The Effect of Reduced GnRH Dose on Ovulation and Follicular Dynamics in Ovsynch Programme of Pure and Bunaji-Crossbred Cows.

Our objective was to compare the efficacy of reducing GnRH dose from 100 µg to 50 µg on the formation of ovulation and sizes of ovarian structures following Ovsynch in apparently healthy Bunaji and Friesian × Bunaji Cows. Thirty female multiparous-apparently-healthy adult [Bunaji (n = 15) and Friesian × Bunaji (n = 15)] breeds of cattle were used. Five cows each were allocated randomly to three groups [control; full dose (FD), and half dose (HD)]. Cows in the control group were treated with 2 ml normal saline while FD-group received 100 µg lecirelin on day 0, with 500 µg clorprostenol on day 7 and with 100 µg lecirelin two days later. Furthermore, HD-group received the same treatment as FD-cows but the dose of lecirelin was reduced to 50 µg at both times of GnRH administration. Ovarian structures were monitored by ultrasound with a 5-MHZ linear transrectal probe on days - 1 to 12. The ovarian responses of the various groups to first GnRH administration showed (0%, 40% and 60%) ovulation rate for C, HD and FD groups respectively in Bunaji breeds while in Friesian × Bunaji, it was (0%, 60%, 60%). Following second GnRH administration ovulation rate for Bunaji was (20%, 60%, and 60%) for Control, HD and FD-groups, respectively, while for Friesian × Bunaji cows it was (20%, 60%, and 80%). There was no significant difference (p > 0.05) in the days of new follicular wave emergence following the first GnRH administration. It was concluded that 50 µg Lecirelin reduced the cost of drug without affecting the efficiency of Ovsynch protocol.

Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3R451C Mouse Model of Autism.

Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3R451C mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3R451C mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3R451C mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3R451C mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3R451C mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABAA antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3R451C p = 0.002), but not the ileum, in both wild-type and Nlgn3R451C mice. These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein.

HISTOPATHOLOGICAL ANALYSIS OF NON-NEOPLASTIC OVARIAN LESIONS SEEN IN A TERTIARY HEALTH CENTRE IN NORTH WESTERN NIGERIA.

Introduction: Ovarian lesions may present as enlargements of the ovary and may occur at any age. Non-neoplastic enlargements develop almost exclusively during the childbearing years. They may be asymptomatic or, in rare cases, cause acute symptoms due to complications and account for the most prevalent cause of hospital admissions. They frequently form a pelvic mass and potentially mimic an ovarian neoplasm. Objective: To study the frequency and histopathological classification of non-neoplastic ovarian lesions in a tertiary institution in North-western Nigeria. Methodology: A retrospective study in which surgical biopsy specimens seen over a 9-year period were reviewed with respect to age and histopathological characteristics. Results: A total of 83 non-neoplastic lesions were histologically diagnosed during the period under review. They constitute 5.16 % and 40.9 % of both gynaecological and ovarian samples received respectively. Of which 33.7% were Corpus luteum, 13.3% were both Follicular cysts and simple cysts respectively. Luteoma of pregnancy and Infarction constitute 9.6% each respectively. Endometriosis and no pathology as part of TAH, 6.0% respectively. Ovarian ectopic gestation was 4.8% cases, Nonspecific inflammation (oophoritis) 2.4%, and 1.2% complex cyst. Majority of cases 45.8% occurred among women in the third decade and 26.5% in the fourth decade, cases within the fifth decade were 9.6% and the second decade constituted 8.4% cases. Conclusion: Ovarian non-neoplastic lesions are common in our environment; they potentially mimic ovarian neoplasms thereby posing a diagnostic challenge. Proper classifications are important for appropriate management.

Past and present experience shifts audiovisual temporal perception in rats.

