Dedifferentiation maintains melanocyte stem cells in a dynamic niche.

For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations1, which leads to hair greying in most humans and mice2,3. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli4-8. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.

Kismet/CHD7/CHD8 affects gut microbiota, mechanics, and the gut-brain axis in Drosophila melanogaster.

The gut microbiome affects brain and neuronal development and may contribute to the pathophysiology of neurodevelopmental disorders. However, it is unclear how risk genes associated with such disorders affect gut physiology in a manner that could impact microbial colonization and how the mechanical properties of the gut tissue might play a role in gut-brain bidirectional communication. To address this, we used Drosophila melanogaster with a null mutation in the gene kismet, an ortholog of chromodomain helicase DNA-binding protein (CHD) family members CHD7 and CHD8. In humans, these are risk genes for neurodevelopmental disorders with co-occurring gastrointestinal symptoms. We found that kismet mutant flies have a significant increase in gastrointestinal transit time, indicating the functional homology of kismet with CHD7/CHD8 in vertebrates. Rheological characterization of dissected gut tissue revealed significant changes in the mechanics of kismet mutant gut elasticity, strain stiffening behavior, and tensile strength. Using 16S rRNA metagenomic sequencing, we also found that kismet mutants have reduced diversity and abundance of gut microbiota at every taxonomic level. To investigate the connection between the gut microbiome and behavior, we depleted gut microbiota in kismet mutant and control flies and quantified the flies' courtship behavior. Depletion of gut microbiota rescued courtship defects of kismet mutant flies, indicating a connection between gut microbiota and behavior. In striking contrast, depletion of the gut microbiome in the control strain reduced courtship activity, demonstrating that antibiotic treatment can have differential impacts on behavior and may depend on the status of microbial dysbiosis in the gut prior to depletion. We propose that Kismet influences multiple gastrointestinal phenotypes that contribute to the gut-microbiome-brain axis to influence behavior. We also suggest that gut tissue mechanics should be considered as an element in the gut-brain communication loop, both influenced by and potentially influencing the gut microbiome and neurodevelopment.

Interleukin-15 is a hair follicle immune privilege guardian.

The autoimmunity-promoting cytokine, Interleukin-15 (IL-15), is often claimed to be a key pathogenic cytokine in alopecia areata (AA). Yet, rhIL-15 promotes human hair follicle (HF) growth ex vivo. We have asked whether the expression of IL-15 and its receptor (IL-15R) isoforms is altered in human AA and how IL-15 impacts on human HF immune privilege (HF-IP) in the presence/absence of interferon-γ (IFNγ), the well-documented key AA-pathogenic cytokine, as well as on hair regrowth after experimental AA induction in vivo. Quantitative immunohistomorphometry showed the number of perifollicular IL-15+ T cells in AA skin biopsies to be significantly increased compared to healthy control skin, while IL-15, IL-15Rα, and IL-15Rγ protein expression within the hair bulb were significantly down-regulated in AA HFs. In organ-cultured human scalp HFs, rhIL-15 significantly reduced hair bulb expression of MICA, the key "danger" signal in AA pathogenesis, and increased production of the HF-IP guardian, α-MSH. Crucially, ex vivo, rhIL-15 prevented IFNγ-induced HF-IP collapse, restored a collapsed HF-IP by IL-15Rα-dependent signaling (as documented by IL-15Rα-silencing), and protected AA-preventive immunoinhibitory iNKT10 cells from IFNγ-induced apoptosis. rhIL-15 even promoted hair regrowth after experimental AA induction in human scalp skin xenotransplants on SCID/beige mice in vivo. Our data introduce IL-15 as a novel, functionally important HF-IP guardian whose signaling is constitutively defective in scalp HFs of AA patients. Our data suggest that selective stimulation of intrafollicular IL-15Rα signaling could become a novel therapeutic approach in AA management, while blocking it pharmacologically may hinder both HF-IP restoration and hair re-growth and may thus make HFs more vulnerable to AA relapse.

