The genetic architecture of blood pressure variability: A genome-wide association study of 9370 participants from UK Biobank.

Long-term blood pressure variability (BPV) is a risk factor for cardiovascular diseases, dementia, and stroke. However, its genetic architecture is not fully understood. This study aims to explore its genetic factors and provide more evidence on the mechanisms and further pathological study of BPV. The genome-wide association study (GWAS) is based on the UK Biobank cohort. There were four data collection rounds from 2006 to 2020, and 9370 participants with more than three blood pressure measurements were included. They had a median age of 55 and a male percentage of 50.1%. The phenotypes (BPV) were calculated by four methods and the genetic data contains 6 884 260 single nucleotide polymorphisms (SNPs) after imputation and quality control. A linear regression model was performed with adjustments for sex, age, genotype array, and a significant principal component. Subgroup analysis was performed on hypertension-free participants. The significant and suggestive significant P thresholds were set as 5 × 10-8 and 1 × 10-6 . Six genetic loci (BAD, CCDC88B, GPR137, PLCB3, RPS6KA4 for systolic BPV, and WWC2 for diastolic BPV) were identified by coding region SNPs at the suggestive significant P threshold (1 × 10-6 ). Among them, gene CCDC88B and RPS6KA4 reached the significant P threshold (5 × 10-8 ), with the strongest signal of SNP rs1229536170 (P = 6.36 × 10-8 , ß = -.29). The annotation results indicate that genes CCDC88B, GPR137, RPS6KA4, and BAD are associated with long-term SBPV. Their functions of inflammation, epithelial dysfunction, and apoptosis are related to artery stiffness, which was reported as potential mechanisms of BPV.

Cost-effectiveness of pharmacological therapies for people with Alzheimer's disease and other dementias: a systematic review and meta-analysis.

OBJECTIVES: This study aims to synthesize the empirical economic evidence of pharmaceutical therapies for people with dementia. STUDY DESIGN: Systematic review and meta-analysis. Literature evaluating the costs and effects of drug therapies for dementia was indexed until December 2021. Quality of study was assessed using the Cochrane Risk of Bias Tool and Consensus on Health Economic Criteria list. Cost data were standardized to 2020 US dollars and analyzed from healthcare service and societal perspectives. Random-effects models were used to synthesize economic and clinical data, based on mean differences (MDs) and standardized MDs. RESULTS: Ten unique studies were identified from 11,771 records. Acetylcholinesterase inhibitors (AChEIs) and memantine improved dementia-related symptoms, alongside nonsignificant savings in societal cost (AChEIs: MD-2002 [- 4944 ~ 939]; memantine: MD-6322 [- 14355 ~ 1711]). Despite decreases in cost, antidepressants of mirtazapine and sertraline and second-generation antipsychotics were limited by their significant side effects on patients' cognitive and activity functions. Subgroup analysis indicated that the impacts of AChEIs on cost were affected by different analytical perspectives, follow-up periods, and participant age. CONCLUSIONS: AChEIs and memantine are cost-effective with improvements in dementia-related symptoms and trends of cost-savings. More empirical evidence with non-industrial sponsorships and rigorous design in different settings is warranted.

Comparing drawing under instructions with image copying for mild cognitive impairment (MCI) or dementia screening: a meta-analysis of 92 diagnostic studies.

OBJECTIVES: Drawing is a major component of cognitive screening for dementia. It can be performed without language restriction. Drawing pictures under instructions and copying images are different screening approaches. The objective of this study was to compare the diagnostic performance between drawing under instructions and image copying for MCI and dementia screening. METHOD: A literature search was carried out in the OVID databases with keywords related to drawing for cognitive screening. Study quality and risk of bias were assessed by QUADAS-2. The level of diagnostic accuracy across different drawing tests was pooled by bivariate analysis in a random effects model. The area under the hierarchical summary receiver-operating characteristic curve (AUC) was constructed to summarize the diagnostic performance. RESULTS: Ninety-two studies with sample size of 22,085 were included. The pooled results for drawing under instructions showed a sensitivity of 79% (95% CI: 76 - 83%) and a specificity of 80% (95% CI: 77 - 83%) with AUC of 0.87 (95% CI: 0.83 - 0.89). The pooled results for image copying showed a sensitivity of 71% (95% CI: 62 - 79%) and a specificity of 83% (95% CI: 72 - 90%) with AUC of 0.83 (95% CI: 0.80 - 0.86). Clock-drawing test was the screening test used in the majority of studies. CONCLUSION: Drawing under instructions showed a similar diagnostic performance when compared with image copying for cognitive screening and the administration of image copying is relatively simpler. Self-screening for dementia is feasible to be done at home in the near future.