Our brains have a propensity to integrate closely-timed auditory and visual stimuli into a unified percept; a phenomenon that is highly malleable based on prior sensory experiences, and is known to be altered in clinical populations. While the neural correlates of audiovisual temporal perception have been investigated using neuroimaging and electroencephalography techniques in humans, animal research will be required to uncover the underlying cellular and molecular mechanisms. Prior to conducting such mechanistic studies, it is important to first confirm the translational potential of any prospective animal model. Thus, in the present study, we conducted a series of experiments to determine if rats show the hallmarks of audiovisual temporal perception observed in neurotypical humans, and whether the rat behavioral paradigms could reveal when they experienced perceptual disruptions akin to those observed in neurodevelopmental disorders. After training rats to perform a temporal order judgment (TOJ) or synchrony judgment (SJ) task, we found that the rats' perception was malleable based on their past and present sensory experiences. More specifically, passive exposure to asynchronous audiovisual stimulation in the minutes prior to behavioral testing caused the rats' perception to predictably shift in the direction of the leading stimulus; findings which represent the first time that this form of audiovisual perceptual malleability has been reported in non-human subjects. Furthermore, rats performing the TOJ task also showed evidence of rapid recalibration, in which their audiovisual temporal perception on the current trial was predictably influenced by the timing lag between the auditory and visual stimuli in the preceding trial. Finally, by manipulating either experimental testing parameters or altering the rats' neurochemistry with a systemic injection of MK-801, we showed that the TOJ and SJ tasks could identify when the rats had difficulty judging the timing of audiovisual stimuli. These findings confirm that the behavioral paradigms are indeed suitable for future testing of rats with perceptual disruptions in audiovisual processing. Overall, our collective results highlight that rats represent an excellent animal model to study the cellular and molecular mechanisms underlying the acuity and malleability of audiovisual temporal perception, as they showcase the perceptual hallmarks commonly observed in humans.

The Association of Cognitive Status and Post-Operative Opioid Prescribing in Older Adults.

Objective: To examine the differences in opioid prescribing by cognitive status following common elective surgical procedures among Medicare beneficiaries. Background: Older individuals commonly experience changes in cognition with age. Although opioid prescribing is common after surgery, differences in opioid prescribing after surgery by cognitive status are poorly understood. Methods: We conducted a retrospective analysis of patients ≥65 years participating in the Health and Retirement Study (HRS) linked with Medicare claims data who underwent surgeries between January 2007 and November 2016 and had cognitive assessments before the index operation. Cognitive status was defined as normal cognition, mild cognitive impairment (MCI), or dementia. Outcomes assessed were initial perioperative opioid fill rates, refill rates, and high-risk prescriptions fill rates. The total amount of opioids filled during the 30-day postdischarge period was also assessed. Adjusted rates were estimated for patient factors using the Cochran-Armitage test for trend. Results: Among the 1874 patients included in the analysis, 68% had normal cognition, 21.3% had MCI, and 10.7% had dementia. Patients with normal cognition (58.1%) and MCI (54.5%) had higher initial preoperative fill rates than patients with dementia (33.5%) (P < 0.001). Overall, patients with dementia had similar opioid refill rates (21%) to patients with normal cognition (24.1%) and MCI (26.5%) (P = 0.322). Although prior opioid exposure did not differ by cognitive status (P = 0.171), among patients with high chronic preoperative use, those with dementia had lower adjusted prescription sizes filled within 30 days following discharge (281 OME) than patients with normal cognition (2147 OME) and MCI (774 OME) (P < 0.001; P = 0.009 respectively). Among opioid-naive patients, patients with dementia also filled smaller prescription sizes (97 OME) compared to patients with normal cognition (205 OME) and patients with MCI (173 OME) (P < 0.001 and P = 0.019, respectively). Conclusions: Patients with dementia are less likely to receive postoperative prescriptions, less likely to refill prescriptions, and receive prescriptions of smaller sizes compared to patients with normal cognition or MCI. A cognitive assessment is an additional tool surgeons can use to determine a patient's individualized postoperative pain control plan.

Patient Cognitive Status and Physician Recommendations for Cardiovascular Disease Treatment: Results of Two Nationwide, Randomized Survey Studies.