Beyond the Surface: A Systematic Review of Perforating and Penetrating Globe Injuries From Blepharoplasty.

PURPOSE: This study aims to address the infrequent but serious complication of globe injuries in blepharoplasty. METHODS: A case series of 3 patients with globe injuries postblepharoplasty is presented, along with a systematic literature review that revealed 13 previously reported cases. Quantitative and comparative analysis is described. RESULTS: Injuries ranged from deep thermal burns to full-thickness corneal or scleral lacerations, with one instance of traumatic cataract. The median time from surgery to symptom onset was 1 day, with a concerning median delay of 7 days to presentation to an ophthalmologist. Visual outcomes were generally poor, with nearly all patients experiencing permanent visual morbidity. The systematic review revealed 3 cases of endophthalmitis following perforating scleral injuries. Comparative analysis showed no significant differences in visual outcomes between penetrating and perforating injuries. CONCLUSIONS: The findings of this study emphasize the need for increased vigilance for globe injuries that require prompt ophthalmological evaluation following blepharoplasty, especially considering the observed delay in presentation and the extent of visual morbidity. The study advocates for improved practitioner training in recognizing and managing these complications and underscores the importance of patient education regarding the potential risks and the necessity of timely postoperative care.

Harmonizing florbetapir and PiB PET measurements of cortical Aß plaque burden using multiple regions-of-interest and machine learning techniques: An alternative to the Centiloid approach.

INTRODUCTION: Machine learning (ML) can optimize amyloid (Aß) comparability among positron emission tomography (PET) radiotracers. Using multi-regional florbetapir (FBP) measures and ML, we report better Pittsburgh compound-B (PiB)/FBP harmonization of mean-cortical Aß (mcAß) than Centiloid. METHODS: PiB-FBP pairs from 92 subjects in www.oasis-brains.org and 46 in www.gaain.org/centiloid-project were used as the training/testing sets. FreeSurfer-extracted FBP multi-regional Aß and actual PiB mcAß in the training set were used to train ML models generating synthetic PiB mcAß. The correlation coefficient (R) between the synthetic/actual PiB mcAß in the testing set was assessed. RESULTS: In the testing set, the synthetic/actual PiB mcAß correlation R = 0.985 (R2  = 0.970) using artificial neural network was significantly higher (p ≤ 6.6e-4) than the FBP/PiB correlation R = 0.927 (R2  = 0.860), improving total variance percentage (R2 ) from 86% to 97%. Other ML models such as partial least square, ensemble, and relevance vector regressions also improved R (p = 9.677e-05 /0.045/0.0017). DISCUSSION: ML improved mcAß comparability. Additional studies are needed for the generalizability to other amyloid tracers, and to tau PET. Highlights Centiloid is a calibration of the amyloid scale, not harmonization. Centiloid unifies the amyloid scale without improving inter-tracer association (R2 ). Machine learning (ML) can harmonize the amyloid scale by improving R2 . ML harmonization maps multi-regional florbetapir SUVRs to PiB mean-cortical SUVR. Artificial neural network ML increases Centiloid R2 from 86% to 97%.

Mass Balance of the Indoleamine 2,3-Dioxygenase Inhibitor Navoximod (GDC-0919) in Rats and Dogs: Unexpected Cyanide Release from Imidazo[5,1-a]isoindole and Species Differences in Glucuronidation.

