Multi-Class Analysis of 57 Drugs Quantitatively in Blood and Qualitatively in Urine by LC-MS/MS to Complement Comprehensive DFC, DUID and Postmortem Testing.

A streamlined LC-MS/MS method utilizing protein precipitation and filtration extraction was developed to consolidate analyses for drug-facilitated crime (DFC), postmortem investigations, and driving under the influence of drugs (DUID) testing. Fifty-seven target drug and metabolite analytes eluted in under 6-minutes and compromised of GHB precursors (1), hallucinogens (3), muscle relaxants (3), anticonvulsants (7), antidepressants (20), antihistamines (5), antipsychotics (11), antihypertensives and alpha-adrenergics (3), analgesics and anesthetics (3), and miscellaneous (1) in blood (quantitatively) and urine (qualitatively). Limits of detection were set to meet the more challenging sensitivity requirements for DFC, and are therefore also suitable for postmortem investigations, and other forensic casework, including DUID. Comprehensive ASB/ANSI validation was performed, and applicability studies examined 72 proficiency test blood and urine samples, along with 9,206 unique blood and urines samples from 5,192 authentic forensic cases that resulted in 11,961 positive analytes in samples. By expanding the analytical reach across multiple drug classes through a unified approach and screening a wider number of drugs, the technique can identify substances that might have previously evaded detection, thereby enhancing laboratory efficiency by minimizing the need for multiple tests. When combined with a recently developed in-house method, this integrated testing strategy meets the testing requirements outlined in ASB/ANSI standards and recommendations for DFC, postmortem, and Tier 1 DUID analyses.

Analysis of over 250 novel synthetic opioids and xylazine by LC-MS-MS in blood and urine.

Novel Synthetic Opioids (NSO) are frequently found in postmortem (PM) and human performance (HP) forensic toxicology casework, resulting in impairment and fatal overdoses. Developing a broad NSO method benefits public health, as it can be used to identify trends in potent opioid use to develop risk management programs. This project aimed to design a comprehensive, rapid and routine method for the selective analysis of over 250 novel synthetic opioids in blood and urine. This method rapidly extracted 150 µL of blood or urine via protein precipitation followed by size-exclusion filtration, evaporation and reconstitution. Separation and data acquisition were achieved on a 12 min LC-MS-MS method using an F5 column. Data processing was expedited with a custom built-in query created in-house that automated processing and enhanced quality assurance. Validation according to ASB/ANSI Standard 036 was performed and applicability of the method was assessed using proficiency test and authentic casework samples. Assessed in blood and urine qualitatively were 261 unique analytes including fentanyl analogs (fentalogs), nitazenes and other miscellaneous synthetic opioids. As 59 isomeric target analytes were placed into groups due to co-elution, there were 202 distinct acquired targets or target - groups. To demonstrate applicability, 27 proficiency test blood samples received over an approximate 4-year period were analyzed with 126 expected results assessed comprising 25 unique target analytes. Additionally, 617 fatal accidental overdoses within San Francisco in 2022 were retroactively analyzed by this method with almost 10% of cases containing a new NSO substance(s). Such trends and NSO substances were previously unknown in this community.

A Single Method for 127 Recommended and Additional DUID Drugs in Blood and Urine by LC-MS-MS.

Driving under the influence of drug (DUID) cases continue to challenge forensic toxicologists as both the volume and complexity of casework increases. Comprehensive DUID testing should also meet the drafted Academy Standards Board (ASB)/ American National Standard Institute (ANSI) standard and the National Safety Council's Alcohol, Drugs and Impairment Division (NSC-ADID) recommendations. A simple method using protein precipitation followed by filtration extraction with an 8 minute run time by liquid chromatography-tandem mass spectrometry (LC-MS-MS) was developed, and a comprehensive ASB/ANSI validation was performed. Target drugs and metabolites were quantitatively assessed in blood and qualitatively assessed in urine. Included were 127 target analytes including cannabinoids (12), amphetamines (11), cocaine and metabolites (6), benzodiazepines (36), Z-drugs (5), opioids (27), anticonvulsants (3), first-generation antihistamines (6), muscle relaxants (2), dissociatives and hallucinogens (6), barbiturates (10), and miscellaneous substances (3). Limits of detection are appropriate for DUID and other forensic casework such as drug-facilitated crime (DFC) and postmortem investigations. To demonstrate applicability, 78 proficiency test blood and urine samples and 1,645 blood and urine samples from authentic cases samples demonstrated effective detection of target analytes in forensic casework. By increasing the analytical scope of multiple drug classes via a single method, this technique detects drugs that may have previously gone undetected, such as flualprazolam, etizolam, mitragynine, gamma-hydroxybutyric acid and psilocin and improves laboratory efficiency by reducing the number of tests required. The described method is, to the authors' best knowledge, the only published single procedure to meet all drugs listed in the drafted ASB/ANSI standard and recommended Tier 1 and traditional drugs from Tier 2 for DUID screening, while also achieving many drug scope and sensitivity recommendations for DFC and postmortem testing.

