The diagnostic accuracy of the Mini-Cog screening tool for the detection of cognitive impairment-A systematic review and meta-analysis.

BACKGROUND: The Mini-Cog is a rapid screening tool that can be administered to older adults to detect cognitive impairment (CI); however, the accuracy of the Mini-Cog to detect CI for older patients in various healthcare settings is unclear. OBJECTIVES: To evaluate the diagnostic accuracy of the Mini-Cog to screen for cognitive impairment in older patients across different healthcare settings. METHODS/DESIGN: We searched nine electronic databases (including MEDLINE, Embase) from inception to January 2023. We included studies with patients ≥60 years old undergoing screening for cognitive impairment using the Mini-Cog across all healthcare settings. A cut-off of ≤ 2/5 was used to classify dementia, mild cognitive impairment (MCI), and cognitive impairment (defined as either MCI or dementia) across various settings. The diagnostic accuracy of the Mini-Cog was assessed against gold standard references such as the Diagnostic and Statistical Manual of Mental Disorders (DSM). A bivariate random-effects model was used to estimate accuracy and diagnostic ability. The risk of bias was assessed using QUADAS-2 criteria. RESULTS: The systematic search resulted in 4,265 articles and 14 studies were included for analysis. To detect dementia (six studies, n = 4772), the Mini-Cog showed 76% sensitivity and 83% specificity. To detect MCI (two studies, n = 270), it showed 84% sensitivity and 79% specificity. To detect CI (eight studies, n = 2152), it had 67% sensitivity and 83% specificity. In the primary care setting, to detect either MCI, dementia, or CI (eight studies, n = 5620), the Mini-Cog demonstrated 73% sensitivity and 84% specificity. Within the secondary care setting (seven studies, n = 1499), the Mini-Cog to detect MCI, dementia or CI demonstrated 73% sensitivity and 76% specificity. A high or unclear risk of bias persisted in the patient selection and timing domain. CONCLUSIONS: The Mini-Cog is a quick and freely available screening tool and has high sensitivity and specificity to screen for CI in older adults across various healthcare settings. It is a practical screening tool for use in time-sensitive and resource-limited healthcare settings.

Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model.

The widely used chemotherapy cisplatin causes permanent hearing loss in 40%-60% of patients with cancer. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer drug, in a clinically relevant multidose cisplatin mouse model. The protective effects of dabrafenib, given orally twice daily with cisplatin, were determined by functional hearing tests and cochlear outer hair cell counts. Toxicity of the drug cotreatment was evaluated, and levels of phosphorylated ERK were measured. A dabrafenib dose of 3 mg/kg BW, twice daily, in mice, was determined to be the minimum effective dose, and it is equivalent to one-tenth of the daily FDA-approved dose for human cancer treatment. The levels of hearing protection acquired, 20-25 dB at the 3 frequencies tested, in both female and male mice, persisted for 4 months after completion of treatments. Moreover, dabrafenib exhibited a good in vivo therapeutic index (> 25), protected hearing in 2 mouse strains, and diminished cisplatin-induced weight loss. This study demonstrates that dabrafenib is a promising candidate drug for protection from cisplatin-induced hearing loss.

Diagnostic accuracy of Ascertain Dementia 8-item Questionnaire by participant and informant-A systematic review and meta-analysis.

BACKGROUND: The Ascertain Dementia 8-item Questionnaire (AD8) is a screening tool for cognitive impairment that can be administered to older persons and/or their informants. OBJECTIVES: To evaluate the diagnostic accuracy and compare the predictive parameters of the informant and participant-completed Ascertain Dementia 8-item Questionnaire (iAD8 and pAD8, respectively) in older adults with cognitive impairment. METHODS/DESIGN: We searched ten electronic databases (including MEDLINE (Ovid), Embase) from tool inception to March 2022. We included studies with patients ≥60 years old that were screened for cognitive impairment using AD8 in any healthcare setting. Predictive parameters were assessed against reference standards to estimate accuracy and diagnostic ability using bivariate random-effects meta-analyses. We used QUADAS-2 criteria to assess risk of bias. RESULTS: A cut-off of ≥2/8 was used to classify mild cognitive impairment (MCI), dementia, and cognitive impairment (MCI or dementia). Seven studies using the iAD8 (n = 794) showed a sensitivity of 80% and specificity of 79% to detect MCI. Nine studies using the iAD8 (n = 2393) established 91% sensitivity and 64% specificity to detect dementia. To detect MCI using the pAD8, four studies (n = 836) showed 57% sensitivity and 71% specificity. To detect dementia using the pAD8, four studies (n = 3015) demonstrated 82% sensitivity and 75% specificity. Recurring high or unclear risk of bias was noted in the domains of "Index test" and "reference standard". CONCLUSIONS: The diagnostic accuracy of iAD8 is superior to that of pAD8 when screening for cognitive impairment. The AD8 may be an acceptable alternative to screen for cognitive impairment in older adults when there are limitations to formal testing.