Navoximod (GDC-0919) is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) developed to reduce T cell immunosuppression associated with cancer. This study describes the absorption, metabolism, and excretion (AME) of navoximod in rats and dogs after a single oral dose of [14C]-navoximod. An unexpected thiocyanate metabolite M1 and a chiral inversion metabolite M51 were captured as the major circulating metabolites in rats, accounting for 30% and 18% of 0-24 hours exposure, respectively. These two metabolites combined had much lower systemic exposure in dogs and humans (<6% and <1%). The novel cyanide release is proposed to occur via 4,5-epoxidation on the fused imidazole ring, leading to ring opening and rearrangement along with the release of cyanide. The decyanated metabolites were identified and confirmed by synthetic standards, which supported the proposed mechanism. In dogs, glucuronidation to M19 was the major clearance mechanism, representing 59% of the dose in the bile of bile duct-cannulated (BDC) dogs and 19% of the dose in the urine of intact dogs. Additionally, M19 also represented 52% of drug related exposure in circulation in dogs. In comparison, in humans, navoximod was mainly cleared through glucuronidation to M28 and excreted in urine (60% of the dose). The differences in the metabolism and elimination observed in vivo were qualitatively recapitulated in vitro with liver microsomes, suspended hepatocytes, and cocultured primary hepatocytes. The striking species differences in regioselective glucuronidation is likely explained by the species differences in UGT1A9, which was mainly responsible for M28 formation in humans. SIGNIFICANCE STATEMENT: The results from this study demonstrated significant species differences in metabolism (especially glucuronidation) and elimination of navoximod among rats, dogs, and humans. The study also illustrated the mechanism of a novel cyanide release metabolism from the fused imidazo[5,1-a]isoindole ring. Such biotransformation should be kept in mind when working with imidazole-containing new chemical entities in drug discovery and development.

Concentration-dependent stimulation of melanin production as well as melanocyte and keratinocyte proliferation by melatonin in human eyelid epidermis.

It remains unclear how the multifunctional indoleamine neurohormone, melatonin, alters melanin production and melanocytes within intact human epidermis under physiologically relevant conditions. In the current pilot study, we aimed to clarify this in long-term organ-cultured, full-thickness human eyelid skin, selected for its clinically recognized sensitivity to pigmentation-modulatory hormones. Warthin-Starry histochemistry showed that 100 µM melatonin significantly increased epidermal melanin content and melanocyte dendricity after 6 days of organ culture, even though tyrosinase activity in situ was inhibited, as assessed by quantitative immunohistomorphometry. While the higher melatonin dose tested here (200 µM) did not change epidermal melanization, but again inhibited tyrosinase activity, it increased the number and proliferation of both gp100+ epidermal melanocytes and keratinocytes as well as protein expression of the premelanosomal marker, gp100, ex vivo. Contrary to most previous studies, these eyelid skin organ culture results suggest that long-term melatonin application exerts overall stimulatory, dose-dependent effects on the epidermal pigmentary unit within intact human skin, which appear surprisingly tyrosinase-independent. While these provocative preliminary findings require further work-up and independent confirmation, they encourage one to systematically explore whether prolonged melatonin therapy can (re-)stimulate melanogenesis and increase the pool/activity of epidermal melanocytes in hypopigmented skin lesions.

Filling a nick in NIK: Extending the half-life of a NIK inhibitor through structure-based drug design.

Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design. This led to the identification of an azabicyclo[3.1.0]hexanone motif that attenuated in vitro and in vivo clearance while maintaining NIK potency and increasing selectivity over other kinases, resulting in a greater than ten-fold reduction in predicted human dose.

Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination.

BACKGROUND: Non-crossover (NCO) refers to a mechanism of homologous recombination in which short tracks of DNA are copied between homologue chromatids. The allelic changes are typically restricted to one or few SNPs, which potentially allow for the gradual adaptation and maturation of haplotypes. It is assumed to be a stochastic process but the analysis of archaic and modern human haplotypes revealed a striking variability in local NCO recombination rates. METHODS: NCO recombination rates of 1.9 million archaic SNPs shared with Denisovan hominids were defined by a linkage study and correlated with functional and genomic annotations as well as ChIP-Seq data from modern humans. RESULTS: We detected a strong correlation between NCO recombination rates and the function of the respective region: low NCO rates were evident in introns and quiescent intergenic regions but high rates in splice sites, exons, 5'- and 3'-UTRs, as well as CpG islands. Correlations with ChIP-Seq data from ENCODE and other public sources further identified epigenetic modifications that associated directly with these recombination events. A particularly strong association was observed for 5-hydroxymethylcytosine marks (5hmC), which were enriched in virtually all of the functional regions associated with elevated NCO rates, including CpG islands and 'poised' bivalent regions. CONCLUSION: Our results suggest that 5hmC marks may guide the NCO machinery specifically towards functionally relevant regions and, as an intermediate of oxidative demethylation, may open a pathway for environmental influence by specifically targeting recently opened gene loci.

