Multidomain Intervention for the Reversal of Cognitive Frailty Using a Personalized Approach (AGELESS Trial): Recruitment and Baseline Characteristics of Participants.

BACKGROUND: Reversal of cognitive frailty through a multidomain intervention is desirable to prevent dementia. AGELESS Trial was conducted to determine the effectiveness of a comprehensive, multidomain intervention on older adults with cognitive frailty in Malaysia. However, conducting a clinical trial, particularly during and after Covid-19, posed unique challenges. OBJECTIVE: We aimed to investigate the recruitment process and baseline characteristics of the AGELESS Trial participants to better understand an at-risk population and those who agree to participate in an intervention. DESIGN/SETTING: 24-month, randomized controlled trial. PARTICIPANTS: Community-dwelling older adults with independent mobility, aged ≥ 60 years, with a mini mental state examination score of 19-25, a clinical dementia rating of 0.5 ≥ 1 Fried's physical frailty criteria, and < 22 Beck depression inventory. INTERVENTION: Participants were randomized 1:1 to a structured multidomain intervention consisting of vascular management, diet, exercise, cognitive and psychosocial stimulation, or to the arm, including routine care and general health consultation. MEASUREMENT: We analyzed the group differences between (1) cognitive frailty and non- cognitive frailty screened subjects, (2) recruited and non-recruited participants, (3) baseline characteristics of participants by arm, (4) adherence to AGELESS intervention at 12 months, and (5) preliminary findings on the effectiveness of the intervention at 12 months. RESULTS: A total of 957 older adults from two locations, i.e., urban (n = 764) and rural (n = 193) areas, were screened, of whom 38.9% had cognitive frailty and were eligible to participate. Those with cognitive frailty had fewer years of education (B = -0.08; 95%CI = 0.88-0.97; p = 0.002), and lower functioning cognition (B = -0.24; 95%CI = 0.74-0.84; p < 0.001). Among those from urban areas, only 33.1% (n = 106) agreed to participate, particularly those with multimorbidity (B = 0.86; 95%CI = 1.31-4.30; p = 0.01), higher physical activity (B = -1.02; 95%CI = 0.19-0.69; p = 0.002), slower walking speed (B = 1.26; 95%CI = 1.62-7.61; p = 0.001), and higher systolic blood pressure (B = 0.02; 95%CI = 1.00-1.03; p = 0.03). At baseline, participants' mean age was 68.1±5.6, years of education was 8.3±3.9, body mass index was 27.5±5.3 kg/m2, and mini mental state examination score was 22.7±4.0. Generally, there were no significant differences between the intervention and control groups for the main outcomes, except those in the intervention group had higher body mass index, mid-upper-arm circumference, and waist circumference (p < 0.05 for all parameters). Overall intervention adherence at 12 months was 52.8%, ranging from 52.8%-90.6% for each of the modules. Preliminary analysis of the effectiveness of the intervention at 12 months was positive on most of the cognitive domains, some of the nutrient intake and food groups, physical function, and vascular outcomes (p < 0.05 for all parameters). CONCLUSION: Despite the challenges posed by the pandemic, screening, recruitment, and 12-month intervention delivery were achieved in a Malaysian multidomain preventive randomized controlled trial in older adults at risk of dementia, with a satisfactory adherence rate and cognitive benefits at 12 months.

Improvement in chrono-nutrition is associated with robust weight loss outcomes: An extension of the feasibility study.