BACKGROUND: Clinical guidelines recommend that older patients (65+) with mild cognitive impairment (MCI) and early-stage dementia receive similar guideline-concordant care after cardiovascular disease (CVD) events as those with normal cognition (NC). However, older patients with MCI and dementia receive less care for CVD and other conditions than those with NC. Whether physician recommendations for guideline-concordant treatments after two common CVD events, acute myocardial infarction (AMI) and acute ischemic stroke (stroke), differ between older patients with NC, MCI, and early-stage dementia is unknown. OBJECTIVE: To test the influence of patient cognitive status (NC, MCI, early-stage dementia) on physicians' recommendations for guideline-concordant treatments for AMI and stroke. DESIGN: We conducted two parallel, randomized survey studies for AMI and stroke in the US using clinical vignettes where the hypothetical patient's cognitive status was randomized between physicians. PARTICIPANTS: The study included cardiologists, neurologists, and generalists who care for most patients hospitalized for AMI and stroke. MAIN MEASURES: The primary outcome was a composite quality score representing the number of five guideline-concordant treatments physicians recommended for a hypothetical patient after AMI or stroke. KEY RESULTS: 1,031 physicians completed the study (58.5% response rate). Of 1,031 respondents, 980 physicians had complete information. After adjusting for physician factors, physicians recommended similar treatments after AMI and stroke in hypothetical patients with pre-existing MCI (adjusted ratio of expected composite quality score, 0.98 [95% CI, 0.94, 1.02]; P = 0.36) as hypothetical patients with NC. Physicians recommended fewer treatments to hypothetical patients with pre-existing early-stage dementia than to hypothetical patients with NC (adjusted ratio of expected composite quality score, 0.90 [0.86, 0.94]; P < 0.001). CONCLUSION: In these randomized survey studies, physicians recommended fewer guideline-concordant AMI and stroke treatments to hypothetical patients with early-stage dementia than those with NC. We did not find evidence that physicians recommend fewer treatments to hypothetical patients with MCI than those with NC.

Platelet Rich Plasma and Adipose-Derived Mesenchymal Stem Cells Mitigate Methotrexate-Induced Nephrotoxicity in Rat via Nrf2/Pparγ/HO-1 and NF-Κb/Keap1/Caspase-3 Signaling Pathways: Oxidative Stress and Apoptosis Interplay.

BACKGROUND: the nephrotoxicity of methotrexate (MTX) is observed in high-dose therapy. Moreover, low-dose MTX therapy for rheumatic diseases is debatable and claimed to cause renal impairment. This study aimed at studying the effect of methotrexate in repeated low doses on rat kidneys and assessing the efficacy of adipose-derived mesenchymal stem cells (AD-MSCs) and platelet rich plasma (PRP) for attenuating this effect. METHODS: Forty-two male Wistar rats were used, 10 rats were donors of AD-MSCs and PRP, 8 rats served as control, and the remaining rats were subjected to induction of nephrotoxicity by MTX intraperitoneal injection once weekly for successive 8 weeks and then assigned into 3 groups of 8 animals each: Group II: received MTX only. Group III: received MTX + PRP. Group IV: received MTX + AD-MSCs. After one month, rats were anaesthetized, serum-sampled, and renal tissue removed for biochemical, histological, and ultrastructural evaluation. RESULTS: there was significant tubular degeneration, glomerulosclerosis, fibrosis, decreased renal index, along with increased levels of urea and creatinine in the MTX group compared to the control group. Immunohistochemical expression of caspase-3 and iNOS in the renal tissue was significantly increased in group II compared to groups III and IV. Biochemical results revealed higher tissue malondialdehyde (MDA) concentration in the MTX-injected group which decreased significantly in co-treatment with either AD-MSC or PRP + MTX. MSC promoted the activation of the Nrf2/PPARγ/HO-1 and NF-κB/Keap1/caspase-3 pathways, increased antioxidant enzyme activities, reduced lipid peroxidation levels, and alleviated oxidative damage and apoptosis. PRP showed therapeutic effects and molecular mechanisms similar to MSC. Furthermore, MSC and PRP treatment significantly reduced MTX-induced upregulation of the pro-inflammatory (NF-κB, interleukin-1ß, and TNF-α), oxidative stress (Nrf-2, hemoxygenase-1, glutathione, and malondialdehyde), and nitrosative stress (iNOS) markers in the kidney. CONCLUSION: repeated administration of low-dose MTX resulted in massive renal tissue toxicity and deterioration of renal function in rats which proved to be attenuated by PRP and AD-MSCs through their anti-inflammatory, anti-apoptotic and anti-fibrotic properties.