The Association Between Computerized Tomography Findings and Ocular Trauma Score in Open Globe Injury: The Prognostic Value of Imaging.

PURPOSE: The aim of this study was to evaluate the association between CT findings and Ocular Trauma Score (OTS) in open globe injury. METHODS: In 182 eyes with open globe injury, CT findings were categorized into 5 major types: scleral irregularity with decreased globe volume, dislocation of the crystalline lens, abnormal vitreous density, thickening of the chorioretinal layer, and intraocular foreign body/air. Association between different types and number of CT findings with OTS stages were evaluated through a multivariate analysis. RESULTS: Mean age of the patients was 38 ± 8.5 years. The most common CT findings were severe scleral irregularity or globe collapse (71.9%) and abnormal vitreous density (56%). The most common OTS stages were II (44.5%) and I (30.7%). In multivariate analysis, abnormal vitreous density (odds ratio [OR] = 2.11, p < 0.001), chorioretinal thickening (OR = 1.89, p < 0.001), and intraocular foreign body/air (OR = 1.58, p = 0.001) were associated with more advanced OTS stages (I or II). Mean OTS in eyes with 1, 2, and 3 CT findings were 66 (stage III), 47 (stage II), and 37 (stage I), respectively ( p value = 0.008). Presence of 2 (OR = 2.46, p < 0.001) and 3 (OR = 2.92, p < 0.001) CT findings were associated with more advanced OTS stages (I or II). CONCLUSIONS: The type and number of CT findings may help to predict the OTS stage and visual prognosis in eyes with open globe injury.

Teprotumumab for the Treatment of Recalcitrant Thyroid Eye Disease.

PURPOSE: Teprotumumab, an insulin-like growth factor 1 receptor monoclonal antibody, is FDA-approved to treat thyroid eye disease (TED). The initial clinical trials excluded patients with previous orbital irradiation, surgery, glucocorticoid use (cumulative dose >1 gm), or prior biologic treatment. Information on the use of teprotumumab for patients who failed prior therapy is limited. Our purpose is to characterize the efficacy of teprotumumab for the treatment of recalcitrant TED. METHODS: This is a multicenter retrospective study of all patients treated with teprotumumab for moderate-to-severe TED after failing conventional therapy with corticosteroids, orbital radiation, surgical decompression, biologics, or other steroid-sparing medications. Treatment failure was defined as an incomplete response to or reactivation after previous treatment. Only patients who received at least 4 infusions of teprotumumab were included in the analysis. Primary outcome measures comprised proptosis response (≥2 mm reduction in the study eye without a similar increase in the other eye), clinical activity score (CAS) response (≥2-point reduction in CAS), and diplopia response (≥1 point improvement in Gorman diplopia score in patients with baseline diplopia) following treatment. Adverse events and risk factors for recalcitrant disease were also evaluated. RESULTS: Sixty-six patients were included in this study, 46 females and 20 males. Average age was 59.3 years (range 29-93). The mean duration of disease from TED diagnosis to first infusion was 57.8 months. The proptosis, CAS, and diplopia responses in this recalcitrant patient population were 85.9%, 93.8%, and 69.1%, respectively. Patients experienced a mean reduction in proptosis of 3.1 ± 2.4 mm and a mean improvement in CAS of 3.8 ± 1.6. Patients who underwent prior decompression surgery experienced a statistically significant decrease in diplopia response (46.7% vs. 77.5%, p = 0.014) and proptosis response (75.0% vs. 90.9%, p = 0.045) when compared with nondecompression patients. Additionally, there were no significant differences in proptosis, CAS, and diplopia responses between patients with acute (defined as disease duration <1 year) versus chronic (disease duration ≥1 year) TED. While most adverse events were mild to moderate, 4 patients reported serious adverse events related to persistent hearing loss. CONCLUSIONS: Patients with recalcitrant TED demonstrated a significant improvement after teprotumumab in each of the primary study outcomes. The degree of proptosis reduction, diplopia response, and CAS improvement in the recalcitrant group were similar to those of treatment-naïve patients from the pivotal clinical trials. Patients with a prior history of orbital decompression, however, demonstrated poor improvement in diplopia and less reduction in proptosis than surgery naïve patients. These results indicate that teprotumumab is a treatment option for the treatment of patients with TED recalcitrant to prior medical therapies.