Previously we had demonstrated the development and feasibility of an integrated chrono-nutrition weight reduction program among non-shift workers with morning and evening chronotypes. In this current paper, we described the association between the changes in chrono-nutrition practice and weight loss outcomes upon completing the weight reduction program. A total of 91 overweight/obese non-shift workers participated in the 12-week integrated chrono-nutrition weight reduction program (Age: 39.6 ± 6.3 y; 74.7% women; BMI: 31.2 ± 4.5 kg/m2). All the assessments including anthropometry, dietary, sleep habits, physical activity, and process of change were measured during pre- and post-intervention. Participants who had lost ≥3% of their body weight were categorized as satisfactory weight loss outcome, and those who did not achieve 3% weight loss were categorized as unsatisfactory weight loss. The satisfactory weight loss had greater daily percent energy intake during earlier in the day from protein (Mean difference (MD): +3.2%, 95% CI: 1.6, 4.9, p < .001) and smaller intake from fat during later in the day (MD: -2.6%, 95% CI: -5.1, -0.1, p = .045), earlier last mealtime (MD: -49.5 min, 95% CI: -86.5, -12.6, p = .009) and midpoint of eating (MD: -27.3 min, 95% CI: -46.3, -8.2, p = .006), shorter eating window (-0.8 h, 95% CI: -1.4, -0.1, p = .031) and greater reduction in night eating syndrome score (MD: -2.4, 95% CI: -4.3, -0.5, p = .015) compared to unsatisfactory weight loss outcome. After accounting for potential confounders, the temporal pattern of energy, protein, and fat intake were associated with greater odds of achieving a satisfactory weight loss. The findings suggest a promising role of chrono-nutrition as one of the strategies in weight reduction intervention.

Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors.

The role of corticosterone (Cort), the immune system's major stress hormone, in the regulation of hematopoietic stem and progenitor cells (HSPCs) and their dynamic bone marrow (BM) microenvironment is currently unknown. We report that corticotropin-releasing factor receptor 1 (CRFR1) mutant mice with chronically low Cort levels showed aberrant HSPC regulation, having higher HSPC numbers and upregulation of the chemokine CXCL12, phenotypes that were restored by Cort supplementation. Expanded stromal progenitors known to support HSPCs were also observed in these low-Cort-containing mice. A similar phenotype was induced in wild-type (WT) mice by Metyrapone, a Cort synthesis inhibitor. Conversely, high Cort exposure induced HSPC apoptosis, reduced long-term BM repopulation and decreased stromal progenitor cell numbers. We documented circadian oscillations of Cort in WT BM but not in CRFR1 mutant mice, leading to diminished circadian BM CXCL12 fluctuations and increased number of circulating HSPCs in these mice. Finally, low Cort induced expansion of stromal progenitors, CXCL12 expression, HSPC proliferation and BM repopulation capacity, involving Notch1 signaling. This was associated with upregulation of the Notch ligand, Jagged1, in BM myeloid cells. Our results suggest that daily physiologic Cort oscillations are critical for balanced HSPC proliferation and function involving Notch1 signaling and their supportive BM microenvironment.

Injection of vascular endothelial growth factor into knee joints induces osteoarthritis in mice.

UNLABELLED: Osteoarthritis (OA) is a common joint disorder affecting circa 2% of the population. OBJECTIVES: It has been suggested that secretion of vascular endothelial growth factor (VEGF) could play a role in the chain of events leading to OA. METHODS: In the present study, healthy mice were injected intra-articularly with VEGF. RESULTS: Shortly after the administration of VEGF, synovial hyperplasia, increased calcification of the articular cartilage and bone sclerosis were observed. Consequently, cartilage degradation characteristic of OA was found. These changes were seen to a lesser degree in the opposite knees of VEGF-injected mice and did not occur in the control mice. CONCLUSIONS: The findings suggest an active role of VEGF in the pathogenesis of OA and render support to a possible role for subchondral bone sclerosis in the pathogenesis of cartilage degradation.

Comparison of scratching behaviour of growing pigs with sarcoptic mange before and after treatment, employing two distinct approaches.

