Frailty Index Based on Common Laboratory Tests for Patients Starting Home-Based Medical Care.

OBJECTIVES: To determine whether a Frailty Index based on laboratory tests (FI-lab) is associated with clinical outcomes independently of a standard nonlaboratory Frailty Index (FI-clinical) in older patients starting home-based medical care. DESIGN: Secondary analysis of data from a multicenter prospective cohort study. SETTING AND PARTICIPANTS: Patients aged ≥65 years who were starting home-based medical care services provided by doctors and nurses at Nagoya, Japan. METHODS: We calculated FI-lab (proportion of abnormal results out of 25 commonly tested laboratory parameters) and FI-clinical using 42 items based on data obtained at enrollment. The primary outcome was mortality within 2 years after starting home-based medical care. A sensitivity analysis was also conducted with 1-year mortality as the outcome. Other outcomes included hospitalization and nursing home admission within 2 years. RESULTS: In total, 188 patients (mean age 79.9 ± 10.2 years, 57.5% male) were included. The median FI-lab was 0.40 [interquartile range (IQR) 0.29-0.50] and the median FI-clinical was 0.32 (IQR 0.24-0.43). Sixty-nine patients (36.7%) died within 2 years of starting home-based medical care. A Cox proportional hazards regression analysis including age, sex, FI-lab, and FI-clinical as independent variables revealed that FI-lab was associated with 2-year mortality independently of FI-clinical [FI-lab per 0.1 unit, odds ratio (OR) 1.49, 95% CI 1.25-1.77; FI-clinical per 0.1 unit, OR 1.13, 95% CI 0.90-1.41]. The sensitivity analysis showed similar results for 1-year mortality. Neither FI-lab nor FI-clinical was associated with hospitalization or nursing home admission within 2 years. CONCLUSIONS AND IMPLICATIONS: FI-lab was associated with 2-year mortality in patients starting home-based medical care, independently of FI-clinical, and may be useful for risk assessment in this population. Studies with larger sample sizes are needed.

Dual Sensory Impairment Predicts an Increased Risk of Postdischarge Falls in Older Patients.

OBJECTIVES: The purpose of this study was to determine the associations of vision impairment, hearing impairment, and comorbid vision and hearing impairment [ie, dual sensory impairment (DSI)] on admission to hospital with falls within 3 months of discharge in older patients. DESIGN: This prospective multicenter study included patients admitted to and discharged from geriatric wards at 3 university hospitals and 1 national medical center in Japan between October 2019 and July 2023. SETTING AND PARTICIPANTS: Of 1848 individuals enrolled during the study period, 1141 were excluded, leaving 707 for inclusion in the analysis. METHODS: Participants' background factors were compared in terms of whether they had a fall during the 3 months postdischarge. Logistic regression analysis was then performed using the presence or absence of falls after discharge as the objective variable. Three models were created using vision impairment, hearing impairment, and DSI as covariates. Other covariates included physical function, cognitive function, and depression. In addition, logistic regression analysis was performed with falls during hospitalization as the objective variable. RESULTS: DSI was significantly more common in the falls group (P = .004). Logistic regression analysis showed that the risk of falls after discharge was higher in patients with DSI (odds ratio 3.432, P = .006) than in those with vision or hearing impairment alone. When adjusted for physical function, cognitive function, depression, and discharge location, DSI was significantly associated with an increased risk of falls after discharge (odds ratio 3.107, P = .021). The association between DSI and falls during hospitalization did not reach statistical significance, but a trend was observed. CONCLUSIONS AND IMPLICATIONS: This study is the first to show an association between DSI and falls after discharge. Simple interventions for patients with DSI may be effective in preventing falls, and we suggest that they be actively implemented early during hospitalization.

Objective physical function declines in the absence of subjective physical complaints among patients with amnestic mild cognitive impairments and mild alzheimer's disease.