Persistence of spike-specific immune responses in BNT162b2-vaccinated donors and generation of rapid ex-vivo T cells expansion protocol for adoptive immunotherapy: A pilot study.

Introduction: The BNT162b2 mRNA-based vaccine has shown high efficacy in preventing COVID-19 infection but there are limited data on the types and persistence of the humoral and T cell responses to such a vaccine. Methods: Here, we dissect the vaccine-induced humoral and cellular responses in a cohort of six healthy recipients of two doses of this vaccine. Results and discussion: Overall, there was heterogeneity in the spike-specific humoral and cellular responses among vaccinated individuals. Interestingly, we demonstrated that anti-spike antibody levels detected by a novel simple automated assay (Jess) were strongly correlated (r=0.863, P<0.0001) with neutralizing activity; thus, providing a potential surrogate for neutralizing cell-based assays. The spike-specific T cell response was measured with a newly modified T-spot assay in which the high-homology peptide-sequences cross-reactive with other coronaviruses were removed. This response was induced in 4/6 participants after the first dose, and all six participants after the second dose, and remained detectable in 4/6 participants five months post-vaccination. We have also shown for the first time, that BNT162b2 vaccine enhanced T cell responses also against known human common viruses. In addition, we demonstrated the efficacy of a rapid ex-vivo T cell expansion protocol for spike-specific T cell expansion to be potentially used for adoptive-cell therapy in severe COVID-19, immunocompromised individuals, and other high-risk groups. There was a 9 to 13.7-fold increase in the number of expanded T cells with a significant increase of anti-spike specific response showing higher frequencies of both activation and cytotoxic markers. Interestingly, effector memory T cells were dominant in all four participants' CD8+ expanded memory T cells; CD4+ T cells were dominated by effector memory in 2/4 participants and by central memory in the remaining two participants. Moreover, we found that high frequencies of CD4+ terminally differentiated memory T cells were associated with a greater reduction of spike-specific activated CD4+ T cells. Finally, we showed that participants who had a CD4+ central memory T cell dominance expressed a high CD69 activation marker in the CD4+ activated T cells.

The Influence of Cognitive Impairment on Postoperative Outcomes.

OBJECTIVE: To examine differences in rates of elective surgery, postoperative mortality, and readmission by pre-existing cognitive status among Medicare beneficiaries undergoing surgery. BACKGROUND: MCI is common among older adults, but the impact of MCI on surgical outcomes is understudied. METHODS: We conducted a retrospective cohort study of individuals ≥65 who underwent surgery between 2001 and 2015 using data from the nationally-representative Health and Retirement Study linked with Medicare claims. Cognitive status was assessed by the modified telephone interview for cognitive status score and categorized as normal cognition (score: 12-27), MCI (7-11), and dementia (<7). Outcomes were 30- and 90-day postoperative mortality and readmissions. We used Cox proportional hazard models to estimate the risk of each outcome by cognition, adjusting for patient characteristics. RESULTS: In 6,590 patients, 69.9% had normal cognition, 20.1% had MCI, and 9.9% had dementia. Patients with MCI (79.9%) and dementia (73.6%) were less likely to undergo elective surgery than patients with normal cognition (85.9%). Patients with MCI had similar postoperative mortality and readmissions rates as patients with normal cognition. However, patients with dementia had significantly higher postoperative 90-day mortality (5.2% vs 8.4%, P = 0.002) and readmission rates (13.9% vs 17.3%, P = 0.038). CONCLUSION: Patients with self-reported MCI are less likely to undergo elective surgery but have similar postoperative outcomes compared with patients with normal cognition. Despite the variability of defining MCI, our findings suggest that MCI may not confer additional risk for older individuals undergoing surgery, and should not be a barrier for surgical care.