In a closed pig breeding and finishing herd suffering from sarcoptic mange, two selected groups of pigs were filmed during a period of 10 days before and after treatment. The observation always commenced each hour and lasted for 15 min. Before treatment, observations was done round the clock, after treatment from 8:00 to 22:15. Before treatment the pens were stocked with 11 (pen A) and 10 (pen B) growing pigs (Large WhitexLandrace sows; 5 months old) with an average weight of approximately 70 kg examined for sarcoptic mange by skin scrapings and ELISA. The animals had never been treated with an acaricide or endectocide before. After 10 days, the pigs were treated twice (18 days interval) with Dectomax 1% solution for pigs (Pfizer, Austria) at a dose of 0.3 mg Doramectin i.m./kg body weight. After treatment, seven pigs were observed in both pens. Most scratching actions both before (83.1%) and after (94.5%) treatment were of one to 10 s. After treatment, the 10 s-scratching episodes decreased by 67.3% (from 21.2 to 6.9 mean SRE/pig), and the scratching actions of longer than 10 s by 91.7% (from 4.3 to 0.4 mean SRE/pig), such that the latter could be observed only occasionally after treatment. A distinct increase in scratching activity both before and after treatment could be observed primarily between 10:00 and 15:00. Significant differences of scratching and rubbing activity between before and after treatment could also be seen at midday. The interpretation of the scratching index values before and after the treatment were carried out according to Cargill et al. [Cargill, C., Davies, P., Carmichael, I., Hooke, F., Moore, M., 1994. Treatment of pigs with doramectin to control sarcoptic mange. Proceedings of the 13th IPVS Congress, Bangkok, Thailand, p. 238] with the maximum and minimal limiting values specified in the literature, and compared with calculations using the method described by Hollanders et al. [Hollanders, W., Harbers, A.H.M., Huige, J.C.M., Monster, P., Rambags, P.G.M., Hendrikx, W.M.L., 1995. Control of Sarcoptes scabiei var. suis with ivermectin: influence on scratching behaviour of fattening pigs and occurence of dermatitis at slaughter. Vet. Parasitol. 58, 117-127]. Depending on the methods used and the limiting values set, 6.7-34.6% of the observations before and 2.0-17.3% of the observations after treatment revealed a "strong evidence of mange" or a "suspicion of mange". All other observations indicated that the pigs were free from mange.

Prognosis for papillary serous carcinoma of the endometrium after surgical staging.

BACKGROUND: To investigate the pattern of failure and the prognosis following pathological staging for uterine papillary serous carcinoma (UPSC). PATIENTS AND METHODS: A retrospective review was conducted of 22 patients with UPSC, treated between 1989 and 1998 at a single institution. All patients were surgically staged. Two patients with advanced disease received chemotherapy only. Two patients with early-stage disease were followed without further treatment. Eighteen patients received postoperative irradiation; eight patients received whole abdominal irradiation (WART), and the remaining 10 patients, pelvic irradiation (PRT). In addition, seven of these patients received vaginal cuff irradiation with low-dose-rate or high-dose-rate brachytherapy. Toxicity, pattern of failure, and survival were evaluated and compared to the literature. RESULTS: Seven patients (32%) developed distant metastases, three out of seven (42%) after WART. Four out of seven patients who had distant metastases died from disease progression during subsequent chemotherapy. All patients with distant metastases had locally advanced-stage disease at presentation (six stage III, one stage IV). Four patients with pelvic recurrences developed concurrent (2) and subsequent (2) distant metastases. Three patients had isolated distant metastases. No patient with early stage-disease (stage I and II) died from disease progression. CONCLUSION: Pathological staging should be performed for all patients with UPSC to determine the prognosis as well as to tailor the treatment. The role of abdominal irradiation in the treatment of UPSC is yet to be determined; however, such an approach may not be necessary for the control of disease for patients with early-stage (I and II) disease. Patients with locally advanced-stage (stage III) disease are at risk of local regional failures and distant metastases despite WART. Therefore, the benefit of WART for advanced-stage disease is also questionable. Paclitaxel-based chemotherapy is currently being investigated in this setting.

Combined preoperative chemotherapy and radiation for locally advanced rectal carcinoma.

To determine the efficacy of combined preoperative chemotherapy and radiation therapy for locally advanced rectal carcinoma and the rate of sphincter conservation, a retrospective survey of 39 patients with locally advanced rectal carcinoma treated with various 5-fluorouracil- and leukovorin-based chemotherapy regimens and radiation prior to surgery in a single institution was reviewed. Toxicity, local control and survival were evaluated and compared to previous studies with similarly staged patients. Long-term follow-up was available on 35 patients. The actuarial local failure was 5.7% while the actuarial 5-year survival was 87%. The mortality rate was low (2.5%) and the rate of long-term serious complications acceptable (11.4%). Combined preoperative chemotherapy and radiation provided excellent local regional control despite the poor prognostic factors associated with size, fixation, and the initial advanced tumor stage with acceptable morbidity. In addition, patients with tumors located in the lower third of the rectum may be able to undergo sphincter-sparing surgery. Although the median follow-up is relatively short (32.4 months), the results are in accordance with previous studies of neoadjuvant combined chemotherapy and radiation for locally advanced rectal carcinoma in terms of local and distant control.