Evaluation of Digital Drawing Tests and Paper-and-Pencil Drawing Tests for the Screening of Mild Cognitive Impairment and Dementia: A Systematic Review and Meta-analysis of Diagnostic Studies.

Digital drawing tests have been proposed for cognitive screening over the past decade. However, the diagnostic performance is still to clarify. The objective of this study was to evaluate the diagnostic performance among different types of digital and paper-and-pencil drawing tests in the screening of mild cognitive impairment (MCI) and dementia. Diagnostic studies evaluating digital or paper-and-pencil drawing tests for the screening of MCI or dementia were identified from OVID databases, included Embase, MEDLINE, CINAHL, and PsycINFO. Studies evaluated any type of drawing tests for the screening of MCI or dementia and compared with healthy controls. This study was performed according to PRISMA and the guidelines proposed by the Cochrane Diagnostic Test Accuracy Working Group. A bivariate random-effects model was used to compare the diagnostic performance of these drawing tests and presented with a summary receiver-operating characteristic curve. The primary outcome was the diagnostic performance of clock drawing test (CDT). Other types of drawing tests were the secondary outcomes. A total of 90 studies with 22,567 participants were included. In the screening of MCI, the pooled sensitivity and specificity of the digital CDT was 0.86 (95% CI = 0.75 to 0.92) and 0.92 (95% CI = 0.69 to 0.98), respectively. For the paper-and-pencil CDT, the pooled sensitivity and specificity of brief scoring method was 0.63 (95% CI = 0.49 to 0.75) and 0.77 (95% CI = 0.68 to 0.84), and detailed scoring method was 0.63 (95% CI = 0.56 to 0.71) and 0.72 (95% CI = 0.65 to 0.78). In the screening of dementia, the pooled sensitivity and specificity of the digital CDT was 0.83 (95% CI = 0.72 to 0.90) and 0.87 (95% CI = 0.79 to 0.92). The performances of the digital and paper-and-pencil pentagon drawing tests were comparable in the screening of dementia. The digital CDT demonstrated better diagnostic performance than paper-and-pencil CDT for MCI. Other types of digital drawing tests showed comparable performance with paper-and-pencil formats. Therefore, digital drawing tests can be used as an alternative tool for the screening of MCI and dementia.

Supporting Informal Caregivers of People With Dementia in Cost-Effective Ways: A Systematic Review and Meta-Analysis.

OBJECTIVES: Caring for persons with dementia is a heavy burden for informal caregivers. This study aimed to appraise the economic evidence of interventions supporting informal caregivers of people with dementia. METHODS: Literature was searched, and trial-based studies evaluating the costs and effects of interventions supporting informal caregivers of people with dementia were included. Cost data were analyzed from both healthcare and societal perspectives. Random-effects models were used to synthesize cost and effect data, based on mean differences (MDs) or standardized MDs. RESULTS: Of 33 eligible studies identified from 48 588 records, 14 (42.4%) showed net savings in total cost regardless of analytical perspectives. Among 22 studies included in meta-analyses, caregiver-focused psychosocial interventions showed improvements in caregivers' psychological health (n = 4; standardized MD 0.240; 95% confidence interval 0.094-0.387); nevertheless, the increases in societal cost were significant (n = 5; MD 3144; 95% confidence interval 922-5366). Psychological intervention and behavioral management engaging patient-caregiver dyads showed positive effects on caregivers' subjective burden, also with increases in total cost. Subgroup analyses indicated that the inclusion of different intervention components, the caregiver characteristics, and the follow-up periods could affect the costs and effects of interventions supporting informal caregivers. CONCLUSIONS: Psychosocial interventions directed at informal caregivers and dyad-based psychological and behavioral interventions are effective but also expensive. The use of these interventions depends on the society's willingness to pay. More comprehensive economic evidence of interventions supporting informal caregivers is required, and the design of intervention should focus more on different intervention components, characteristics of patients and caregivers, and healthcare systems.

Diagnostic accuracy of dementia screening tools in the Chinese population: a systematic review and meta-analysis of 167 diagnostic studies.

