Recovery rates of persistent post-COVID-19 olfactory dysfunction using psychophysical assessment: A longitudinal cohort study.

Objectives: Persistent olfactory dysfunction (OD) following loss of smell associated with SARS-CoV-2 infection is a major feature of long COVID. Perspectives on the prevalence of persistent OD predominantly rely on self-reported olfactory function. Few studies have tracked longitudinal rates of recovery using psychophysical assessment among patients presenting for evaluation of persistent OD beyond a window of acute recovery. Data anchored in standardized testing methods are needed to counsel patients who fail to acutely regain their sense of smell. This study aims to quantify the degree of persistent OD in post-COVID-19 patients who experience subjective and psychophysical OD. Methods: We grouped participants presenting for OD evaluation into cohorts based on both subjective and psychophysical olfactory status at a baseline assessment and assessed their olfactory abilities with a visual analogue scale and the Sniffin' Sticks extended test at baseline and 1-year time points. Participants had confirmed a history of COVID-19 by lab evaluation or clinical diagnosis if lab evaluation was not available. Results: Baseline olfactory evaluation was completed by 122 participants, 53 of whom completed the 1-year follow-up assessment. Among participants presenting with perceived OD, 74.5% had confirmed psychophysical OD at baseline, with 55.1% at 1-year follow-up. Participants had reliable trends in self-rated versus psychophysically tested olfactory function at both time points. The total threshold, discrimination, and identification (TDI) score improved by +3.25 points in the cohort with psychophysical OD (p = 0.0005), with this improvement largely attributable to an increase in median threshold scores (+2.75 points; p = 0.0004). Conclusions: OD persists in a significant number of patients who fail to acutely recovery their sense of smell after COVID-19, with many demonstrating lingering deficits at 1-year. Improvements in threshold, but not discrimination or identification, most significantly mediate improvement of total TDI score at follow-up.

Cell-free assays reveal the HIV-1 capsid protects reverse transcripts from cGAS.

Retroviruses can be detected by the innate immune sensor cyclic GMP-AMP synthase (cGAS), which recognizes reverse-transcribed DNA and activates an antiviral response. However, the extent to which HIV-1 shields its genome from cGAS recognition remains unclear. To study this process in mechanistic detail, we reconstituted reverse transcription, genome release, and innate immune sensing of HIV-1 in a cell-free system. We found that wild-type HIV-1 capsids protect their genomes from cGAS even after completion of reverse transcription. Viral DNA could be "deprotected" by thermal stress, capsid mutations, or reduced concentrations of inositol hexakisphosphate (IP6) that destabilize the capsid. Strikingly, capsid inhibitors also disrupted viral cores and dramatically potentiated cGAS activity, both in vitro and in cellular infections. Our results provide biochemical evidence that the HIV-1 capsid lattice conceals the genome from cGAS and that chemical or physical disruption of the viral core can expose HIV-1 DNA and activate innate immune signaling.

Subjective versus Psychophysical Measures of Chemosensory Alterations following COVID-19.

INTRODUCTION: Olfactory dysfunction is a common symptom of COVID-19. However, subjective perception of olfactory function does not always correlate well with more objective measures. This study seeks to clarify associations between subjective and psychophysical measures of olfaction and gustation in patients with subjective chemosensory dysfunction following COVID-19. METHODS: Adults with persistent COVID-19-associated chemosensory disturbance were recruited for a prospective, longitudinal cohort study at a tertiary care institution. Participants provided subjective measures of olfactory and gustatory function and underwent psychophysical assessment using Sniffin' Sticks olfactory and Monell gustatory tests. RESULTS: Data analysis (n = 65) showed a statistically significant association between subjective and psychophysical measures of olfaction (p < 0.001). For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.11 (95% CI: 0.06, 0.16; p < 0.001) point increase in TDI score while adjusting for age at baseline assessment, sex, and follow-up time. For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.04 (95% CI: 0.02, 0.06; p < 0.001) point and 0.05 (95% CI: 0.03, 0.07; p < 0.001) point increase in discrimination and identification scores, respectively, when adjusting for age at baseline assessment, sex, and follow-up time. CONCLUSION: Subjective olfaction shows a mild to moderate association with psychophysical measures, but it fails to comprehensively assess persistent COVID-19-associated chemosensory deficits. The lack of significant association between subjective olfaction and threshold limits the utility of subjective olfaction in tracking recovery. These findings support the push for more widespread psychophysical chemosensory testing.

Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.

BMI Increases in Individuals with COVID-19-Associated Olfactory Dysfunction.

(1) Background: Reports suggest COVID-19-associated olfactory dysfunction (OD) may result in alterations in dietary behaviors and perceived weight change, but few studies using psychophysical evaluation of post-COVID-19-associated chemosensory dysfunction and body mass index (BMI) exist. The purpose of this study is to assess the impact of both quantitative and qualitative features of COVID-19-associated OD on BMI; (2) Methods: Recruitment of thirty-one participants with self-reported OD in the form of quantitative loss with and without qualitative features. Surveys with questions specific to qualitative olfactory function, Sniffin' Sticks tests, and BMI measures were completed at two visits, one year apart. Group differences were assessed with Wilcoxon signed-rank tests and the Holm-Bonferroni method; (3) Results: Individuals with persistent quantitative OD (n = 15) and self-reported parosmia (n = 19) showed statistically significant increases in BMI after 1 year (p = 0.004, adjusted α = 0.0125; p = 0.011, adjusted α = 0.0167). Controls with transient quantitative OD (n = 16) and participants without self-reported parosmia (n = 12) showed no statistically significant changes in BMI over the same time period (p = 0.079, adjusted α = 0.05; p = 0.028, adjusted α = 0.025); (4) Conclusions: This study shows an association between COVID-19-associated OD and BMI, suggesting olfaction may play a role in altering dietary habits and nutrition in this population. Larger study cohorts are needed to further evaluate this relationship.

PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects.

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

Otolaryngologic manifestations among MPOX patients: A systematic review and meta-analysis.

PURPOSE: MPOX has numerous otolaryngologic presentations that have been recognized as clinically important, especially with the onset of the 2022 outbreak. However, how these features vary across region and outbreak have yet to be elucidated or supported by meta-analysis. The objective of this study is to identify the otolaryngologic manifestations of MPOX across previous and current outbreaks and among endemic and non-endemic regions. BASIC PROCEDURES: Data sources of MEDLINE (PubMed), the Cochrane Library, Scopus, Embase, Web of Science, Google Scholar, and OpenGrey were searched through August 2022. All observational studies reporting data on laboratory-confirmed MPOX patients with otolaryngologic symptoms were included. Two authors independently performed the screening process while a third resolved disagreements. Data were extracted into a structured form by two authors independently. We performed a meta-analysis of the prevalence of otorhinolaryngologic symptoms using MetaXL software (version 5.3) under a random-effects model. MAIN FINDINGS: 38 studies with 5952 patients were included. The four most prevalent manifestations were headache at 31 % (95 % CI [0.16-0.49], I 2  = 99 %), sore throat at 22 % (95 % CI [0.09-0.37], I 2  = 99 %), cough at 16 % (95 % CI [0.05-0.30], I 2  = 99 %), and cervical lymphadenopathy at 10 % (95 % CI [0.01-0.26], I 2  = 100 %). Otolaryngologic features were more prevalent in previous outbreaks as compared to the 2022 outbreak including 37 % prevalence of headache (95 % CI [0.11-0.66], I 2  = 100 %), 33 % prevalence of cough (95 % CI [0.21-0.47], I 2  = 98 %), 27 % prevalence of sore throat (95 % CI [0.07-0.53], I 2  = 99 %), 15 % prevalence of cervical lymphadenopathy (95 % CI [0.00-0.428], I 2  = 100 %), 13 % prevalence of oral ulcers (95 % CI [0.02-0.30], I 2  = 99 %), 6 % prevalence of oral exanthem (95 % CI [0.00-0.17], I 2  = 99 %), 5 % prevalence of dysphagia (95 % CI [0.00-0.18], I 2  = 99 %), and 5 % prevalence of tonsillar signs (95 % CI [0.00-0.13], I 2  = 99 %). Features that were more prevalent in endemic areas versus non-endemic areas include 27 % prevalence of cough (95 % CI [0.14-0.41], I 2  = 99 %), 15 % prevalence of oral ulcers (95 % CI [0.02-0.36], I 2  = 99 %), 6 % prevalence of tonsillar signs (95 % CI [0.00-0.18], I 2  = 99 %), and 19 % prevalence of cervical lymphadenopathy (95 % CI [0.00-0.48], I 2  = 100 %), while the only feature more prevalent in non-endemic areas was headache with a prevalence of 36 % (95 % CI [0.24-0.47], I 2  = 96 %). PRINCIPAL CONCLUSIONS: In this systematic review and meta-analysis, four symptoms - headache, sore throat, cough, and cervical lymphadenopathy - were found to be the most prevalent otolaryngologic features of MPOX. Otolaryngologic manifestations of MPOX were more pronounced in prior outbreaks and in endemic areas as compared to the 2022 outbreak and non-endemic areas. These findings may aid MPOX recognition in an otolaryngology setting.