Long-term household material socioeconomic resources and cognitive health in a population-based cohort of older adults in rural northeast South Africa, 2001-2015.

Material resources owned by households that affect daily living conditions may be salient for cognitive health during aging, especially in low-income settings, but there is scarce evidence on this topic. We investigated relationships between long-term trends in household material resources and cognitive function among older adults in a population-representative study in rural South Africa. Data were from baseline interviews with 4580 adults aged ≥40 in "Health and Ageing in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI) in 2014/2015 linked to retrospective records on their household material resources from the Agincourt Health and Socio-Demographic Surveillance System (HDSS) from 2001 to 2013. Household material resources were assessed biennially in the Agincourt HDSS using a five-point index that captured dwelling materials, water and sanitation, sources of power, livestock, and technological amenities. Cognitive function was assessed in HAALSI and analyzed as a z-standardized latent variable capturing time orientation, episodic memory, and numeracy. We evaluated the relationships between quintiles of each of the mean resource index score, volatility in resource index score, and change in resource index score and subsequent cognitive function, overall and by resource type. Higher mean household resources were positively associated with cognitive function (ßadj = 0.237 standard deviation [SD] units for the highest vs. lowest quintile of mean resource index score; 95% CI: 0.163-0.312; p-trend<0.0001), as were larger improvements over time in household resources (ßadj = 0.122 SD units for the highest vs. lowest quintile of change in resources; 95% CI: 0.040-0.205; p-trend = 0.001). Results were robust to sensitivity analyses assessing heterogeneity by age and restricting to those with formal education. The findings were largely driven by technological amenities including refrigerators, stoves, telephones, televisions, and vehicles. These amenities may support cognitive function through improving nutrition and providing opportunities for cognitive stimulation through transportation and social contact outside of the home.

Comparing the Gut Microbiome in Autism and Preclinical Models: A Systematic Review.

Many individuals diagnosed with autism spectrum disorder (ASD) experience gastrointestinal (GI) dysfunction and show microbial dysbiosis. Variation in gut microbial populations is associated with increased risk for GI symptoms such as chronic constipation and diarrhoea, which decrease quality of life. Several preclinical models of autism also demonstrate microbial dysbiosis. Given that much pre-clinical research is conducted in mouse models, it is important to understand the similarities and differences between the gut microbiome in humans and these models in the context of autism. We conducted a systematic review of the literature using PubMed, ProQuest and Scopus databases to compare microbiome profiles of patients with autism and transgenic (NL3R451C, Shank3 KO, 15q dup), phenotype-first (BTBR) and environmental (Poly I:C, Maternal Inflammation Activation (MIA), valproate) mouse models of autism. Overall, we report changes in fecal microbial communities relevant to ASD based on both clinical and preclinical studies. Here, we identify an overlapping cluster of genera that are modified in both fecal samples from individuals with ASD and mouse models of autism. Specifically, we describe an increased abundance of Bilophila, Clostridium, Dorea and Lactobacillus and a decrease in Blautia genera in both humans and rodents relevant to this disorder. Studies in both humans and mice highlighted multidirectional changes in abundance (i.e. in some cases increased abundance whereas other reports showed decreases) for several genera including Akkermansia, Bacteroides, Bifidobacterium, Parabacteroides and Prevotella, suggesting that these genera may be susceptible to modification in autism. Identification of these microbial profiles may assist in characterising underlying biological mechanisms involving host-microbe interactions and provide future therapeutic targets for improving gut health in autism.

Synthesis of the α-Linked Digitoxose Trisaccharide Fragment of Kijanimicin: An Unexpected Application of Glycosyl Sulfonates.