Association between postoperative delirium and adverse outcomes in older surgical patients: A systematic review and meta-analysis.

STUDY OBJECTIVE: To assess the incidence of postoperative delirium and its outcomes in older non-cardiac surgical patients. DESIGN: A systematic review and meta-analysis with multiple databases searched from inception to February 22, 2022. SETTING: Postoperative assessments. PATIENTS: Non-cardiac and non-neurological surgical patients aged ≥60 years with and without postoperative delirium. Included studies must report ≥1 postoperative outcome. Studies with a small sample size (N < 100 subjects) were excluded. MEASUREMENTS: Outcomes comprised the pooled incidence of postoperative delirium and its postoperative outcomes, including mortality, complications, unplanned intensive care unit admissions, length of stay, and non-home discharge. For dichotomous and continuous outcomes, OR and difference in means were computed, respectively, with a 95% CI. MAIN RESULTS: Fifty-four studies (20,988 patients, 31 elective studies, 23 emergency studies) were included. The pooled incidence of postoperative delirium was 19% (95% CI: 16%, 23%) after elective surgery and 32% (95% CI: 25%, 39%) after emergency surgery. In elective surgery, postoperative delirium was associated with increased mortality at 1-month (OR: 6.60; 95% CI: 1.58, 27.66), 6-month (OR: 5.69; 95% CI: 2.33, 13.88), and 1-year (OR: 2.87; 95% CI: 1.63, 5.06). The odds of postoperative complications, unplanned intensive care unit admissions, prolonged length of hospital stay, and non-home discharge were also higher in delirium cases. In emergency surgery, patients with postoperative delirium had greater odds of mortality at 1-month (OR: 3.56; 95% CI: 1.77, 7.15), 6-month (OR: 2.60; 95% CI: 1.88, 3.61), and 1-year (OR: 2.30; 95% CI: 1.77, 3.00). CONCLUSIONS: Postoperative delirium was associated with higher odds of mortality, postoperative complications, unplanned intensive care unit admissions, length of hospital stay, and non-home discharge. Prevention and perioperative management of delirium may optimize surgical outcomes.

ZBTB20 is essential for cochlear maturation and hearing in mice.

The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional network governing cochlear late-stage maturation and particularly the differentiation of its lateral nonsensory region. Here, we establish ZBTB20 as an essential transcription factor required for cochlear terminal differentiation and maturation and hearing. ZBTB20 is abundantly expressed in the developing and mature cochlear nonsensory epithelial cells, with transient expression in immature hair cells and spiral ganglion neurons. Otocyst-specific deletion of Zbtb20 causes profound deafness with reduced endolymph potential in mice. The subtypes of cochlear epithelial cells are normally generated, but their postnatal development is arrested in the absence of ZBTB20, as manifested by an immature appearance of the organ of Corti, malformation of tectorial membrane (TM), a flattened spiral prominence (SP), and a lack of identifiable Boettcher cells. Furthermore, these defects are related with a failure in the terminal differentiation of the nonsensory epithelium covering the outer border Claudius cells, outer sulcus root cells, and SP epithelial cells. Transcriptome analysis shows that ZBTB20 regulates genes encoding for TM proteins in the greater epithelial ridge, and those preferentially expressed in root cells and SP epithelium. Our results point to ZBTB20 as an essential regulator for postnatal cochlear maturation and particularly for the terminal differentiation of cochlear lateral nonsensory domain.

Apicosome: Newly identified cell-type-specific organelle in mouse cochlear and vestibular hair cells.

Cochlear and vestibular hair cells are highly specialized sensory receptors for hearing and balance. Here, we report a serendipitous identification of a hair-cell-specific organelle in neonatal mouse inner ear, which we name "apicosome." The apicosome is ∼500 nm in diameter and shows itinerant nature and transient appearance during development in cochlear hair cells. In contrast to cochlear hair cells, the apicosome persists in vestibular hair cells even in adult. The timing of apicosome translocation and disappearance in cochlear hair cells during development is correlated with kinocilium development and maintenance. The apicosome is not seen in supporting cells despite the fact that nascent supporting cells have microvilli and a primary cilium. Interestingly, transdifferentiated hair cells from supporting cells also contain apicosome, suggesting that it is unique to hair cells. Thus, our study identifies a previously undescribed organelle in hair cells and lays the foundation for further characterization of this specialized structure.

