Association of Depression and Antidepressant Use With Driving Behaviors in Older Adults: A LongROAD Study.

Older adults aged 70 and older who drive have higher crash death rates per mile driven compared to middle aged (35-54 years) adults who drive in the US. Prior studies have found that depression and or antidepressant medication use in older adults are associated with an increase in the vehicular crash rate. Using data from the prospective multi-site AAA Longitudinal Research on Aging Drivers Study, this analysis examined the independent and interdependent associations of self-reported depression and antidepressant use with driving behaviors that can increase motor vehicle crash risk such as hard braking, speeding, and night-time driving in adults over age 65. Of the 2951 participants, 6.4% reported having depression and 21.9% were on an antidepressant medication. Correcting for age, race, gender, and education level, participants on an antidepressant had increased hard braking events (1.22 [1.10-1.34]) but self-reported depression alone was not associated with changes in driving behaviors.

Pumping the brakes: A noncanonical RNA-binding domain in FMRP stalls elongating ribosomes.

Loss of function of the RNA-binding protein FMRP causes fragile X syndrome, the most common inherited form of intellectual disability and autism spectrum disorders. FMRP is suggested to modulate synaptic plasticity by regulating the synthesis of proteins involved in neuronal and synaptic function; however, the mechanism underlying FMRP mRNA targeting specificity remains unclear. Intriguing recent work published in JBC by Scarpitti and colleagues identifies and characterizes a noncanonical RNA-binding domain that is required for FMRP-mediated translation regulation, shedding light on FMRP function.

Equipping Small Businesses to Navigate Health Orders and Occupational Safety During the COVID-19 Pandemic.

From July 2020 to June 2021, the UC San Diego COVID-19 Small Business Outreach Project conducted COVID-19-related educational outreach to small businesses in high-risk communities of San Diego County and distributed over 1,200 toolkits containing COVID-19-related safety tips, best practices, and a summary of pertinent guidelines and COVID-19 vaccine information.

Studies of a mosaic patient with DBA and chimeric mice reveal erythroid cell-extrinsic contributions to erythropoiesis.

We follow a patient with Diamond-Blackfan anemia (DBA) mosaic for a pathogenic RPS19 haploinsufficiency mutation with persistent transfusion-dependent anemia. Her anemia remitted on eltrombopag (EPAG), but surprisingly, mosaicism was unchanged, suggesting that both mutant and normal cells responded. When EPAG was withheld, her anemia returned. In addition to expanding hematopoietic stem/progenitor cells, EPAG aggressively chelates iron. Because DBA anemia, at least in part, results from excessive intracellular heme leading to ferroptotic cell death, we hypothesized that the excess heme accumulating in ribosomal protein-deficient erythroid precursors inhibited the growth of adjacent genetically normal precursors, and that the efficacy of EPAG reflected its ability to chelate iron, limit heme synthesis, and thus limit toxicity in both mutant and normal cells. To test this, we studied Rpl11 haploinsufficient (DBA) mice and mice chimeric for the cytoplasmic heme export protein, FLVCR. Flvcr1-deleted mice have severe anemia, resembling DBA. Mice transplanted with ratios of DBA to wild-type marrow cells of 50:50 are anemic, like our DBA patient. In contrast, mice transplanted with Flvcr1-deleted (unable to export heme) and wild-type marrow cells at ratios of 50:50 or 80:20 have normal numbers of red cells. Additional studies suggest that heme exported from DBA erythroid cells might impede the nurse cell function of central macrophages of erythroblastic islands to impair the maturation of genetically normal coadherent erythroid cells. These findings have implications for the gene therapy of DBA and may provide insights into why del(5q) myelodysplastic syndrome patients are anemic despite being mosaic for chromosome 5q deletion and loss of RPS14.

A survey of distracted driving and electronic device use among app-based and taxi drivers.