Mid-life social outcomes for a population-based sample of adults with ASD.

Adults with autism spectrum disorders (ASD) fall short of social outcomes of non-ASD peers in mid-life, as documented by currently published research. The aim of the current study was to extend what is known about social functioning, employment, independent living, and use of social services by examining details of the current life status for a population-based sample of adults with ASD (mean age = 35.5 years, range = 22.2-51.4). We collected outcome data via direct assessment and informant report for 169 individuals. Three-fourths of the sample had cognitive abilities in the intellectually disabled range. Social functioning outcomes, as a single measure, mirror those reported previously for other samples, including samples with a high proportion of individuals with normal range intellectual abilities, with 20% achieving the most independent outcomes and 46% requiring high levels of support across most life areas. Participant subgroups who achieved maximal outcomes represented a range of social and intellectual abilities for several outcome metrics. Participants used high levels of public and private supports, yet specific areas of clear, unmet need were also identified. Autism Res 2018, 11: 142-152. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This paper describes the social functioning outcomes for 169 adults with autism spectrum disorders in mid-life. Adult participants spanned the full range of functional and cognitive ability levels, with over 75% functioning in the cognitively impaired range. While summary descriptions of outcomes for this sample were similar to those reported for other groups of adults, this report provides detailed information regarding employment outcomes, social relationships, leisure activities, participation in the community, residential situations, public service use, and involvement with law enforcement.

A description of medical conditions in adults with autism spectrum disorder: A follow-up of the 1980s Utah/UCLA Autism Epidemiologic Study.

This study describes medical conditions experienced by a population-based cohort of adults with autism spectrum disorder whose significant developmental concerns were apparent during childhood. As part of a 25-year outcome study of autism spectrum disorder in adulthood, medical histories were collected on 92 participants (N = 69 males) who were first ascertained as children in the mid-1980s, 11 of whom were deceased at the time of follow-up. Questionnaires queried medical symptoms, disorders, hospitalizations, surgeries, and medication use. Median age at follow-up was 36 years (range: 23.5-50.5 years), and intellectual disability co-occurred in 62%. The most common medical conditions were seizures, obesity, insomnia, and constipation. The median number of medical conditions per person was 11. Increased medical comorbidity was associated with female gender (p = 0.01) and obesity (p = 0.03), but not intellectual disability (p = 0.79). Adults in this cohort of autism spectrum disorder first ascertained in the 1980s experience a high number of chronic medical conditions, regardless of intellectual ability. Understanding of these conditions commonly experienced should direct community-based and medical primary care for this population.

Identifying autism in a brief observation.

BACKGROUND: Pediatricians, neurologists, and geneticists are important sources for autism surveillance, screening, and referrals, but practical time constraints limit the clinical utility of behavioral observations. We analyzed behaviors under favorable conditions (ie, video of autism evaluations reviewed by experts) to determine what is optimally observable within 10-minute samples, asked for referral impressions, and compared these to formal screening and developmental testing results. METHODS: Participants (n = 42, aged 15 to 33 months) were typically developing controls and children who screened positive during universal autism screening within a large community pediatric practice. Diagnostic evaluations were performed after screening to determine group status (autism, language delay, or typical). Licensed psychologists with toddler and autism expertise, unaware of diagnostic status, analyzed two 10-minute video samples of participants' autism evaluations, measuring 5 behaviors: Responding, Initiating, Vocalizing, Play, and Response to Name. Raters were asked for autism referral impressions based solely on individual 10-minute observations. RESULTS: Children who had autism showed more typical behavior (89% of the time) than atypical behavior (11%) overall. Expert raters missed 39% of cases in the autism group as needing autism referrals based on brief but highly focused observations. Significant differences in cognitive and adaptive development existed among groups, with receptive language skills differentiating the 3 groups. CONCLUSIONS: Brief clinical observations may not provide enough information about atypical behaviors to reliably detect autism risk. High prevalence of typical behaviors in brief samples may distort clinical impressions of atypical behaviors. Formal screening tools and general developmental testing provide critical data for accurate referrals.

Psychiatric comorbidity and medication use in adults with autism spectrum disorder.