PURPOSE: To examine the extent to which patients with amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD) perceive their own physical decline. METHODS: This study included 4450 outpatients (1008 normal cognition [NC], 1605 aMCI, and 1837 mild AD) who attended an initial visit to a memory clinic between July 2010 and June 2021. Their physical function was assessed by the Timed Up and Go test, one-leg standing test, and grip strength. For physical complaints, data were obtained on reports of fear of falling and dizziness or staggering. Logistic regression analysis was performed to compare the patients' physical function and complaints for each stage of NC, aMCI, and mild AD. RESULTS: Objective physical function declined from aMCI and the mild AD stage, but subjective physical complaints decreased by 20-50% in aMCI and 40-60% in mild AD compared with the NC group. CONCLUSION: As objective physical functional declined from the aMCI stage onward, subjective physical complaints decreased. This suggests a need for objective assessment of physical function in aMCI and mild AD patients even when they have no physical complaints in the clinical setting.

NSPlex: an efficient method to analyze non-specific peaks amplified using commercial STR kits.

Commercial short tandem repeat (STR) kits exclusively contain human-specific primers; however, various non-human organisms with high homology to the STR kit's primer sequences can cause cross-reactivity. Owing to the proprietary nature of the primers in STR kits, the origins and sequences of most non-specific peaks (NSPs) remain unclear. Such NSPs can complicate data interpretation between the casework and reference samples; thus, we developed "NSPlex", an efficient method to discover the biological origins of NSPs. We used leftover STR kit amplicons after capillary electrophoresis and performed advanced bioinformatics analyses using next-generation sequencing followed by BLAST nucleotide searches. Using our method, we could successfully identify NSP generated from PCR amplicons of a sample mixture of human DNA and DNA extracted from matcha powder (finely ground powder of green tea leaves and previously known as a potential source of NSP). Our results showed our method is efficient for NSP analysis without the need for the primer information as in commercial STR kits.

Association of marital relationship with quality of life among older adults with mild cognitive impairment and mild dementia.

The marital relationship is associated with the quality of life among those with cognitive impairment, but sarcopenia status seems to play an important role in the association.

Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis.

Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl ß-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.

Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant.

Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.

Relationship between cognitive function and phase angle measured with a bioelectrical impedance system.

PURPOSE: The purpose of this study was to investigate the relationship between cognitive function and phase angle (PhA), an indicator of muscle quality. METHODS: This cross-sectional study enrolled outpatients who visited a memory clinic at the Nagoya University hospital from January 2016 to June 2022. We enrolled 153 participants with body composition measurements. Inclusion criteria were a Mini-Mental State Examination score of 20-30 and a clinical diagnosis of Alzheimer's dementia (AD) or amnesic mild cognitive impairment (aMCI). The background characteristics of the participants were compared according to AD and aMCI. Next, linear regression analysis was performed with PhA as the objective variable. In addition, logistic regression analysis was performed for AD diagnosis. RESULTS: PhA was lower in the AD group (P = 0.009). In linear regression analysis, PhA consistently decreased with worsening ADAS score. In logistic regression analysis, high PhA was associated with absence of AD. Gender-specific analyses showed these associations existed only in men. CONCLUSIONS: Our study of patients with AD and aMCI found that PhA decreased with worsening of cognitive function. Compared with aMCI, AD was associated with significantly lower PhA. Our results strengthen the limited evidence in the literature showing that low muscle quality is associated with poor cognitive function.

Unilateral gluteal myositis as a unique presentation in mesenteric Kikuchi-Fujimoto disease.

