Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population.

The folate receptor alpha autoantibodies (FRAAs) are associated with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD). Both of these syndromes have overlapping characteristics with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Thus, we propose that the FRAAs may contribute to the symptomatology of PANS/PANDAS. To test this hypothesis, 1 mL of serum from 47 patients (age range = 6-18 years old) clinically diagnosed with PANS/PANDAS was sent to Vascular Strategies (Plymouth Meeting, PA, USA) for analysis of FRAAs. Moreover, 63.8% of PANS/PANDAS patients (male = 15; female = 15) were found to have either the blocking and/or blinding FRAAs, with 25 (83.3%; male = 14; female = 11) having binding FRAAs, two (6.7%; all female = 2) having blocking FRAAs, and 3 (10%; male = 1; female = 2) having both binding and blocking. Furthermore, surprisingly, ASD was associated with a 0.76 lower binding titer (p = 0.02), and severe tics were associated with a 0.90 higher binding titer (p = 0.01). A case of a FRAA-positive patient is provided to illustrate that a treatment plan including leucovorin can result in symptom improvement in patients with PANS/PANDAS who are FRAA-positive. These data, for the first time, demonstrate that PANS/PANDAS is associated with FRAAs and suggest folate metabolism abnormalities may contribute to PANS/PANDAS symptomatology. Further studies investigating the therapeutic nature of leucovorin in the treatment of PANS/PANDAS are needed. Such studies may open up an alternative, safe, and well-tolerated treatment for those with the PANS/PANDAS diagnosis.

Measuring Subjective Cognitive Decline in Older Adults: Harmonization Between the Cognitive Change Index and the Measurement of Everyday Cognition Instruments.

BACKGROUND: Self and informant (proxy or study partner) reports of everyday cognitive functioning have been shown to be associated with incipient neurodegenerative disease. The 20-item Cognitive Change Index (CCI) and the 39-item Measurement of Everyday Cognition (ECog) were each developed to characterize early subjective changes in cognitive function. OBJECTIVE: We examined the relationship between CCI and ECog self and informant-based evaluations to determine content overlap and provide a co-calibration for converting between these widely used instruments. METHODS: 950 participants (57.1% female, mean age = 71.2 years) from ADNI and the Indiana ADRC with self-based evaluations and 279 participants (60.9% female, mean age = 71.8 years) with informant-based evaluations (Indiana ADRC) were included. Analyzed variables for the CCI and ECog included domain mean scores, memory domain total scores, and total scores for all items. Spearman correlations, regression analyses, and frequency distributions were used to assess the relationship between CCI and ECog. Sex, age, years of education, race/ethnicity, APOE ɛ4 carrier status, and baseline diagnosis were also analyzed as potentially relevant covariates. RESULTS: CCI and ECog total scores were highly correlated for the self (r = 0.795, p < 0.001) and informant-based (r = 0.840, p < 0.001) versions, as expected. Frequency distributions of self and informant total scores were generated and plotted separately. Quadratic regressions for self (r2 = 0.626) and informant (r2 = 0.741) scores were used to create a translation table between the CCI and ECog total scores. CONCLUSION: Self and informant total scores can be harmonized and translated between the CCI and ECog to facilitate cross-study and longitudinal assessment of perceived cognitive change, an important patient-reported outcome.

The Effect of Prearrest Acid-Base Status on Response to Sodium Bicarbonate and Achievement of Return of Spontaneous Circulation.