OBJECTIVES: The purpose of this study was to identify, characterize and compare attitudes, beliefs, behaviors and other factors related to electronic device (ED) use and distracted driving (DD) among taxi and app-based drivers. METHODS: A survey among drivers in San Diego and across the United States was used to collect self-reported attitudes and behaviors among taxi and app-based passenger-carrying drivers from October 1, 2016 to January 31, 2017. Chi-square or Fisher's exact test was used to assess the difference between sociodemographics, ED use, ED use attitudes, and citation and crash history by driver type. Prevalence ratios were assessed for differences in ED use and ED use attitudes by driver type using Poisson regression models with robust error variance and a log link function. The final models adjusted for age, sex, level of experience, education and English fluency. All analyses were performed using SAS version 9.4. RESULTS: Of the 175 drivers that met eligibility criteria, 131 reported driving for app-based services and 44 identified as taxi drivers. Compared to taxi drivers, app-based drivers were more likely to be female, native English speaking, and have fewer than 3 years of experience in the transportation business. All drivers reported at least one type of DD while the car was in motion. App-based drivers were significantly more likely to use a smartphone while driving (adjusted prevalence ratio (APR): 1.42), report that while driving it is safe or very safe to accept a call (APR: 1.73), receive/respond to a passenger request (APR: 3.40), or process a payment (APR: 5.39). Taxi drivers were more likely to either receive a citation for ED use (31.8% v 7.6%, p < 0.001) or be in a collision while using ED (29.6% v 4.6%, p < 0.001). Almost all drivers who received a citation or who were involved in a crash reported becoming somewhat or significantly more cautious about using ED while driving. CONCLUSIONS: Drivers in the small passenger-carrying transportation industry engage in DD frequently due to occupational demands. Given the known increased crash risk with DD, effective policies and interventions for app-based and taxi drivers are needed.

Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia.

Diamond Blackfan Anemia (DBA) is a congenital macrocytic anemia associated with ribosomal protein haploinsufficiency. Ribosomal dysfunction delays globin synthesis, resulting in excess toxic free heme in erythroid progenitors, early differentiation arrest, and pure red cell aplasia. In this study, DBA induced pluripotent stem cell (iPSC) lines were generated from blood mononuclear cells of DBA patients with inactivating mutations in RPS19 and subjected to hematopoietic differentiation to model disease phenotypes. In vitro differentiated hematopoietic cells were used to investigate whether eltrombopag, an FDA-approved mimetic of thrombopoietin with robust intracellular iron chelating properties, could rescue erythropoiesis in DBA by restricting the labile iron pool (LIP) derived from excessive free heme. DBA iPSCs exhibited RPS19 haploinsufficiency, reduction in the 40S/60S ribosomal subunit ratio and early erythroid differentiation arrest in the absence of eltrombopag, compared to control isogenic iPSCs established by CRISPR/Cas9-mediated correction of the RPS19 point mutation. Notably, differentiation of DBA iPSCs in the presence of eltrombopag markedly improved erythroid maturation. Consistent with a molecular mechanism based on intracellular iron chelation, we observed that deferasirox, a clinically licensed iron chelator able to permeate into cells, also enhanced erythropoiesis in our DBA iPSC model. In contrast, erythroid maturation did not improve substantially in DBA iPSC differentiation cultures supplemented with deferoxamine, a clinically available iron chelator that poorly accesses LIP within cellular compartments. These findings identify eltrombopag as a promising new therapeutic to improve anemia in DBA.

Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review.

Rare pathogenic EIF2S3 missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novel EIF2S3 pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of the EIF2S3 encoded eIF2γ subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.

Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB.

Dysregulation of cellular protein synthesis is linked to a variety of diseases. Mutations in EIF2S3, encoding the γ subunit of the heterotrimeric eukaryotic translation initiation factor eIF2, cause MEHMO syndrome, an X-linked intellectual disability disorder. Here, using patient-derived induced pluripotent stem cells, we show that a mutation at the C terminus of eIF2γ impairs CDC123 promotion of eIF2 complex formation and decreases the level of eIF2-GTP-Met-tRNAiMet ternary complexes. This reduction in eIF2 activity results in dysregulation of global and gene-specific protein synthesis and enhances cell death upon stress induction. Addition of the drug ISRIB, an activator of the eIF2 guanine nucleotide exchange factor, rescues the cell growth, translation, and neuronal differentiation defects associated with the EIF2S3 mutation, offering the possibility of therapeutic intervention for MEHMO syndrome.