Kikuchi-Fujimoto disease (KFD) is a self-limiting disease, characterised by fever and cervical lymphadenopathy. Lymphadenopathy without cervical lymph node involvement is rare and may mimic lymphoma. Although KFD can be associated with extranodal involvement, muscle involvement has not been reported. Herein, we report a novel case of unilateral gluteal myositis associated with mesenteric KFD in a patient who presented with persistent fever and right hip pain. Radiological imaging revealed an inflammatory lesion on the right gluteal muscle and multiple enlarged abdominal lymph nodes. No cervical lymphadenopathy was observed. A mesenteric lymph node biopsy was performed, and the histopathological findings led to a diagnosis of KFD. By day 29, the patient's body temperature gradually returned to normal without any therapeutic intervention. Follow-up radiological imaging showed resolution of the gluteal lesion and a significant decrease in abdominal lymph node size. Considering the clinical course, the unilateral myositis may have developed as an extranodal involvement of KFD. Even if the clinical findings appear unrelated to those of KFD, a differential diagnosis that includes KFD should be considered in patients with unknown origin of fever.

Relationship Between Non-Cognitive Intrinsic Capacity and Activities of Daily Living According to Alzheimer's Disease Stage.

BACKGROUND: Few studies have examined the relationship between non-cognitive factors and activities of daily living (ADL) according to Alzheimer's disease (AD) stage. OBJECTIVE: We aimed to identify the differences in non-cognitive factors according to AD stages and their involvement in basic and instrumental ADL performance by using intrinsic capacity (IC) in groups with cognition ranging from normal to moderate or severe AD. METHODS: We enrolled 6397 patients aged≥65 years who visited our memory clinic. Non-cognitive IC was assessed using the locomotion, sensory, vitality, and psychological domains. Multiple logistic regression was performed to identify how non-cognitive IC declines over the AD course and examine the correlation between non-cognitive IC and basic and instrumental ADL performance. RESULTS: Non-cognitive IC declined from the initial AD stage and was significantly correlated with both basic and instrumental ADL performance from the aMCI stage through all AD stages. In particular, the relationship between IC and basic ADL was stronger in mild and moderate to severe AD than in the aMCI stage. On the other hand, the relationship between IC and instrumental ADL was stronger in aMCI than in later AD stages. CONCLUSIONS: The results show non-cognitive factors, which decline from the aMCI stage, are correlated with ADL performance from the aMCI stage to almost all AD stages. Considering that the relationship strength varied by ADL type and AD stage, an approach tailored to ADL type and AD stage targeting multiple risk factors is likely needed for effectively preventing ADL performance declines.

Intrinsic capacity in acutely hospitalized older adults.

OBJECTIVES: We aimed to examine the association between intrinsic capacity (IC) and adverse outcomes of hospitalization. DESIGN: A prospective observational cohort study. SETTING AND PARTICIPANTS: We recruited patients aged 65 years or older who were admitted to the geriatric ward of an acute hospital between Oct 2019 and Sep 2022. MEASUREMENTS: Each of the five IC domains (locomotion, cognition, vitality, sensory, and psychological capacity) was graded into three levels, and the composite IC score was calculated (0, lowest; 10, highest). Hospital-related outcomes were defined as in-hospital death, hospital-associated complications (HACs), length of hospital stay, and frequency of discharge to home. RESULTS: In total, 296 individuals (mean age 84.7 ± 5.4 years, 42.7 % males) were analyzed. Mean composite IC score was 6.5 ± 1.8, and 95.6 % of participants had impairment in at least one IC domain. A higher composite IC score was independently associated with lower frequency of in-hospital death (odds ratio [OR] 0.59) and HACs (OR 0.71), higher frequency of discharge to home (OR 1.50), and shorter length of hospital stay (ß = -0.24, p < 0.01). The locomotion, cognition, and psychological domains were independently associated with the occurrence of HACs, discharge destination, and length of hospital stay. CONCLUSION: Evaluating IC was feasible in the hospital setting and was associated with outcomes of hospitalization. For older inpatients with decreased IC, integrated management may be required to achieve functional independence.

Combined use of the Clinical Frailty Scale and laboratory tests in acutely hospitalized older patients.