Nociceptor activity induces nonionotropic NMDA receptor signaling to enable spinal reconsolidation and reverse pathological pain.

Chronic, pathological pain is a highly debilitating condition that can arise and be maintained through central sensitization. Central sensitization shares mechanistic and phenotypic parallels with memory formation. In a sensory model of memory reconsolidation, plastic changes underlying pain hypersensitivity can be dynamically regulated and reversed following the reactivation of sensitized sensory pathways. However, the mechanisms by which synaptic reactivation induces destabilization of the spinal "pain engram" are unclear. We identified nonionotropic N-methyl-d-aspartate receptor (NI-NMDAR) signaling as necessary and sufficient for the reactive destabilization of dorsal horn long-term potentiation and the reversal of mechanical sensitization associated with central sensitization. NI-NMDAR signaling engaged directly or through the reactivation of sensitized sensory networks was associated with the degradation of excitatory postsynaptic proteins. Our findings identify NI-NMDAR signaling as a putative synaptic mechanism by which engrams are destabilized in reconsolidation and as a potential means of treating underlying causes of chronic pain.

Incidence of preoperative instrumental activities of daily living (IADL) dependence and adverse outcomes in older surgical patients: A systematic review and meta-analysis.

STUDY OBJECTIVE: Instrumental activities of daily living (IADLs) are essential to patient function and quality of life after surgery. In older surgical patients, the incidence of preoperative IADL dependence has not been well characterized in the literature. This systematic review and meta-analysis aimed to determine the pooled incidence of preoperative IADL dependence and the associated adverse outcomes in the older surgical population. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE, MEDLINE Epub Ahead of Print and In-Process, In-Data-Review & Other Non-Indexed Citations, Embase/Embase Classic, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews, ClinicalTrials.Gov, the WHO ICTRP (International Clinical Trials Registry Platform) were searched for relevant articles from 1969 to April 2022. PATIENTS: Patients aged ≥60 years old undergoing surgery with preoperative IADL assessed by the Lawton IADL Scale. INTERVENTIONS: Preoperative assessment. MEASUREMENT: The primary outcome was the pooled incidence of preoperative IADL dependency. Additional outcomes included post-operative mortality, postoperative delirium [POD], functional status improvement, and discharge disposition. MAIN RESULTS: Twenty-one studies (n = 5690) were included. In non-cardiac surgeries, the pooled incidence of preoperative IADL dependence was 37% (95% CI: 26.0%, 48.0%) among 2909 patients. Within cardiac surgeries, the pooled incidence of preoperative IADL dependence was 53% (95% CI: 24.0%, 82.0%) among 1074 patients. Preoperative IADL dependence was associated with an increased risk of postoperative delirium than those without IADL dependence (44.9% vs 24.4, OR 2.26; 95% CI: 1.42, 3.59; I2: 0%; P = 0.0005). CONCLUSIONS: There is a high incidence of IADL dependence in older surgical patients undergoing non-cardiac and cardiac surgery. Preoperative IADL dependence was associated with a two-fold risk of postoperative delirium. Further work is needed to determine the feasibility of using the IADL scale preoperatively as a predictive tool for postoperative adverse outcomes.

The prevalence and risk factors of sleep disturbances in surgical patients: A systematic review and meta-analysis.

Determining the prevalence and risk factors related to sleep disturbance in surgical patients would be beneficial for risk stratification and perioperative care planning. The objectives of this systematic review and meta-analysis are to determine the prevalence and risk factors of sleep disturbances and their associated postoperative complications in surgical patients. The inclusion criteria were: (1) patients ≥18 years old undergoing a surgical procedure, (2) in-patient population, and (3) report of sleep disturbances using a validated sleep assessment tool. The systematic search resulted in 21,951 articles. Twelve patient cohorts involving 1497 patients were included. The pooled prevalence of sleep disturbances at preoperative assessment was 60% (95% Confidence Interval (CI): 50%, 69%) and the risk factors for postoperative sleep disturbances were a high preoperative Pittsburgh sleep quality index (PSQI) score indicating preexisting disturbed sleep and anxiety. Notably, patients with postoperative delirium had a higher prevalence of pre- and postoperative sleep disturbances and high preoperative wake after sleep onset percentage (WASO%). The high prevalence of preoperative sleep disturbances in surgical patients has a negative impact on postoperative outcomes and well-being. Further work in this area is warranted.