Radiotherapy for pediatric genitourinary tumors. Its role and long-term consequences.

Radiation therapy has traditionally played a major role in the treatment of pediatric genitourinary malignancies. In particular, Wilms' tumor, rhabdomyosarcoma, and neuroblastoma often include radiotherapy in the local control phase of treatment. Recently, clinical trials have focused on decreasing the toxicity of radiotherapy through dose modifications and conformal field arrangements. Radiotherapy will continue to be a major treatment modality for this patient group if technologic advances in radiation delivery continue to increase efficacy without comorbidities.

Neuroblastoma producing spinal cord compression: rapid relief with low dose of radiation.

Symptomatic spinal cord compression requires emergency treatment to alleviate symptoms and to avoid irreversible damage. We describe a successful decompression by low dose radiation to a progressing neuroblastoma in a child. Magnetic resonance imaging post radiation should be performed to assess the response of the tumor to radiation.

[Late results of Childs-Phillips mesenteric plication for therapy and prevention of small intestine ileus]. / Spätresultate der Mesenterialplikatur nach Childs-Phillips zur Therapie und Prophylaxe des Dünndarmileus.

During the past 7 years 45 patients have been operated upon using the Childs-Phillips method. Of those, 37 were subsequently examined for the study--7 patients had died in the meantime. None of the deaths occurred as a direct result of transmesenteric small-bowel plication. An early recurrence of intestinal obstruction occurred in 4.4% and a laparotomy was repeated. During the most recent examinations 86.5% of those patients checked had (virtually) no complaints--91.9% based upon the Visick classification. A subtotal intestinal obstruction occurred during the period of the study in 8.1% of cases, but could be conservatively treated. Up until the most recent examination there were still no instances of a late recurrence. Most intestinal obstruction recurrences are due to errors specific to the technique and are early recurrences. On the basis of our results, we are of the opinion that plication in the presence of existing peritonitis, as well as partial plication, is acceptable.

[Thoracic sympathectomy in palmar hyperhidrosis: comparison of open with thorascopic procedure]. / Die thorakale Sympathektomie bei der Hyperhidrosis palmarum: Vergleich / thorakoskopisches Vorgehen.

Between 1976 and 1994 we performed 26 thoracic sympathectomies for treatment of therapy-resistant palmar hyperhidrosis. Until the end of 1992 the operation was performed using an open transaxillary approach, since 1993 sympathectomy was done by video-assisted thoracoscopy. Both procedures consisted in excision of the thoracic ganglia T2 to T5. The only complication was a pneumothorax in the open surgery group (successfully treated by drainage). Compensatory sweating occurred in 70% of our patients, compared to results in the literature of 60-90%. We did not note further complications, e.g. no Horner's syndrome. All of our patients were satisfied with the result of the operation. Comparison of the two collectives shows significant advantages for video-assisted thoracoscopic surgery. the procedure is easier to perform, exposure is better, cosmetic results are favourable, operation-time and hospital stay are reduced.

[Surgical treatment of varices at the stage of trophic disorders in chronic venous insufficiency]. / Le traitement chirurgical des varices au stade des troubles trophiques lors d'insuffisance veineuse chronique.

Most ulcers of the lower limbs are caused by existing chronic venous insufficiency. Later on, true social and professional problems will arise, with serious economic and psychological consequences not only for the patient himself, but for the community as well, such as huge medical costs--hence the importance of prevention and treatment, which must in no case be purely symptomatic. The ligation of the arch and of the perforating veins and stripping of the affected vein are part of the classical management of varices. These procedures can may prove to be virtually impossible in case of chronic venous insufficiency, if the patient also presents with subcutaneous liposclerosis or atrophy in an already pregangrenous skin. This preulcerous stage can be aggravated later on if the requirements for surgical repair are not met. Necrosis can then occur, if too aggressive surgery directly or indirectly injures the microcirculatory system of the damaged skin. Omitted or undesirable acts are dangerous at the stage of trophic disorders and surgery may fail to reach its aim, which of course would be to definitively and quickly eliminate the varicose disease.