'Just Drive': An Employee-Based Intervention to Reduce Distracted Driving.

Distracted driving is a major danger on today's roadways. Employers play a critical role in developing distracted driving policies and promoting a culture of workplace driving safety. The purpose of this study was to evaluate the effectiveness of an in-person work-based class to reduce distracted driving in participating employees. The "Just Drive-Take Action Against Distraction" class was designed by the UC San Diego Training, Research and Education for Driving Safety (TREDS) program to increase awareness of the dangers of distracted driving and to encourage employees to be safe and responsible drivers, both on and off the job. Participants completed pre- and post-anonymous surveys and, in a subset of attendees, volunteers were contacted via email 3 months post-intervention to complete a driving-behavior survey on Surveymonkey.com. 115 classes for 6896 employees were delivered at 54 agencies in Southern California. A total of 4928 participants completed the pre- and post-survey; 2014 n = 2263 and 2015 n = 2665. The course was found useful (85%) and engaging (85.6%). For non-commercial drivers, 55.6% of participants reported an increase of 80-100% in awareness of the dangers of distracted driving, and 67.2% reported an increase of 80-100% in their motivation to change. For commercial drivers, 71.3% reported a motivation increase of 80-100%. There were significant increases in knowledge for both groups. In the three-month follow-up survey, participants identified multiple positive changes in distracted driving behavior. This 1-h employer-supported intervention demonstrated positive changes in short-term intention and medium-term behaviors.

Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation.

BACKGROUND: The heterotrimeric GTP-binding protein eIF2 forms a ternary complex with initiator methionyl-tRNA and recruits it to the 40S ribosomal subunit for start codon selection and thereby initiates protein synthesis. Mutations in EIF2S3, encoding the eIF2γ subunit, are associated with severe intellectual disability and microcephaly, usually as part of MEHMO syndrome. METHODS: Exome sequencing of the X chromosome was performed on three related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. In situ hybridisation on human embryonic tissue, EIF2S3-knockdown studies in a human pancreatic cell line, and yeast assays on the mutated corresponding eIF2γ protein, were performed in this study. FINDINGS: We report a novel hemizygous EIF2S3 variant, p.Pro432Ser, in the three boys (heterozygous in their mothers). EIF2S3 expression was detectable in the developing pituitary gland and pancreatic islets of Langerhans. Cells lacking EIF2S3 had increased caspase activity/cell death. Impaired protein synthesis and relaxed start codon selection stringency was observed in mutated yeast. INTERPRETATION: Our data suggest that the p.Pro432Ser mutation impairs eIF2γ function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. Untreated hypoglycaemia in previous cases may have contributed to their more severe neurological impairment and seizures in association with impaired EIF2S3. FUND: GOSH, MRF, BRC, MRC/Wellcome Trust and NIGMS funded this study.

MEHMO syndrome mutation EIF2S3-I259M impairs initiator Met-tRNAiMet binding to eukaryotic translation initiation factor eIF2.