Occlusion of two semicircular canals does not disrupt normal hearing in adult mice.

Vertigo is a debilitating disease affecting 15-20% of adults worldwide. Vestibular peripheral vertigo is the most common cause of vertigo, often due to Meniere's disease and benign paroxysmal positional vertigo. Although some vertigo symptoms can be controlled by conservative treatment and/or vestibular rehabilitation therapy, these treatments do not work for some patients. Semicircular canal occlusion surgery has proven to be very effective for these patients with intractable vertigo. However, its application is limited due to concern that the procedure will disrupt normal hearing. In this study, we investigated if occlusion of two semicircular canals would jeopardize auditory function by comparing auditory function and hair cell morphology between the surgical and contralateral ears before and after the surgery in a mouse model. By measuring the auditory brainstem response and distortion product otoacoustic emission 4 weeks post-surgery, we show that auditory function does not significantly change between the surgical and contralateral ears. In addition, confocal imaging has shown no hair cell loss in the cochlear and vestibular sensory epithelia, and scanning electron microscopy also indicates normal stereocilia morphology in the surgical ear. More importantly, the endocochlear potential measured from the surgical ear is not significantly different than that seen in the contralateral ear. Our study suggests that occlusion of two semicircular canals does not disrupt normal hearing in the mouse model, providing a basis to extend the procedure to patients, even those with normal hearing, benefitting more patients with intractable vertigo attacks.

Profiling mouse cochlear cell maturation using 10× Genomics single-cell transcriptomics.

Juvenile and mature mouse cochleae contain various low-abundant, vulnerable sensory epithelial cells embedded in the calcified temporal bone, making it challenging to profile the dynamic transcriptome changes of these cells during maturation at the single-cell level. Here we performed the 10x Genomics single-cell RNA sequencing (scRNA-seq) of mouse cochleae at postnatal days 14 (P14) and 28. We attained the transcriptomes of multiple cell types, including hair cells, supporting cells, spiral ganglia, stria fibrocytes, and immune cells. Our hair cell scRNA-seq datasets are consistent with published transcripts from bulk RNA-seq. We also mapped known deafness genes to corresponding cochlear cell types. Importantly, pseudotime trajectory analysis revealed that inner hair cell maturation peaks at P14 while outer hair cells continue development until P28. We further identified and confirmed a long non-coding RNA gene Miat to be expressed during maturation in cochlear hair cells and spiral ganglia neurons, and Pcp4 to be expressed during maturation in cochlear hair cells. Our transcriptomes of juvenile and mature mouse cochlear cells provide the sequel to those previously published at late embryonic and early postnatal ages and will be valuable resources to investigate cochlear maturation at the single-cell resolution.

Strategies and progresses for enhancing targeted antibiotic delivery.

Antibiotic resistance is a global health issue and a potential risk for society. Antibiotics administered through conventional formulations are devoid of targeting effect and often spread to various undesired body sites, leading to sub-lethal concentrations at the site of action and thus resulting in emergence of resistance, as well as side effects. Moreover, we have a very slim antibiotic pipeline. Drug-delivery systems have been designed to control the rate, time, and site of drug release, and innovative approaches for antibiotic delivery provide a glint of hope for addressing these issues. This review elaborates different delivery strategies and approaches employed to overcome the limitations of conventional antibiotic therapy. These include antibiotic conjugates, prodrugs, and nanocarriers for local and targeted antibiotic release. In addition, a wide range of stimuli-responsive nanocarriers and biological carriers for targeted antibiotic delivery are discussed. The potential advantages and limitations of targeted antibiotic delivery strategies are described along with possible solutions to avoid these limitations. A number of antibiotics successfully delivered through these approaches with attained outcomes and potentials are reviewed.

Postoperative outcomes in older surgical patients with preoperative cognitive impairment: A systematic review and meta-analysis.