Improving models for student retention and graduation using Markov chains.

Graduation rates are a key measure of the long-term efficacy of academic interventions. However, challenges to using traditional estimates of graduation rates for underrepresented students include inherently small sample sizes and high data requirements. Here, we show that a Markov model increases confidence and reduces biases in estimated graduation rates for underrepresented minority and first-generation students. We use a Learning Assistant program to demonstrate the Markov model's strength for assessing program efficacy. We find that Learning Assistants in gateway science courses are associated with a 9% increase in the six-year graduation rate. These gains are larger for underrepresented minority (21%) and first-generation students (18%). Our results indicate that Learning Assistants can improve overall graduation rates and address inequalities in graduation rates for underrepresented students.

Short-term medical student placements completed consecutively at a rural general practice positively impact chronic disease management.

INTRODUCTION: Little is known about how medical school placements in rural areas impact key stakeholders such as patients, host organisations and the wider rural community. With engagement from rural communities crucial to the success of rural medical training, this case study sought to demonstrate the benefit that rural clinical placements can have on rural general practices (systems) and likely impacts on communities (health outcomes). Specifically, we describe how a series of consecutive short-term student placements in a single rural practice were the drivers of a series of clinical audits and interventions resulting in improved management of chronic disease. METHODS: Data for this project were obtained from student research reports completed as part of a rural and remote medicine rotation at an Australian medical school. For this series of projects, eight consecutive students were based at the same rural medical centre, with each attending for 6 weeks across a 15-month period, completing a report for a quality improvement activity and evaluating the outcomes. Each project related to chronic kidney disease (CKD), with CKD chosen based on the needs of the medical centre and the higher burden of this disease in rural areas. Each project was developed and delivered in consultation with the practice, taking into account student interest and skills, and related projects completed prior or concurrently. Projects were related to database management (n=2), alignment between CKD management and best-practice guidelines (n=3), patient health literacy (n=3), and a summary and staff perceptions of the preceding quality improvement activities (n=1). RESULTS: The combination of student projects led to tangible improvements in CKD management at a rural general practice. All doctors at the medical centre (n=4) reported using the database management tools implemented by the students and felt the interventions were sustainable, long-term solutions for ensuring clinical investigations are not being delayed or missed. Following the various interventions completed by the students, clinician knowledge and implementation of best-practice CKD management increased, and some patients became more aware of their condition and how to manage it. CONCLUSION: This case study provides evidence that short-term rural clinical placements for medical students have the potential to greatly improve health care and clinical practice in rural and remote communities, when designed around a consistent topic within a medical practice. Outcomes of the student projects in combination demonstrate that addressing CKD management longitudinally led to improvements in administrative processes, clinical practices, and patient awareness and accountability, despite each student only being at the medical centre for a short period of time. Similar approaches to structuring rural clinical placements and defining community projects for medical students should be considered more broadly.

The Role of Transcriptomics in Redefining Critical Illness.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at  https://www.biomedcentral.com/collections/annualupdate2023 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from  https://link.springer.com/bookseries/8901 .

A large-scale genetic screen identifies genes essential for motility in Agrobacterium fabrum.