Superior Visual Field Testing Using Virtual Reality With and Without Eye Tracking for Functional Upper Eyelid Surgery Evaluation: A Pilot Study.

PURPOSE: To assess the sensitivity and specificity of superior visual field tests administered in virtual reality (VR) with eye tracking (VR-ET) and without eye tracking (VR 0 ) for the fulfillment of insurance coverage criteria for functional upper eyelid surgery as compared with standard automated perimetry (SAP). METHODS: This prospective cross-sectional study included 78 eyes from 41 patients with ptosis, brow ptosis, and dermatochalasis undergoing functional upper eyelid surgery evaluation. Participants underwent serial superior visual field tests using SAP and VR 0 or VR-ET in randomized order. Fulfillment of insurance coverage criteria for blepharoplasty was defined as a 30% increase in the grid seen from the untaped to the taped state. The main outcome measure was the sensitivity and specificity of VR 0 , VR-ET, and overall VR in meeting insurance coverage criteria as compared with SAP. RESULTS: VR had a sensitivity of 84.1% and specificity of 67.6%, with no significant difference between VR 0 and VR-ET. SAP agreed on insurance coverage criteria fulfillment with VR 0 in 28 (71.8%) eyes and with VR-ET in 32 (82.1%) eyes. Insurance coverage criteria fulfillment rates varied significantly by diagnosis on SAP ( p = 0.012) but not VR ( p = 0.059). CONCLUSIONS: VR may be an alternative to SAP for functional upper eyelid surgery evaluation. Future studies are needed to determine differences in patient satisfaction, testing and waiting time, and test-retest reliability between VR and SAP.

Outcomes of Patients With Thyroid Eye Disease Partially Treated With Teprotumumab.

PURPOSE: In response to the coronavirus (COVID-19) pandemic, teprotumumab production was temporarily halted with resources diverted toward vaccine production. Many patients who initiated treatment with teprotumumab for thyroid eye disease were forced to deviate from the standard protocol. This study investigates the response of teprotumumab when patients receive fewer than the standard 8-dose regimen. METHODS: This observational cross-sectional cohort study included patients from 15 institutions with active or minimal to no clinical activity thyroid eye disease treated with the standard teprotumumab infusion protocol. Patients were included if they had completed at least 1 teprotumumab infusion and had not yet completed all 8 planned infusions. Data were collected before teprotumumab initiation, within 3 weeks of last dose before interruption, and at the visit before teprotumumab reinitiation. The primary outcome measure was reduction in proptosis more than 2 mm. Secondary outcome measures included change in clinical activity score (CAS), extraocular motility restriction, margin reflex distance-1 (MRD1), and reported adverse events. RESULTS: The study included 74 patients. Mean age was 57.8 years, and 77% were female. There were 62 active and 12 minimal to no clinical activity patients. Patients completed an average of 4.2 teprotumumab infusions before interruption. A significant mean reduction in proptosis (-2.9 mm in active and -2.8 mm in minimal to no clinical activity patients, P < 0.01) was noted and maintained during interruption. For active patients, a 3.4-point reduction in CAS ( P < 0.01) and reduction in ocular motility restriction ( P < 0.01) were maintained during interruption. CONCLUSIONS: Patients partially treated with teprotumumab achieve significant reduction in proptosis, CAS, and extraocular muscle restriction and maintain these improvements through the period of interruption.