BACKGROUND: The rate of undetected dementia is high in China. However, the performance of dementia screening tools may differ in the Chinese population due to the lower education level and cultural diversity. This study aimed to evaluate the diagnostic accuracy of dementia screening tools in the Chinese population. METHODS: Eleven electronic databases were searched for studies evaluating the diagnostic accuracy of dementia screening tools in older Chinese adults. The overall diagnostic accuracy was estimated using bivariate random-effects models, and the area under the summary receiver operating characteristic curve was presented. RESULTS: One hundred sixty-seven studies including 81 screening tools were identified. Only 134 studies qualified for the meta-analysis. The Mini-Mental State Examination (MMSE) was the most commonly studied tool, with a combined sensitivity (SENS) and specificity (SPEC) of 0.87 (95%CI 0.85-0.90) and 0.89 (95%CI 0.86-0.91), respectively. The Addenbrooke's Cognitive Examination-Revised (ACE-R) (SENS: 0.96, 95%CI 0.89-0.99; SPEC: 0.96, 95%CI 0.89-0.98) and Montreal Cognitive Assessment (MoCA) (SENS: 0.93, 95%CI 0.88-0.96; SPEC: 0.90, 95%CI 0.86-0.93) showed the highest performance. The General Practitioner Assessment of Cognition (GPCOG), Hasegawa's Dementia Scale and Cognitive Abilities Screening Instrument had performances comparable to that of the MMSE. The cut-off scores ranged widely across studies, especially for the MMSE (range: 15-27) and MoCA (range: 14-26). CONCLUSIONS: A number of dementia screening tools were validated in the Chinese population after cultural and linguistical adaptations. The ACE-R and MoCA had the best diagnostic accuracy, whereas the GPCOG, with an administration time < 5 minutes, could be considered as a rapid screening tool.

CfaE tip mutations in enterotoxigenic Escherichia coli CFA/I fimbriae define critical human intestinal binding sites.

Enterotoxigenic Escherichia coli (ETEC) use colonization factors to attach to the human intestinal mucosa, followed by enterotoxin expression that induces net secretion and diarrhoeal illness. ETEC strain H10407 expresses CFA/I fimbriae, which are composed of multiple CfaB structural subunits and a CfaE tip subunit. Currently, the contribution of these individual fimbrial subunits in intestinal binding remains incompletely defined. To identify the role of CfaE in attachment in the native ETEC background, an R181A single-amino-acid substitution was introduced by recombination into the H10407 genome. The substitution of R181A eliminated haemagglutination and binding of intestinal mucosa biopsies in in vitro organ culture assays, without loss of CFA/I fimbriae expression. Wild-type in trans plasmid-expressed cfaE restored the binding phenotype. In contrast, in trans expression of cfaE containing amino acid 181 substitutions with similar amino acids, lysine, methionine and glutamine did not restore the binding phenotype, indicating that the loss of the binding phenotype was due to localized areas of epitope disruption. R181 appears to have an irreplaceable role in the formation of a receptor-binding feature on CFA/I fimbriae. The results specifically indicate that the CfaE tip protein is a required binding factor in CFA/I-mediated ETEC colonization, making it a potentially important vaccine antigen.

Continuous double loop closure for midline laparotomy wounds.

OBJECTIVE: To determine the efficiency of continuous double loop closure of midline laparotomy wounds and how it prevents and reduces wound dehiscence. METHODS: A prospective study of one hundred patients who underwent laparotomy through midline incision in Basrah General Hospital over a one year period. This study is designed to compare the difference between 2 suturing techniques for closure of midline laparotomy wounds, one is new and unpopular to use, which is the continuous double loop closure, and the other one is the continuous mass closure technique. RESULTS: By comparison of the 2 techniques, we found that infection of wounds was less using the continuous double loop closure technique (12%) as compared with the control (18%). We also found that wound dehiscence is nil with the continuous double loop closure technique as compared to 8% with the control. CONCLUSION: The continuous double loop closure technique is superior in closure of midline laparotomy wounds and prevention of wound dehiscence and we recommend it for closure of these wounds in high risk patients.

Control of vocal loudness in young and old adults.