STUDY OBJECTIVE: To determine the effect of cognitive impairment (CI) and dementia on adverse outcomes in older surgical patients. DESIGN: A systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs). Various databases were searched from their inception dates to March 8, 2021. SETTING: Preoperative assessment. PATIENTS: Older patients (≥ 60 years) undergoing non-cardiac surgery. MEASUREMENTS: Outcomes included postoperative delirium, mortality, discharge to assisted care, 30-day readmissions, postoperative complications, and length of hospital stay. Effect sizes were calculated as Odds Ratio (OR) and Mean Difference (MD) based on random effect model analysis. The quality of included studies was assessed using the Cochrane Risk Bias Tool for RCTs and Newcastle-Ottawa Scale for observational cohort studies. RESULTS: Fifty-three studies (196,491 patients) were included. Preoperative CI was associated with a significant risk of delirium in older patients after non-cardiac surgery (25.1% vs. 10.3%; OR: 3.84; 95%CI: 2.35, 6.26; I2: 76%; p < 0.00001). Cognitive impairment (26.2% vs. 13.2%; OR: 2.28; 95%CI: 1.39, 3.74; I2: 73%; p = 0.001) and dementia (41.6% vs. 25.5%; OR: 1.96; 95%CI: 1.34, 2.88; I2: 99%; p = 0.0006) significantly increased risk for 1-year mortality. In patients with CI, there was an increased risk of discharge to assisted care (44.7% vs. 38.3%; OR 1.74; 95%CI: 1.05, 2.89, p = 0.03), 30-day readmissions (14.3% vs. 10.8%; OR: 1.36; 95%CI: 1.00, 1.84, p = 0.05), and postoperative complications (40.7% vs. 18.8%; OR: 1.85; 95%CI: 1.37, 2.49; p < 0.0001). CONCLUSIONS: Preoperative CI in older surgical patients significantly increases risk of delirium, 1-year mortality, discharge to assisted care, 30-day readmission, and postoperative complications. Dementia increases the risk of 1-year mortality. Cognitive screening in the preoperative assessment for older surgical patients may be helpful for risk stratification so that appropriate management can be implemented to mitigate adverse postoperative outcomes.

Molecular and cytological profiling of biological aging of mouse cochlear inner and outer hair cells.

Age-related hearing loss (ARHL) negatively impacts quality of life in the elderly population. The prevalent cause of ARHL is loss of mechanosensitive cochlear hair cells (HCs). The molecular and cellular mechanisms of HC degeneration remain poorly understood. Using RNA-seq transcriptomic analyses of inner and outer HCs isolated from young and aged mice, we show that HC aging is associated with changes in key molecular processes, including transcription, DNA damage, autophagy, and oxidative stress, as well as genes related to HC specialization. At the cellular level, HC aging is characterized by loss of stereocilia, shrinkage of HC soma, and reduction in outer HC mechanical properties, suggesting that functional decline in mechanotransduction and cochlear amplification precedes HC loss and contributes to ARHL. Our study reveals molecular and cytological profiles of aging HCs and identifies genes such as Sod1, Sirt6, Jund, and Cbx3 as biomarkers and potential therapeutic targets for ameliorating ARHL.

Mutation of SLC7A14 causes auditory neuropathy and retinitis pigmentosa mediated by lysosomal dysfunction.

Lysosomes contribute to cellular homeostasis via processes including macromolecule degradation, nutrient sensing, and autophagy. Defective proteins related to lysosomal macromolecule catabolism are known to cause a range of lysosomal storage diseases; however, it is unclear whether mutations in proteins involved in homeostatic nutrient sensing mechanisms cause syndromic sensory disease. Here, we show that SLC7A14, a transporter protein mediating lysosomal uptake of cationic amino acids, is evolutionarily conserved in vertebrate mechanosensory hair cells and highly expressed in lysosomes of mammalian cochlear inner hair cells (IHCs) and retinal photoreceptors. Autosomal recessive mutation of SLC7A14 caused loss of IHCs and photoreceptors, leading to presynaptic auditory neuropathy and retinitis pigmentosa in mice and humans. Loss-of-function mutation altered protein trafficking and increased basal autophagy, leading to progressive cell degeneration. This study implicates autophagy-lysosomal dysfunction in syndromic hearing and vision loss in mice and humans.

Grass-roots entrepreneurship complements traditional top-down innovation in lung and breast cancer.

The majority of biomedical research is funded by public, governmental, and philanthropic grants. These initiatives often shape the avenues and scope of research across disease areas. However, the prioritization of disease-specific funding is not always reflective of the health and social burden of each disease. We identify a prioritization disparity between lung and breast cancers, whereby lung cancer contributes to a substantially higher socioeconomic cost on society yet receives significantly less funding than breast cancer. Using search engine results and natural language processing (NLP) of Twitter tweets, we show that this disparity correlates with enhanced public awareness and positive sentiment for breast cancer. Interestingly, disease-specific venture activity does not correlate with funding or public opinion. We use outcomes from recent early-stage innovation events focused on lung cancer to highlight the complementary mechanism by which bottom-up "grass-roots" initiatives can identify and tackle under-prioritized conditions.