The characteristics of spontaneous language in young children identified as language delayed in Mandarin.

BACKGROUND: Little is known about the spontaneous speech characteristics of young children with language delay in Mandarin, relative to their peers. Until the recent development of standardized language assessments normed in China on Mandarin-speaking children, it was difficult to independently identify atypically developing children to study their spontaneous speech, and only case studies have been available. AIM: To investigate which aspects of spontaneous speech might be distinctive for atypical development in a short play session. METHODS & PROCEDURES: A total of 86 Mandarin-speaking children, boys and girls aged 2;6-4;6, were tested using the new standardized assessment for Mandarin, Diagnostic Receptive Expressive Assessment of Mandarin-Comprehensive (DREAM-C), at a major urban hospital in China. Of the children, 39 were identified by DREAM-C as atypically developing in language development (Total Standard score M = 72, SD = 8.9), and 47 scored in the typical range (Total Standard score M = 103, SD = 10.8), using the four scales of Receptive, Expressive Semantics and Syntax. All children then took part in a 15-min semi-structured play session during which their spontaneous speech was recorded by professionals. A variety of games and pictures were used in an attempt to elicit spontaneous questions, negatives and descriptions. Their recorded speech samples were then coded by linguists directly into a database in FilemakerPro for different aspects of vocabulary, sentence variety and grammatical morphemes/structures heard. OUTCOMES & RESULTS: The results describe the characteristics of the speech samples for the typical and atypical groups for age groups 2;6-3.5 (N = 52) and 3;6-4.6 (N = 34). Vocabulary diversity was indicated on an ordinal scale ranging from simple communicative signals including headshakes and words such as 'hi' to 'a rich variety of different content words'. Grammatical diversity similarly ranged from 'only yes/no answers', through to the appearance of multi-clause sentences. Morphosyntax was coded in terms of which morphemes were observed at all in the session, such as aspect markers (LE, ZAI, GUO), and nominal morphemes (DE, GE), and also whether function words such as pronouns, Wh-questions and classifiers were singular or varied in the session. There is considerable optionality in morpheme expression in Mandarin, so measurements such as the percentage supplied in obligatory contexts, though useful for languages such as English, are harder to compute. Nevertheless, the data show change over age in all these aspects of language, and reveal what a typically developing child might be expected to produce in a 15-min sample in such a session. For example, it was rare for the typically developing children by age 3.5 not to have at least simple sentences with some function words, and to use adjectives, nouns and verbs, unlike the children with atypical scores. The morphemes DE, LE and GUO showed significant differences in likelihood across groups for both ages, but BA and ZAI were significantly different only for the older age group. In contrast, GE was common in all groups. The atypical group has markedly lower frequency in several grammatical aspects such as the use of diverse questions, classifiers and pronouns, with much less change across age groups, implying slower growth. The results provide useful information on the relative likelihood of observing different varieties of words, sentence types and morphemes in a short speech sample, which are substantially different in the typical versus atypical groups in both age bands, and change over age. CONCLUSIONS & IMPLICATIONS: These data validate the DREAM-C classifications, but the details can also be used to inform the choice of targets for intervention for young children who experience delays in Mandarin language acquisition. WHAT THIS PAPER ADDS: What is already known on the subject Spontaneous language samples have been used as a means of studying language in China. However, because of the amount of training and time required to transcribe and analyse spontaneous language samples, there is not yet a sufficient basis for identifying language differences between children with and without language disorder in mainland China. What does this paper add to existing knowledge After using DREAM-C to provide an objective measurement of children with and without language disorders, an easy-to-administer spontaneous language assessment protocol and scoring record form allowed the comparison of the spontaneous language of 39 children with atypically developing language with 47 children who scored in the typical range to observe language differences between those with and without typical language development. What are the potential or actual clinical implications of this work? The study documents differences in vocabulary and sentence variety, and use of different morphemes such as classifiers, passives and aspect markers to aid in choosing targets for intervention by demonstrating the path of development. In addition, the spontaneous language assessment protocol and scoring record form holds promise for allowing clinicians and researchers to more easily study the language of individual children to personalize intervention, but also of groups of children to understand the emergence of basic Mandarin linguistic features.