This study examined the effect of aging on respiratory and laryngeal mechanisms involved in vocal loudness control. Simultaneous measures of subglottal pressure and electromyographic (EMG) activity from the thyroarytenoid (TA), lateral cricoarytenoid (LCA), and cricothyroid (CT) muscles were investigated in young and old individuals while they attempted to phonate at three loudness levels, "soft," "comfortable," and "loud." Voice sound pressure level (SPL) and fundamental frequency (F ) measures were also obtained. Across loudness conditions, subglottal pressure levels were similar for both age groups. Laryngeal EMG measures tended to be lower and more variable for old compared with young individuals. These differences were most apparent for the TA muscle. Finally, across the three loudness conditions, the old individuals generated SPLs that were lower overall than those produced by the young individuals but modulated loudness levels in a manner similar to that of the young subjects. These findings suggest that the laryngeal mechanism may be more affected than the respiratory system in these old individuals and that these changes may affect vocal loudness levels.

Short-latency changes in voice F0 and neck surface EMG induced by mechanical perturbations of the larynx during sustained vowel phonation.

Nineteen healthy young adult males with normal voice and speech attempted to sustain the vowel /u/ at a constant pitch (target: 180 Hz) and a constant and comfortable loudness level while receiving a sudden mechanical perturbation to the larynx (thyroid prominence) via a servo-controlled probe. The probe moved toward or away from the larynx in a ramp-and-hold fashion (3.3-mm displacement, 0.7 N force, 20-ms rise time, 250-ms duration) as the subjects attempted to maintain a constant probe-larynx pressure. Eighty stimuli were applied in each direction, one stimulus per phonation. Pairs of surface electromyography (EMG) electrodes were attached to the skin of the anterior neck over laryngeal, infralaryngeal, and supralaryngeal areas. The rectified EMG signals, the voltage analog of the voice fundamental frequency (VAF0), and the voltage analog of the probe displacement were digitized and signal-averaged relative to the onset of the stimulus. Sudden perturbation of the larynx induced an instantaneous decrease or increase in VAF0, depending on the direction of the probe's movement, and a short-latency increase in the EMG (30-35 ms) and VAF0 (55-65 ms). We argue that the instantaneous VAF0 change was related to a mechanical effect, and the short-latency VAF0 and EMG changes to reflexogenic effects-the latter most likely associated with both intrinsic and extrinsic laryngeal sensorimotor mechanisms. Further physiological studies are needed to elucidate the sources of the VAF0 and EMG responses. Once elucidated, the present method may provide a powerful noninvasive tool for studying laryngeal neurophysiology. The theoretical and clinical implications of the present findings are addressed.

Thyroarytenoid muscle activity associated with hypophonia in Parkinson disease and aging.

OBJECTIVE: To compare electromyographic (EMG) amplitudes of the thyroarytenoid (TA) muscle in young and older individuals and individuals with idiopathic PD (IPD) under conditions of known vocal loudness (sound pressure level). BACKGROUND: Voice disorders frequently accompany aging and IPD, but it is unclear how laryngeal muscle physiology is affected by these processes and how changes in laryngeal muscle activity result in characteristic changes of the voice. METHODS: Absolute and relative (to maximum) EMG amplitudes of the TA muscle were compared during speech and nonspeech tasks. Corresponding sound pressure level (SPL) measures were obtained for the speech tasks. RESULTS: Absolute TA amplitudes were consistently the highest in the young individuals, lowest in the individuals with IPD, and intermediate in the older individuals. Relative TA amplitudes were generally the highest for the young individuals, lowest for the older individuals, and intermediate for the individuals with IPD. SPL findings showed the older individuals and individuals with IPD produced most of the speech tasks with comparable SPLs, and these levels were consistently lower than those of the young individuals. CONCLUSIONS: Reduced levels of TA muscle activity may contribute to the characteristic hypophonic voice disorders that frequently accompany IPD and aging.

Preliminary voice and speech analysis following fetal dopamine transplants in 5 individuals with Parkinson disease.

A surgical procedure involving transplantation of fetal dopamine cells into the striatum of persons with advanced Parkinson disease (PD) has recently been performed in an attempt to alleviate Parkinsonian and drug-dose related symptoms (e.g., the "on-off" phenomena). Improvements in limb motor and neurological function, as well as less severe and shorter on-off episodes have been reported following fetal cell transplant (FCT) surgery. Acoustic, electroglottographic, and perceptual measures were analyzed pre- and post-surgery to determine if phonotory and articulatory function were affected by this relatively new form of treatment. In addition, speech and motor exam measures were compared to determine if similar directional changes across motor systems were apparent. Findings suggest that FCT surgery did not systematically influence voice and speech production. Also, it appears that FCT surgery may differentially affect phonatory, articulatory, and limb motor systems. Findings are discussed relative to these differential effects.