Previously, we demonstrated that glycosyl tosylates are effective for the synthesis of ß-glycosides of gluco-configured 2-deoxy sugars. Here, we show the same sulfonate system can be used for the selective synthesis of α-glycosides containing the allo-configured 2-deoxy sugar digitoxose. As with previous work, optimal selectivity is obtained through matching the donor with the appropriate arylsulfonyl chloride promoter. The utility of this method is demonstrated through the synthesis of the α-linked digitoxose trisaccharide fragment of kijanimicin.

The Association Between Mild Cognitive Impairment Diagnosis and Patient Treatment Preferences: a Survey of Older Adults.

BACKGROUND: Older patients (65+) with mild cognitive impairment (MCI) receive less guideline-concordant care for cardiovascular disease (CVD) and other conditions than patients with normal cognition (NC). One potential explanation is that patients with MCI want less treatment than patients with NC; however, the treatment preferences of patients with MCI have not been studied. OBJECTIVE: To determine whether patients with MCI have different treatment preferences than patients with NC. DESIGN: Cross-sectional survey conducted at two academic medical centers from February to December 2019 PARTICIPANTS: Dyads of older outpatients with MCI and NC and patient-designated surrogates. MAIN MEASURES: The modified Life-Support Preferences-Predictions Questionnaire score measured patients' preferences for life-sustaining treatment decisions in six health scenarios including stroke and acute myocardial infarction (range, 0-24 treatments rejected with greater scores indicating lower desire for treatment). KEY RESULTS: The survey response rate was 73.4%. Of 136 recruited dyads, 127 (93.4%) completed the survey (66 MCI and 61 NC). The median number of life-sustaining treatments rejected across health scenarios did not differ significantly between patients with MCI and patients with NC (4.5 vs 6.0; P=0.55). Most patients with MCI (80%) and NC (80%) desired life-sustaining treatments in their current health (P=0.99). After adjusting for patient and surrogate factors, the difference in mean counts of rejected treatments between patients with MCI and patients with NC was not statistically significant (adjusted ratio, 1.08, 95% CI, 0.80-1.44; P=0.63). CONCLUSION: We did not find evidence that patients with MCI want less treatment than patients with NC. These findings suggest that other provider and system factors might contribute to patients with MCI getting less guideline-concordant care.

Subjective social position and cognitive function in a longitudinal cohort of older, rural South African adults, 2014-2019.

BACKGROUND: The relationship between subjective social position (SSP) and cognitive ageing unclear, especially in low-income settings. We aimed to investigate the relationship between SSP and cognitive function over time among older adults in rural South Africa. METHODS: Data were from 3771 adults aged ≥40 in the population-representative 'Health and Ageing in Africa: A Longitudinal Study of an INDEPTH Community in South Africa' from 2014/2015 (baseline) to 2018/2019 (follow-up). SSP was assessed at baseline with the 10-rung MacArthur Network social position ladder. Outcomes were composite orientation and episodic memory scores at baseline and follow-up (range: 0-24). Mortality- and attrition-weighted linear regression estimated the associations between baseline SSP with cognitive scores at each of the baseline and follow-up. Models were adjusted for age, age2, sex, country of birth, father's occupation, education, employment, household assets, literacy, marital status and health-related covariates. RESULTS: SSP responses ranged from 0 (bottom ladder rung/lowest social position) to 10 (top ladder rung/highest social position), with a mean of 6.6 (SD: 2.3). SSP was positively associated with baseline cognitive score (adjusted ß=0.198 points per ladder rung increase; 95% CI 0.145 to 0.253) and follow-up cognitive score (adjusted ß=0.078 points per ladder rung increase; 95% CI 0.021 to 0.136). CONCLUSION: Independent of objective socioeconomic position measures, SSP is associated with orientation and episodic memory scores over two time points approximately 3 years apart among older rural South Africans. Future research is needed to establish the causality of the observed relationships, whether they persist over longer follow-up periods and their consistency in other populations.

Validation of Claims Algorithms to Identify Alzheimer's Disease and Related Dementias.