AIMS: To evaluate the Clinical Frailty Scale (CFS) and a Frailty Index based on laboratory tests (FI-lab) in terms of what each assesses about frailty and to determine the appropriateness of combined use of these two frailty scales. METHODS: This was a prospective observational cohort study in an acute geriatric ward of a university hospital. The FI-lab is the proportion of laboratory parameters that yield abnormal results from a total of 23. The FI-lab and CFS were assessed at admission. Data on activities of daily living (ADL), cognition, geriatric syndromes, and comorbidities were also collected. Main outcomes were in-hospital mortality and 90-day mortality after admission. RESULTS: In total, 378 inpatients (mean age 85.2 ± 5.8 years, 59.3% female) were enrolled. ADL and cognition correlated strongly with the CFS (Spearman's |r|> 0.60) but weakly with the FI-lab (|r|< 0.30). Both the CFS and FI-lab correlated weakly with geriatric syndromes and comorbidities (|r|< 0.40). The correlation between the CFS and FI-lab was also weak (r = 0.28). The CFS and FI-lab were independently associated with in-hospital mortality and 90-day mortality after admission. The Akaike information criterion was lower for models using both the CFS and FI-lab than for models using either tool alone. CONCLUSIONS: The CFS and FI-lab each reflected only some of the aspects of frailty in acutely hospitalized older patients. The model fit was better when the two frailty scales were used together to assess the mortality risk than when either was used alone.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling.

Our previous genome-wide association study to explore genetic loci associated with lean nonalcoholic fatty liver disease (NAFLD) in Japan suggested four candidate loci, which were mapped to chr6, chr7, chr12 and chr13. The present study aimed to identify the locus involved functionally in NAFLD around the association signal observed in chr13. Chromosome conformation capture assay and a database survey suggested the intermolecular interaction among DNA fragments in association signals with the adjacent four coding gene promoters. The four genes were further screened by knockdown (KD) in mice using shRNA delivered by an adeno-associated virus vector (AAV8), and KD of G protein-coupled receptor 180 (Gpr180) showed amelioration of hepatic lipid storage. Gpr180 knockout (KO) mice also showed ameliorated hepatic and plasma lipid levels without influencing glucose metabolism after high-fat diet intake. Transcriptome analyses showed downregulation of mTORC1 signaling and cholesterol homeostasis, which was confirmed by weakened phosphorylation of mTOR and decreased activated SREBP1 in Gpr180KO mice and a human hepatoma cell line (Huh7). AAV8-mediated hepatic rescue of GPR180 expression in KO mice showed recovery of plasma and hepatic lipid levels. In conclusion, ablation of GPR180 ameliorated plasma and hepatic lipid levels, which was mediated by downregulation of mTORC1 signaling.

Clinical significance of geriatric conditions in acute hospitalization.

BACKGROUND: Geriatric conditions (GCs) are common in the elderly population, but their clinical significance in acute care is not well understood. In this study, we first investigated the cross-sectional associations of GCs with frailty and polypharmacy at the time of admission to an acute care geriatric ward. Then, to clarify the clinical significance of GCs in acute care, we prospectively examined the association of GCs with the incidence of hospital-acquired complications and consequences after discharge. METHODS: Participants were 184 patients (40.2% men: mean age 85.0 ± 6.0 years) hospitalized in an acute care geriatric ward at a university hospital. We examined the cross-sectional associations of GCs with frailty and polypharmacy by multiple regression analysis, and then the associations of GCs with the incidence of hospital-acquired complications, falls and death within 3 months of discharge by multiple logistic regression analysis. RESULTS: GCs were associated with frailty and use of polypharmacy, independent of multiple morbidity. GCs were also associated with readmission within 3 months of discharge; however, there was no significant association with the incidence of hospital-acquired complications, falls, or mortality after discharge. CONCLUSIONS: These findings suggest that GCs are clinically significant in the hospitalized elderly and further research on GCs is warranted. Geriatr Gerontol Int 2023; 23: 50-53.

Dehydration and hospital-associated disability in acute hospitalized older adults.