The purpose of this study was to investigate comorbid psychiatric disorders and psychotropic medication use among adults with autism spectrum disorder (ASD) ascertained as children during a 1980's statewide Utah autism prevalence study (n = 129). Seventy-three individuals (56.6 %) met criteria for a current psychiatric disorder; 89 participants (69.0 %) met lifetime criteria for a psychiatric disorder. Caregivers reported a psychiatric diagnosis in 44 participants (34.1 %). Anxiety disorder had the highest current and lifetime prevalence (39.5 and 52.7 %, respectively). Participants with intellectual disability (n = 94, 72.8 %) were significantly less likely to have community-based diagnoses of anxiety (χ(2) = 5.37, p = 0.02) or depression (χ(2) = 13.18, p < 0.001) reported by caregivers. Seventy-six participants (58.9 %) were taking ≥1 psychotropic medication. Comorbid psychiatric disorders occur frequently in adults with ASD, though identifying these disorders poses a challenge in community settings. A greater understanding of the presentation of these conditions within this population will increase assessment validity and the potential for efficacious intervention.

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.

UNLABELLED: Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene. IMPLICATIONS: BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.

Autism spectrum disorder reclassified: a second look at the 1980s Utah/UCLA Autism Epidemiologic Study.

The purpose of the present study was to re-examine diagnostic data from a state-wide autism prevalence study (n = 489) conducted in the 1980s to investigate the impact of broader diagnostic criteria on autism spectrum disorder (ASD) case status. Sixty-four (59 %) of the 108 originally "Diagnosed Not Autistic" met the current ASD case definition. The average IQ estimate in the newly identified group (IQ = 35.58; SD = 23.01) was significantly lower than in the original group (IQ = 56.19 SD = 21.21; t = 5.75; p < .0001). Today's diagnostic criteria applied to participants ascertained in the 1980s identified more cases of autism with intellectual disability. The current analysis puts this historic work into context and highlights differences in ascertainment between epidemiological studies performed decades ago and those of today.

Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA autism epidemiologic study.

This study's purpose was to investigate mortality among individuals with autism spectrum disorders (ASD) ascertained during a 1980s statewide autism prevalence study (n = 305) in relation to controls. Twenty-nine of these individuals (9.5 %) died by the time of follow up, representing a hazard rate ratio of 9.9 (95 % CI 5.7-17.2) in relation to population controls. Death certificates identified respiratory, cardiac, and epileptic events as the most common causes of death. The elevated mortality risk associated with ASD in the study cohort appeared related to the presence of comorbid medical conditions and intellectual disability rather than ASD itself suggesting the importance of coordinated medical care for this high risk sub-population of individuals with ASD.

Primary care for children with autism.

The earliest sign of autism in children is the delayed attainment of social skill milestones, including joint attention, social orienting, and pretend play. Language impairment is a common, but less specific, sign of autism. Repetitive behaviors and restricted interests may not be noted until after social skill and communication impairments are exhibited. Physicians should perform developmental surveillance at all well-child visits, and the American Academy of Pediatrics recommends administering an autism-specific screening tool at the 18- and 24-month visits. A referral for comprehensive diagnostic evaluation is appropriate if concerns arise from surveillance, screening, or parental observations. The goals of long-term management are to maximize functional independence and community engagement, minimize maladaptive behaviors, and provide family and caregiver support. Physicians play an important role in coordinating care through an interdisciplinary team; referring families for specialized services; and treating children's associated conditions, including sleep disturbances, gastrointestinal problems, anxiety, and hyperactivity. Autism is a lifelong condition, but early recognition, diagnosis, and treatment can improve the prognosis, whereas associated medical conditions, psychiatric conditions, and intellectual disability can worsen the prognosis.

Twenty-year outcome for individuals with autism and average or near-average cognitive abilities.

Previous studies found substantial variability in adult outcome for people with autism whose cognitive functioning was within the near-average and average ranges. This study examined adult outcome for 41 such individuals (38 men and 3 women) originally identified through an epidemiological survey of autism in Utah. Mean age at the time of their previous cognitive assessment was 7.2 years (SD=4.1, range=3.1-25.9 years) and at follow-up was 32.5 years (SD=5.7 years, range=22.3-46.4 years). Outcome measures included standardized assessments of diagnostic status, cognitive ability, and adaptive behavior. Additional information collected concerned demographic variables, indicators of independence, social relationships, medical and psychiatric conditions, and social service use. Outcomes for this sample were better than outcomes described in previous work on individuals with similar cognitive functioning. For example, half of the participants were rated as "Very Good" or "Good" on a global outcome measure. As in previous studies, there was considerable variability in measured cognitive ability over time. Over half of the sample had large gains or losses of cognitive ability of greater than 1 standard deviation. Cognitive gain was associated with better outcome, as was better adaptive functioning. While all participants had baseline IQs in the nonimpaired range, there was limited evidence to support the use of other early childhood variables to predict adult outcome.