The genetic and molecular basis of flagellar motility has been investigated for several decades, with innovative research strategies propelling advances at a steady pace. Furthermore, as the phenomenon is examined in diverse bacteria, new taxon-specific regulatory and structural features are being elucidated. Motility is also a straightforward bacterial phenotype that can allow undergraduate researchers to explore the palette of molecular genetic tools available to microbiologists. This study, driven primarily by undergraduate researchers, evaluated hundreds of flagellar motility mutants in the Gram-negative plant-associated bacterium Agrobacterium fabrum. The nearly saturating screen implicates a total of 37 genes in flagellar biosynthesis, including genes of previously unknown function.

Comparison of Intracellular Transcriptional Response of NHBE Cells to Infection with SARS-CoV-2 Washington and New York Strains.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China in December 2019 and caused a global pandemic resulting in millions of deaths and tens of millions of patients positive tests. While studies have shown a D614G mutation in the viral spike protein are more transmissible, the effects of this and other mutations on the host response, especially at the cellular level, are yet to be fully elucidated. In this experiment we infected normal human bronchial epithelial (NHBE) cells with the Washington (D614) strain or the New York (G614) strains of SARS-CoV-2. We generated RNA sequencing data at 6, 12, and 24 hours post-infection (hpi) to improve our understanding of how the intracellular host response differs between infections with these two strains. We analyzed these data with a bioinformatics pipeline that identifies differentially expressed genes (DEGs), enriched Gene Ontology (GO) terms and dysregulated signaling pathways. We detected over 2,000 DEGs, over 600 GO terms, and 29 affected pathways between the two infections. Many of these entities play a role in immune signaling and response. A comparison between strains and time points showed a higher similarity between matched time points than across different time points with the same strain in DEGs and affected pathways, but found more similarity between strains across different time points when looking at GO terms. A comparison of the affected pathways showed that the 24hpi samples of the New York strain were more similar to the 12hpi samples of the Washington strain, with a large number of pathways related to translation being inhibited in both strains. These results suggest that the various mutations contained in the genome of these two viral isolates may cause distinct effects on the host transcriptional response in infected host cells, especially relating to how quickly translation is dysregulated after infection. This comparison of the intracellular host response to infection with these two SARS-CoV-2 isolates suggest that some of the mechanisms associated with more severe disease from these viruses could include virus replication, metal ion usage, host translation shutoff, host transcript stability, and immune inhibition.

Electrostatic loading and photoredox-based release of molecular cargo from oligoviologen-crosslinked microparticles.

Although on-demand cargo release has been demonstrated in a wide range of microparticle platforms, many existing methods lack specific loading interactions and/or undergo permanent damage to the microparticle to release the cargo. Here, we report a novel method for electrostatically loading negatively charged molecular cargo in oligoviologen-crosslinked microparticles, wherein the cargo can be released upon activation by visible light. A water-in-oil (W/O) emulsion polymerization method was used to fabricate narrowly dispersed microparticles crosslinked by a dicationic viologen-based dimer and a poly(ethylene glycol) diacrylate. A zinc-tetraphenyl porphyrin photocatalyst was also polymerized into the microparticle and used to photochemically reduce the viologen subunits to their monoradical cations through a visible-light-mediated photoredox mechanism with triethanolamine (TEOA) as a sacrificial reductant. The microparticles were characterized by microscopy methods revealing uniform, spherical microparticles 481 ± 20.9 nm in diameter. Negatively charged molecular cargo (methyl orange, MO) was electrostatically loaded into the microparticles through counteranion metathesis. Upon irradiation with blue (450 nm) light, the photo-reduced viologen crosslinker subunits lose positive charges, resulting in release of the anionic MO cargo. Controlled release of the dye, as tracked by absorption spectroscopy, was observed over time, yielding release of up to 40% of the cargo in 48 h and 60% in 120 h in single dynamic dialysis experiment. However, full release of cargo was achieved upon transferring the microparticles to a fresh TEOA solution after the initial 120 h period.

Genetic Modification of Primary Human Myeloid Cells to Study Cell Migration, Activation, and Organelle Dynamics.