The heterotrimeric eukaryotic translation initiation factor (eIF) 2 plays critical roles in delivering initiator Met-tRNAiMet to the 40S ribosomal subunit and in selecting the translation initiation site. Genetic analyses of patients with MEHMO syndrome, an X-linked intellectual disability syndrome, have identified several unique mutations in the EIF2S3 gene that encodes the γ subunit of eIF2. To gain insights into the molecular consequences of MEHMO syndrome mutations on eIF2 function, we generated a yeast model of the human eIF2γ-I259M mutant, previously identified in a patient with MEHMO syndrome. The corresponding eIF2γ-I318M mutation impaired yeast cell growth and derepressed GCN4 expression, an indicator of defective eIF2-GTP-Met-tRNAiMet complex formation, and, likewise, overexpression of human eIF2γ-I259M derepressed ATF4 messenger RNA translation in human cells. The yeast eIF2γ-I318M mutation also increased initiation from near-cognate start codons. Biochemical analyses revealed a defect in Met-tRNAiMet binding to the mutant yeast eIF2 complexes in vivo and in vitro. Overexpression of tRNAiMet restored Met-tRNAiMet binding to eIF2 in vivo and rescued the growth defect in the eIF2γ-I318M strain. Based on these findings and the structure of eIF2, we propose that the I259M mutation impairs Met-tRNAiMet binding, causing altered control of protein synthesis that underlies MEHMO syndrome.

Women's experiences with early pregnancy loss in the emergency room: A qualitative study.

OBJECTIVES: To understand the reasons why women present to the Emergency Room (ER) for Early Pregnancy Loss (EPL)-related care, how they perceive care and counseling there, and their overall experience during and after their visit. STUDY DESIGN: This qualitative study utilized semi-structured telephone interviews. Participants were recruited in a large urban ER; women who experienced EPL were interviewed by telephone about their experiences 1-3 weeks after their visit. Audio recordings were transcribed and coded by two independent coders. MAIN OUTCOME MEASURES: This qualitative study utilized semi-structured interviews without the use of formal outcome measurement tools. RESULTS: Of the sixty-seven women recruited, ten completed the full telephone interview. Interview participants' responses were grouped into four categories: Feelings about EPL, reasons for going to the ER, experience in the ER, and experience after leaving the ER. Women had mixed feelings about their ER experiences; many reported chaos, lack of information or lack of emotional support, while a few felt informed and supported. Many did not know much about EPL before their experience. CONCLUSIONS: ER care for women experiencing suspected or confirmed EPL may not be addressing the emotional needs and knowledge gaps of women. Patient education, emotional support, and clear plans for outpatient follow up are critical. Further research is needed to guide interventions to improve care.

Polyamine Control of Translation Elongation Regulates Start Site Selection on Antizyme Inhibitor mRNA via Ribosome Queuing.

Translation initiation is typically restricted to AUG codons, and scanning eukaryotic ribosomes inefficiently recognize near-cognate codons. We show that queuing of scanning ribosomes behind a paused elongating ribosome promotes initiation at upstream weak start sites. Ribosomal profiling reveals polyamine-dependent pausing of elongating ribosomes on a conserved Pro-Pro-Trp (PPW) motif in an inhibitory non-AUG-initiated upstream conserved coding region (uCC) of the antizyme inhibitor 1 (AZIN1) mRNA, encoding a regulator of cellular polyamine synthesis. Mutation of the PPW motif impairs initiation at the uCC's upstream near-cognate AUU start site and derepresses AZIN1 synthesis, whereas substitution of alternate elongation pause sequences restores uCC translation. Impairing ribosome loading reduces uCC translation and paradoxically derepresses AZIN1 synthesis. Finally, we identify the translation factor eIF5A as a sensor and effector for polyamine control of uCC translation. We propose that stalling of elongating ribosomes triggers queuing of scanning ribosomes and promotes initiation by positioning a ribosome near the start codon.

Family planning services for incarcerated women: models for filling an unmet need.