BACKGROUND: The efficacy of sodium bicarbonate (SB) administration during in-hospital cardiac arrest (IHCA) for treatment of acidosis is not well described. The available literature has only evaluated out-of-hospital arrest events in patients with suspected acidosis caused by prolonged arrest. OBJECTIVE: This study evaluated SB and its effects on return of spontaneous circulation (ROSC) in patients experiencing IHCA, based on presence of acidosis at baseline as determined by prearrest bicarbonate levels. METHODS: We conducted a retrospective cohort study of patients who all received intravenous SB during IHCA. Patients with prearrest bicarbonate levels >21 mmol/L (nonacidotic group) were compared with those with prearrest bicarbonate levels ≤21 mmol/L (acidotic group) for the primary outcome of ROSC. RESULTS: A total of 225 patients (102 acidotic, 123 nonacidotic) were evaluated. Asystole (37.3% vs 34.1%; P = 0.63) and pulseless electrical activity (30.4% vs 29.3%; P = 0.85) were the most common presenting rhythms. There were no differences in ROSC in the overall population (53.9% vs 48.8%; P = 0.44) or between those who had early (within 20 minutes) or delayed (after 20 minutes) ROSC. Secondary outcomes, including cardiopulmonary resuscitation duration, epinephrine administration, and total SB, were similar between groups. CONCLUSIONS AND RELEVANCE: In this cohort study, administration of SB for IHCA in patients with prearrest acidosis was not associated with increased incidence of ROSC compared with those without prearrest acidosis. Our data suggest that there may be no benefit to the administration of SB in the setting of IHCA, regardless of prearrest acidotic status. Further investigation into the effect of SB for treatment of acidosis in IHCA is warranted.

Vitamin C and Thiamine for Sepsis and Septic Shock.

BACKGROUND: Sepsis and septic shock are medical emergencies resulting in significant morbidity and mortality. Intravenous (IV) vitamin C, thiamine, and hydrocortisone have shown promise in reducing hospital mortality. The Memphis Veterans Affairs Medical Center (VAMC) similarly implemented this regimen, called the vitamin C protocol, for patients presenting in sepsis or septic shock in the intensive care unit (ICU). METHODS: This retrospective study in Veteran ICU patients with sepsis or septic shock compared outcomes of patients treated with IV vitamin C, thiamine, and hydrocortisone (treatment) with those who received IV hydrocortisone alone (control). Data was propensity matched to ensure comparability at baseline. The Sequential Organ Failure Assessment (SOFA) score was calculated at day of diagnosis (day 0) and daily for 3 subsequent days. At the 24-month follow-up, 12 months after the 1-year-intervention, survival and measures of mental and physical health were collected by telephone interviews. RESULTS: Hospital mortality, the primary outcome, did not differ significantly between groups. Secondary outcomes including ICU, 28-day, and 60-day mortality were also not different, nor were vasopressor duration or hospital length of stay. However, ICU length of stay was significantly reduced in the treatment group compared to control (7.1 vs 15.6 days, respectively, P = 0.04). CONCLUSIONS: Although no significant mortality benefit was observed, the vitamin C protocol was not associated with patient harm. In this Veteran population, there was reduced ICU length of stay, suggesting possible benefit. Though further investigation is warranted, utilization of IV vitamin C, thiamine, and hydrocortisone in patients with sepsis or septic shock may be a treatment option worth considering.

Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion.

Preexisting neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) pose a major, unresolved challenge that restricts patient enrollment in gene therapy clinical trials using recombinant AAV vectors. Structural studies suggest that despite a high degree of sequence variability, antibody recognition sites or antigenic hotspots on AAVs and other related parvoviruses might be evolutionarily conserved. To test this hypothesis, we developed a structure-guided evolution approach that does not require selective pressure exerted by NAbs. This strategy yielded highly divergent antigenic footprints that do not exist in natural AAV isolates. Specifically, synthetic variants obtained by evolving murine antigenic epitopes on an AAV serotype 1 capsid template can evade NAbs without compromising titer, transduction efficiency, or tissue tropism. One lead AAV variant generated by combining multiple evolved antigenic sites effectively evades polyclonal anti-AAV1 neutralizing sera from immunized mice and rhesus macaques. Furthermore, this variant displays robust immune evasion in nonhuman primate and human serum samples at dilution factors as high as 1:5, currently mandated by several clinical trials. Our results provide evidence that antibody recognition of AAV capsids is conserved across species. This approach can be applied to any AAV strain to evade NAbs in prospective patients for human gene therapy.