Myeloid dendritic cells (DCs) and macrophages are mononuclear phagocytes with key roles in the immune system. As antigen-presenting cells, they link innate detection of microbes with programming adaptive immune responses. Myeloid DCs and macrophages also play critical roles in development, promote tissue homeostasis, and direct repair in response to injury and inflammation. As cellular migration and organelle dynamics are intimately connected with these processes, it is necessary to develop tools to track myeloid cell behavior and function. Here, we build on previously established protocols to isolate primary human myeloid cells from peripheral blood and report an optimized method for their genetic modification with lentiviral vectors to study processes related to cell migration, activation, and organelle dynamics. Specifically, we provide a protocol for delivering genetically encoded fluorescent markers into primary monocyte-derived DCs (MDDCs) and monocyte-derived macrophages (MDMs) to label mitochondria, peroxisomes, and whole cells. We describe the isolation of primary CD14+ monocytes from peripheral blood using positive selection with magnetic beads and, alternatively, isolation based on plastic adherence. Isolated CD14+ cells can be transduced with lentiviral vectors and subsequently cultured in the presence of cytokines to derive MDDCs or MDMs. This protocol is highly adaptable for cotransduction with vectors to knock down or overexpress genes of interest. These tools enable mechanistic studies of genetically modified myeloid cells through flow cytometry, fluorescence microscopy, and other downstream assays. © 2022 Wiley Periodicals LLC. Basic Protocol: Transduction of MDDCs and MDMs with lentiviral vectors encoding fluorescent markers Alternate Protocol 1: Isolation of monocytes by plastic adhesion Alternate Protocol 2: Transduction of MDDCs and MDMs with lentiviral vectors to knock down or overexpress genes of interest Support Protocol 1: Production and purification of lentiviral vectors for transduction into primary human myeloid cells Support Protocol 2: Flow cytometry of MDDCs and MDMs Support Protocol 3: Fixed and live-cell imaging of fluorescent markers in MDMs and MDDCs.

A Wearable Soft Robotic Exoskeleton for Hip Flexion Rehabilitation.

Leg motion is essential to everyday tasks, yet many face a daily struggle due to leg motion impairment. Traditional robotic solutions for lower limb rehabilitation have arisen, but they may bare some limitations due to their cost. Soft robotics utilizes soft, pliable materials which may afford a less costly robotic solution. This work presents a soft-pneumatic-actuator-driven exoskeleton for hip flexion rehabilitation. An array of soft pneumatic rotary actuators is used for torque generation. An analytical model of the actuators is validated and used to determine actuator parameters for the target application of hip flexion. The performance of the assembly is assessed, and it is found capable of the target torque for hip flexion, 19.8 Nm at 30°, requiring 86 kPa to reach that torque output. The assembly exhibits a maximum torque of 31 Nm under the conditions tested. The full exoskeleton assembly is then assessed with healthy human subjects as they perform a set of lower limb motions. For one motion, the Leg Raise, a muscle signal reduction of 43.5% is observed during device assistance, as compared to not wearing the device. This reduction in muscle effort indicates that the device is effective in providing hip flexion assistance and suggests that pneumatic-rotary-actuator-driven exoskeletons are a viable solution to realize more accessible options for those who suffer from lower limb immobility.

Developing a Solution for Nasal and Olfactory Transport of Nanomaterials.

With advances in nanotechnology, engineered nanomaterial applications are a rapidly growing sector of the economy. Some nanomaterials can reach the brain through nose-to-brain transport. This transport creates concern for potential neurotoxicity of insoluble nanomaterials and a need for toxicity screening tests that detect nose-to-brain transport. Such tests can involve intranasal instillation of aqueous suspensions of nanomaterials in dispersion media that limit particle agglomeration. Unfortunately, protein and some elements in existing dispersion media are suboptimal for potential nose-to-brain transport of nanomaterials because olfactory transport has size- and ion-composition requirements. Therefore, we designed a protein-free dispersion media containing phospholipids and amino acids in an isotonic balanced electrolyte solution, a solution for nasal and olfactory transport (SNOT). SNOT disperses hexagonal boron nitride nanomaterials with a peak particle diameter below 100 nm. In addition, multiwalled carbon nanotubes (MWCNTs) in an established dispersion medium, when diluted with SNOT, maintain dispersion with reduced albumin concentration. Using stereomicroscopy and microscopic examination of plastic sections, dextran dyes dispersed in SNOT are demonstrated in the neuroepithelium of the nose and olfactory bulb of B6;129P2-Omptm3Mom/MomJ mice after intranasal instillation in SNOT. These findings support the potential for SNOT to disperse nanomaterials in a manner permitting nose-to-brain transport for neurotoxicity studies.