Purpose Incarcerated women around the globe are predominantly of reproductive age. Most of these women have been pregnant before, and many want to be sexually active and avoid pregnancy upon release. Yet few of these women are on a regular method of contraception. Providing contraceptive services for women in custody benefits individual and public health goals of reducing unintended pregnancy. This policy briefing reviews evidence for an unmet need for family planning in the correctional setting, and policy implications for expanding services. The paper aims to discuss these issues. Design/methodology/approach The authors describe four model programs in the USA with established contraceptive services on site, highlighting practical steps other facilities can implement. Findings Correctional facilities health administrators, providers, advocates, and legislators should advance policies which should counsel women on family planning and should make a range of contraceptive methods available before release, while remaining sensitive to the potential pressure these women may feel to use birth control in this unique environment. Practical implications Family planning services for incarcerated women benefits individuals, facilities, and the community. Social implications Policies which enable correctional facilities to provide comprehensive family planning to incarcerated women - including reproductive life goals counseling and contraceptive method provision - promote equity in access to critical reproductive health services and also provide broad scale population level benefits in preventing unintended pregnancy or enabling counseling for healthy pregnancies for a group of women who often have limited access to such services. Originality/value This policy briefing highlights an area of health care in prisons and jails which gets little attention in research and in policy circles: family planning services for incarcerated women. In addition to reviewing the importance of such services for this population, the authors also highlight model family planning programs in correctional facilities. These provide actionable insights for other administrators and providers.

Gaps between Adolescent Risk Behaviors and Disclosure during Outpatient Visits.

Objective. The purpose of this study was to determine the gaps between disclosed high-risk behaviors in low-income, mainly Hispanic youth and the identification of these risks by health care providers. Methods. This cross-sectional study included youth 13-19 years old who participated in a study on latent tuberculosis treatment. Youth were interviewed at baseline by bilingual research assistants; the provider visit was assessed by the chart review. Results. Of 221 youth, the majority (96%) were identified as Hispanic, 45% were foreign-born, and 46% were male. A total of 399 risk behaviors were revealed to research staff by the participants; only 24 risk behaviors were revealed to providers. Conclusions. The majority of risk behaviors based on the chart review were neither queried nor disclosed to the physicians. Physicians providing care to adolescents should consider strategies to improve disclosure as a necessary precursor to interventions.

Road safe seniors: Screening for age-related driving disorders in inpatient and outpatient settings.

INTRODUCTION: Older drivers are increasing in number and they often have health conditions that place them at high risk for motor-vehicle crashes (MVC). Screening is underutilized, and is rarely done in hospital settings. METHODS: A convenience sample of 755 older adults completed age related driving disorders screening at University of California, San Diego inpatient and outpatient health centers. Screening included three strength/frailty tests, two vision tests (acuity and fields), and two cognitive tests, based on AMA recommendations. The average age of participants was 72.5; 55.5% were male and 94% English-speaking; 17.8% of older adults failed at least one aspect of screening. RESULTS: In multivariate analysis, significant associations of failed status were age, male sex, selfrestrictions of driving, and inpatient screening locations. The screening identified one in six adults to be 'high-risk' for age related driving disorders. Screening was effective and feasible in both inpatient and outpatient settings. IMPACT ON INDUSTRY: As the driving population ages, industry, government and health car providers need to plan for the management of driving impairments in older adults.

Age-related driving disorders: screening in hospitals and outpatients settings.

AIM: Older drivers are increasing in number and they often have health conditions that place them at high risk for motor vehicle crashes. The aims of this study were to: (i) evaluate the feasibility and acceptability of screening inpatients and outpatients over the age of 60 years for age-related driving disorders; and (ii) determine the patient characteristics associated with screening outcomes. METHODS: A convenience sample of 397 participants completed age-related driving disorders screening at University of California, San Diego, inpatient and outpatient settings. Eligibility criteria included California-licensed drivers over the age of 60 years who were English or Spanish speaking. Baseline screening included driving habits, restrictions, history of crashes, and medical history, including medications. Screening included visual acuity, visual fields, three strength frailty tests and two cognitive tests. RESULTS: The average age of participants was 72 years; 59% were male and 12% Hispanic. Almost 20% of older adults failed at least one test, and were labeled 'high risk' for age-related driving disorders. In multivariate analysis, significant predictors of high-risk status were age, male sex, self-restrictions of driving and use of larger amounts of prescription drugs. Screening took approximately 15 min and participant satisfaction was high. CONCLUSION: A brief screening evaluation identified one in five adults to be 'high risk' for age-related driving disorders. Screening was effective in both outpatient and inpatient settings, was well received and simple to administer.