BACKGROUND: Using billing data generated through health care delivery to identify individuals with dementia has become important in research. To inform tradeoffs between approaches, we tested the validity of different Medicare claims-based algorithms. METHODS: We included 5 784 Medicare-enrolled, Health and Retirement Study participants aged older than 65 years in 2012 clinically assessed for cognitive status over multiple waves and determined performance characteristics of different claims-based algorithms. RESULTS: Positive predictive value (PPV) of claims ranged from 53.8% to 70.3% and was highest using a revised algorithm and 1 year of observation. The tradeoff of greater PPV was lower sensitivity; sensitivity could be maximized using 3 years of observation. All algorithms had low sensitivity (31.3%-56.8%) and high specificity (92.3%-98.0%). Algorithm test performance varied by participant characteristics, including age and race. CONCLUSION: Revised algorithms for dementia diagnosis using Medicare administrative data have reasonable accuracy for research purposes, but investigators should be cognizant of the tradeoffs in accuracy among the approaches they consider.

ECM-LSE: Prediction of Extracellular Matrix Proteins Using Deep Latent Space Encoding of k-Spaced Amino Acid Pairs.

Extracelluar matrix (ECM) proteins create complex networks of macromolecules which fill-in the extracellular spaces of living tissues. They provide structural support and play an important role in maintaining cellular functions. Identification of ECM proteins can play a vital role in studying various types of diseases. Conventional wet lab-based methods are reliable; however, they are expensive and time consuming and are, therefore, not scalable. In this research, we propose a sequence-based novel machine learning approach for the prediction of ECM proteins. In the proposed method, composition of k-spaced amino acid pair (CKSAAP) features are encoded into a classifiable latent space (LS) with the help of deep latent space encoding (LSE). A comprehensive ablation analysis is conducted for performance evaluation of the proposed method. Results are compared with other state-of-the-art methods on the benchmark dataset, and the proposed ECM-LSE approach has shown to comprehensively outperform the contemporary methods.

The Effect of Childhood Socioeconomic Position and Social Mobility on Cognitive Function and Change Among Older Adults: A Comparison Between the United States and England.

OBJECTIVES: This study aims to examine the relationship between childhood socioeconomic position (SEP) and cognitive function in later life within nationally representative samples of older adults in the United States and England, investigate whether these effects are mediated by later-life SEP, and determine whether social mobility from childhood to adulthood affects cognitive function and decline. METHOD: Using data from the Health and Retirement Study (HRS) and the English Longitudinal Survey of Ageing (ELSA), we examined the relationships between measures of SEP, cognitive performance and decline using individual growth curve models. RESULTS: High childhood SEP was associated with higher cognitive performance at baseline in both cohorts and did not affect the rate of decline. This benefit dissipated after adjusting for education and adult wealth in the United States. Respondents with low childhood SEP, above median education, and high adult SEP had better cognitive performance at baseline than respondents with a similar childhood background and less upward mobility in both countries. DISCUSSION: These findings emphasize the impact of childhood SEP on cognitive trajectories among older adults. Upward mobility may partially compensate for disadvantage early in life but does not protect against cognitive decline.

Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Differences in acute ischemic stroke (AIS) treatment by cognitive status are unclear, but some studies have found patients with preexisting dementia get less treatment. We compared AIS care by preexisting cognitive status. METHODS: Cross-sectional analysis of prospectively obtained data on 836 adults ≥45 with AIS from the population-based Brain Attack Surveillance in Corpus Christi project from 2008 to 2013. We compared receipt of a composite quality measure representing the percentage of 7 treatments/procedures received (ordinal scale; values, <0.75, 0.75-0.99, and 1.0), a binary defect-free quality score, and individual treatments after AIS between patients with preexisting dementia (Informant Questionnaire on Cognitive Decline in the Elderly score ≥3.44), mild cognitive impairment (MCI, score 3.1-3.43), and normal cognition (score ≤3). RESULTS: Among patients with AIS, 42% had normal cognition (47% women; median age [interquartile range], 65 [56-76]), 32% had MCI (54% women; median age, 70 [60-78]), 26% had dementia (56% women; median age, 78 [64-85]). After AIS, 44% of patients with preexisting dementia and 55% of patients with preexisting MCI or normal cognition received defect-free care. Compared with cognitively normal patients, patients with preexisting MCI had similar cumulative odds (unadjusted cumulative odds ratio =0.99, P=0.92), and patients with preexisting dementia had 36% lower cumulative odds of receiving the composite quality measure (unadjusted cumulative odds ratio [OR]=0.64, P=0.005). However, the dementia-quality association became nonsignificant after adjusting for patient factors, namely sex, comorbidity, and body mass index (adjusted cumulative OR [acOR]=0.79, P=0.19). Independent of patient factors, preexisting MCI was negatively associated with receipt of IV tPA (intravenous tissue-type plasminogen activator; acOR=0.36, P=0.04), rehabilitation assessment (acOR=0.28, P=0.016), and echocardiogram (acOR=0.48, P<0.001). Preexisting dementia was negatively associated with receipt of antithrombotic by day 2 (acOR=0.39, P=0.04) and echocardiogram (acOR=0.42, P<0.001). CONCLUSIONS: Patients with preexisting MCI and dementia, compared with cognitively normal patients, may receive less frequently some treatments and procedures, but not the composite quality measure, after AIS.

Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation.

Mutant-selective KRASG12C inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRAS G12C-mutant cancers, including non-small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRASG12C inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with KRAS G12C NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (KRAS, NRAS, BRAF, MAP2K1), all of which converge to reactivate RAS-MAPK signaling. Notably, a novel KRAS Y96D mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein-drug interactions and confers resistance to these inhibitors in engineered and patient-derived KRAS G12C cancer models. Interestingly, a novel, functionally distinct tricomplex KRASG12C active-state inhibitor RM-018 retained the ability to bind and inhibit KRASG12C/Y96D and could overcome resistance. SIGNIFICANCE: In one of the first reports of clinical acquired resistance to KRASG12C inhibitors, our data suggest polyclonal RAS-MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRASG12C inhibitor.See related commentary by Pinnelli and Trusolino, p. 1874.This article is highlighted in the In This Issue feature, p. 1861.

Hypertension and Cognitive Health Among Older Adults in India.

OBJECTIVES: To assess the prevalence of diagnosed and undiagnosed hypertension and their relationship to cognitive function in older adults in India. DESIGN: Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD), an in-depth national study of late-life cognition and dementia. SETTING: Geriatric hospitals and respondents' homes across 14 states in India. PARTICIPANTS: N = 2,874 individuals aged 60 years and older from LASI-DAD. MEASUREMENTS: Hypertension was identified by self-report of physician diagnosis or measured blood pressure (BP) of 140/90 mmHg or higher. Undiagnosed hypertension was defined as hypertensive BP measurements, but no physician diagnosis. Controlled hypertension was defined as BP lower than 140/90 mmHg among those with a physician diagnosis. Total hypertension included both diagnosed and undiagnosed hypertension. A summary cognition score, derived from the sum of 18 cognitive tests administered in the LASI-DAD (range = 0-360) was used to assess cognitive function. RESULTS: Total hypertension prevalence was 63.2% (41.5% diagnosed and 21.6% undiagnosed). Among those with hypertension, 34.5% were undiagnosed, 34.2% were diagnosed but uncontrolled, and 31.3% were diagnosed and controlled. Neither diagnosed nor undiagnosed hypertension was related to cognitive function in fully adjusted models. Older age, female sex, less education, being widowed, rural residence, residing in the north or central regions, being in a scheduled caste or tribe, low consumption, being underweight, and history of stroke were all independently associated with worse cognitive test performance. CONCLUSION: Two-thirds of older Indian adults had hypertension, with the majority being undiagnosed or diagnosed but not adequately controlled. Hypertension was not independently associated with cognitive function, whereas sociodemographic factors were independently related to cognitive function. J Am Geriatr Soc 68:S29-S35, 2020.