Digital dementia in the internet generation: excessive screen time during brain development will increase the risk of Alzheimer's disease and related dementias in adulthood.

Converging evidence from biopsychosocial research in humans and animals demonstrates that chronic sensory stimulation (via excessive screen exposure) affects brain development increasing the risk of cognitive, emotional, and behavioural disorders in adolescents and young adults. Emerging evidence suggests that some of these effects are similar to those seen in adults with symptoms of mild cognitive impairment (MCI) in the early stages of dementia, including impaired concentration, orientation, acquisition of recent memories (anterograde amnesia), recall of past memories (retrograde amnesia), social functioning, and self-care. Excessive screen time is known to alter gray matter and white volumes in the brain, increase the risk of mental disorders, and impair acquisition of memories and learning which are known risk factors for dementia. Chronic sensory overstimulation (i.e., excessive screen time) during brain development increases the risk of accelerated neurodegeneration in adulthood (i.e., amnesia, early onset dementia). This relationship is affected by several mediating/moderating factors (e.g., IQ decline, learning impairments and mental illness). We hypothesize that excessive screen exposure during critical periods of development in Generation Z will lead to mild cognitive impairments in early to middle adulthood resulting in substantially increased rates of early onset dementia in later adulthood. We predict that from 2060 to 2100, the rates of Alzheimer's disease and related dementias (ADRD) will increase significantly, far above the Centres for Disease Control (CDC) projected estimates of a two-fold increase, to upwards of a four-to-six-fold increase. The CDC estimates are based entirely on factors related to the age, sex, race and ethnicity of individuals born before 1950 who did not have access to mobile digital technology during critical periods of brain development. Compared to previous generations, the average 17-19-year-old spends approximately 6 hours a day on mobile digital devices (MDD) (smartphones, tablets, and laptop computers) whereas individuals born before 1950 at the same age spent zero. Our estimates include the documented effects of excessive screen time on individuals born after 1980, Millennials and Generation Z, who will be the majority of individuals ≥65 years old. An estimated 4-to-6-fold increase in rates of ADRD post-2060 will result in widespread societal and economic distress and the complete collapse of already overburdened healthcare systems in developed countries. Preventative measures must be set in place immediately including investments and interventions in public education, social policy, laws, and healthcare.

Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency.

PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and missense constrained, and has been identified as a candidate gene for autism spectrum disorder (ASD). We describe 16 individuals from 12 families who carry deletions involving PAX5 and surrounding genes, de novo frameshift variants that are likely to trigger nonsense-mediated mRNA decay, a rare stop-gain variant, or missense variants that affect conserved amino acid residues. Four of these individuals were published previously but without detailed clinical descriptions. All these individuals have been diagnosed with one or more neurodevelopmental phenotypes including delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. Seizures were documented in four individuals. No recurrent patterns of brain magnetic resonance imaging (MRI) findings, structural birth defects, or dysmorphic features were observed. Our findings suggest that PAX5 haploinsufficiency causes a neurodevelopmental disorder whose cardinal features include DD, variable ID, and/or ASD.

Iterative step-growth synthesis and degradation of unimolecular polyviologens under mild conditions.

An iterative step-growth addition method was used to expedite the gram-scale synthesis of main-chain polyviologens by several days, while also producing the longest main-chain polyviologen (i.e., 26 viologen subunits) reported to date. Facile degradation using inorganic and organic aqueous bases was also demonstrated for a representative oligoviologen (6V-Me·12Cl), a polyviologen (26V-Me·52Cl), and oligoviologen-crosslinked hydrogels.