIONS: When DHM and MOM are fortified interchangeably, preterm infants receiving incremental amounts of DHM are at increased risk of postnatal growth restriction. The dose-response relationship between DHM, MOM, and PF and long-term growth and neurodevelopmental outcomes warrants further research.

Predictive validity of developmental screening in young children with sickle cell disease: a longitudinal follow-up study.

AIM: To assess the predictive validity of developmental screenings in children with sickle cell disease (SCD) for academic outcomes and stroke risk. METHOD: Parent questionnaires and medical record data were collected for a cohort receiving developmental screenings between September 2004 and May 2008 as toddlers or early school age. Screening outcomes were dichotomized (positive, negative) by a priori criteria. Questionnaires assessed school and social functioning, services received, and quality of life. Medical record data assessed general SCD morbidity and stroke risk. RESULTS: Forty-one toddlers (mean age 2y 5mo; 25 males, 16 females) and 49 early school-age children (mean age 6y 5mo; 26 males, 23 females) completed follow-up. The mean follow-up period was 8 years 6 months (range 6.1-10.8y). For toddlers, positive screenings for language delays predicted lower academic performance (p=0.023). For older children, positive screenings for cognitive delays predicted more frequent academic/attentional problems at school (p<0.001), grade retention (p=0.007), and lower academic performance (p=0.001). Positive screenings were associated with an earlier onset of school problems and lower quality of life. Positive screenings for language/cognitive delays predicted increased stroke risk (both p<0.05). INTERPRETATION: Screening for language or cognitive development in young children with SCD predicts academic outcomes and stroke risk. WHAT THIS PAPER ADDS: Developmental screening predicts academic outcomes in sickle cell disease. Children with concerning language/cognitive screenings have early-onset school difficulties. Developmental screenings may help predict cerebrovascular complications.