The development of a parent report instrument of early communication and language skills of infants and toddlers in mainland China.

OBJECTIVE: This study was designed to produce a new parent-report measure, the Diagnostic Receptive Expressive Assessment of Mandarin-Infant Toddler Assessment of Communication and Language (DREAM-IT) in order to provide norms for the developmental skills of children aged 0-36 months in four areas: expressive language, receptive language, cognitive play and social skills. METHODOLOGY: The scale was designed to be both broader and deeper than existing instruments that neglect one or more of these significant domains involved in early language. Items were chosen by a group of specialists with clinical experience working with the age group and with attention to the developmental literature. Caregivers were tested individually by a trained person who asked the questions and provided examples. In addition to an extensive health questionnaire, caregivers answered questions in Mandarin about their child's behaviour using a scale of 'not yet', 'sometimes' or 'always' or listing out words and/or sounds understood or said by the child. The 476 participating caregivers were recruited at maternal and child healthcare clinics centred in Chengdu, China, 191 of whom were tested a second time seven months later. The children were sampled in three-month age-bands from 0 to 36 months. The sample was balanced for child gender by age band, and parental education was balanced. Caregivers of 0-24-month-old children and caregivers of 12-36 months were each asked a different set of questions, to determine the appropriate age range and cutoff points for each question, requiring the sample size to be doubled for children aged 12-24 months. RESULTS: The results were subject to item-response theory analysis to remove outlying items, and the resulting internal reliability was high for each domain (average Cronbach's alpha=0.87). The final instrument (between 67 and 113 questions in total) was refined to include the least redundant questions that had the highest intercorrelations, with attention paid to coverage of all domains across the age range. Two scales were developed: one for children 0-18 months, the second for children aged 18-36 months. The longitudinal design permitted the creation of growth curves and norms for each domain for six-month intervals from 0 to 36 months. A small sample of 32 parents of children with Down syndrome aged 18-36 months provided validation that the scales are highly sensitive to developmental delay. CONCLUSION: The instrument shows considerable promise for detecting early communication problems in children in China. WHAT THIS PAPER ADDS: What is already known on the subject In China, efforts were made in recent years to develop language assessments for infants and toddlers, but limitations existed with the domains included and number of items included per age group. Many clinical practitioners also continued to rely on language subtests of general developmental scales, which were limited in depth and breadth of language skills tested and were never intended for diagnosis of language delay. What this paper adds to existing knowledge This paper discusses the development of a valid caregiver report instrument for early communication and language skills of infants and toddlers in mainland China. The Diagnostic Receptive Expressive Assessment of Mandarin-Infant Toddler (DREAM-IT) includes foundational domains necessary for language and communication development in young children (receptive language, expressive language, cognitive play and social communication domains). The results show strong internal reliability (Cronbach's alpha) for each domain on a sample of 716 children sampled in three-month age bands from 0 to 36 months. The external validity proved strong when tested on a group of 32 young children with Down syndrome. What are the potential or actual clinical implications of this work? Besides helping to inform the diagnosis of language delays in infants and toddlers in China, the caregiver report instrument has special features to support clinical practitioners in a field that is just emerging in China. The unique support features include the automatic generation of a profile of relative strengths and weaknesses of the child on the report and the recommendation of child-specific caregiver coaching videos on a companion app.

A public resource of baseline data from the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial.

INTRODUCTION: The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aß) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. METHODS: We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. RESULTS: Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. DISCUSSION: Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aß plaque deposition.

Prevalence of Body Dysmorphic Disorder in Orbital Plastic Surgery and Its Relationship with the Use of Social Media.