PURPOSE: Dehydration is highly prevalent in hospitalized older adults and has been linked to poor outcomes. It is considered a modifiable factor, so early identification and intervention may avoid adverse events and improve quality of life after discharge. Hospital-associated disability (HAD) is known to be a poor prognostic factor and can be categorized into mobility impairment and self-care impairment in setting goals for management. Few studies have directly examined the association between dehydration and HAD and therefore here we examined whether dehydration is a predictor of HAD categorized into mobility and self-care impairment among acute hospitalized older adults. METHODS: Patients aged 65 years or older who were admitted to the geriatric ward of an acute hospital were recruited for this prospective cohort study. Estimated serum osmolarity > 300 mOsm/kg was defined as current dehydration. HAD was assessed between baseline and discharge and at 3 months after discharge, and was evaluated separately for mobility and self-care impairments. RESULTS: In total, 192 patients (mean age, 84.7 years; male, 41.1%; dehydration, 31.3%) were analyzed. The occurrence of HAD was significantly higher in the dehydrated group than in the non-dehydrated group (42.4% vs 26.5%) from baseline to 3 months after discharge. In multiple logistic regression analysis, dehydration was significantly associated with HAD in self-care from baseline to 3 months after discharge (odds ratio, 2.25; 95% confidence interval, 1.03-4.94). CONCLUSIONS: Dehydration could predict the occurrence of HAD in acute hospitalized older adults. A multifaceted approach may be necessary to improve the management of dehydration in these patients.

KBTBD11, encoding a novel PPARγ target gene, is involved in NFATc1 proteolysis by interacting with HSC70 and HSP60.

We previously revealed that Kbtbd11 mRNA levels increase during 3T3-L1 differentiation and Kbtbd11 knockdown suppresses whereas its overexpression promotes adipogenesis. However, how Kbtbd11 mRNA is regulated during adipocyte differentiation and how the KBTBD11 protein functions in adipocytes remain elusive. This study aimed to examine the transcriptional regulatory mechanism of Kbtbd11 during adipocyte differentiation, KBTBD11-interacting protein functions, and elucidate the role of KBTBD11 in adipocytes. First, we identified the PPRE consensus sequences in the Kbtbd11 exon 1- and intron 1-containing region and demonstrated that PPARγ acts on this region to regulate Kbtbd11 expression. Next, we purified the KBTBD11 protein complex from 3T3-L1 adipocytes and identified heat shock proteins HSC70 and HSP60 as novel KBTBD11-interacting proteins. HSC70 and HSP60 inhibition increased KBTBD11 protein levels that promoted NFATc1 ubiquitination. These data suggest that HSC70 and HSP60 are involved in KBTBD11 stabilization and are responsible for NFATc1 regulation on the protein level. In summary, this study describes first the protein regulatory mechanism of NFATc1 through the HSC70/HSP60-KBTBD11 interaction that could provide a potential new target for the differentiation and proliferation of various cells, including adipocytes and tumors.

Association between changes in frailty during hospitalization in older adults and 3-month mortality after discharge.

Frailty is a dynamic status that can worsen or improve. However, changes in their frailty status that occur during hospitalization and their significance have not been comprehensively investigated. In this study, we explored the association between such changes and mortality 3 months after discharge in older adults hospitalized for acute care. In total, 257 participants (mean age 84.95 ± 5.88, 41.6% male) completed comprehensive geriatric assessments, including the Clinical Frailty Scale (CFS) at admission and discharge. Mean CFS score was 5.14 ± 1.35 at admission. CFS scores increased, indicating deteriorating frailty, in 29.2% of the participants (75/257) during hospitalization. Multiple logistic regression analysis demonstrated a positive association between increased CFS score during hospitalization and mortality (odds ratio, 2.987) independent of potential co-founding factors. This deterioration in frailty during hospitalization may be modifiable risk factor of poor prognosis in older adults who need acute care hospitalization.