BACKGROUND: The prevalence of body dysmorphic disorder (BDD) in the general population ranges from 0.7 to 2.4%; however, higher rates are seen among aesthetic patients. Given the recent rise in popularity of cosmetic surgery, particularly in the post-COVID pandemic setting, the authors hypothesize the prevalence has increased. The purpose of the study is to examine the prevalence of BDD in patients presenting to an oculoplastic surgery clinic at an academic center and determine correlation with social media use. METHODS: This is a survey of patients presenting to the oculoplastic surgery clinic. Participants completed the Dysmorphic Concern Questionnaire (DCQ), in addition to survey questions about social media use. Main outcomes included a positive screen and social media use. RESULTS: A total of 175 patients that presented to the oculoplastic and reconstructive surgery clinic were surveyed. All patients, including cosmetic, functional, and non-surgical, were offered participation in the survey. 9.13% of all patients screened positive for BDD. Patients that screened positive were more commonly female (71.43%). The distribution of patients with BDD was even between Hispanics (52.38%) and non-Hispanics, and 85.71% of patients with BDD were Caucasian. Of patients that screened positive, 71.43% use social media. CONCLUSIONS: The prevalence of BDD may have increased in the past seven years and is seen most in females and Caucasians. There is a positive correlation with social media, which has increased in popularity since the COVID-19 pandemic. It is important to maintain a high clinical suspicion for BDD and consider screening if there is concern. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo.

Human skin aging is associated with functional deterioration on multiple levels of physiology, necessitating the development of effective skin senotherapeutics. The well-tolerated neurohormone melatonin unfolds anti-aging properties in vitro and in vivo, but it remains unclear whether these effects translate to aged human skin ex vivo. We tested this in organ-cultured, full-thickness human eyelid skin (5-6 donors; 49-77 years) by adding melatonin to the culture medium, followed by the assessment of core aging biomarkers via quantitative immunohistochemistry. Over 6 days, 200 µM melatonin significantly downregulated the intraepidermal activity of the aging-promoting mTORC1 pathway (as visualized by reduced S6 phosphorylation) and MMP-1 protein expression in the epidermis compared to vehicle-treated control skin. Conversely, the transmembrane collagen 17A1, a key stem cell niche matrix molecule that declines with aging, and mitochondrial markers (e.g., TFAM, MTCO-1, and VDAC/porin) were significantly upregulated. Interestingly, 100 µM melatonin also significantly increased the epidermal expression of VEGF-A protein, which is required and sufficient for inducing human skin rejuvenation. In aged human dermis, melatonin significantly increased fibrillin-1 protein expression and improved fibrillin structural organization, indicating an improved collagen and elastic fiber network. In contrast, other key aging biomarkers (SIRT-1, lamin-B1, p16INK4, collagen I) remained unchanged. This ex vivo study provides proof of principle that melatonin indeed exerts long-suspected but never conclusively demonstrated and surprisingly differential anti-aging effects in aged human epidermis and dermis.

Ophthalmic artery occlusion following n-butyl cyanoacrylate embolization of an orbital arteriovenous malformation.

A 33-year-old pregnant woman presented with six months of right-sided proptosis. Neuroimaging revealed a right orbital arteriovenous malformation arising from the second segment of the ophthalmic artery. As she was 9 weeks pregnant, the decision was made to monitor her closely. Over the following six months, her proptosis progressed, accompanied by decreased visual acuity, afferent pupillary defect, and red desaturation concerning for compressive optic neuropathy. After planned c-section, she underwent embolization with n-butyl cyanoacrylate. Upon awakening after embolization, she had no light perception vision from her right eye and was found to have ophthalmic artery obstruction. She ultimately developed a blind painful right eye and underwent enucleation with histopathology demonstrating glue in the central retinal artery, posterior ciliary arteries, and choroid. This case highlights ophthalmic artery occlusion as a rare complication of orbital arteriovenous malformation embolization and demonstrates correlating histopathological findings, which have not previously been reported.

Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling.

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS+MB), by transiently opening the blood-brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUSonly), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.