The low indexes of metabolism intervention trial (LIMIT): design and baseline data of a randomized controlled clinical trial to evaluate how alerting primary care teams to low metabolic values, could affect the health of patients aged 75 or older.

BACKGROUND: Too-low body mass index (BMI), HbA1c% or cholesterol levels predicts poor survival. This study investigates whether e-mails about these low values, improve health of people older than 75 years. METHODS: LIMIT - an open label randomized trial - compares usual care to the addition of an e-mail which alerts the family physicians and nurses to low metabolic indexes of a specific patient and advises on nutritional and medical changes. PARTICIPANTS: Clalit Health Services (CHS) patients in the Northern and Southern Districts, aged ≥75 years with any of the following inclusion criteria: a. Significant weight loss: BMI < 23 kg/m2 with BMI drop of ≥2 kg/m2 during previous two years and without dietitian counseling during previous year. b. Tight diabetic control: HbA1c% ≤ 6.5% and received anti-diabetic medicines during previous 2 months. c. Drug associated hypocholesterolemia: total cholesterol <160 mg/dL and received cholesterol-lowering medicines during previous 2 months. Excluded from criterion c, were patients diagnosed with either ischemic heart disease, transient ischemic attack or stroke. The primary outcome was death from any cause, within one year. In a population of 48,623 people over the age of 75 years, 8584 (17.7%) patients were identified with low metabolic indices and were randomized to intervention or control groups. E-mails were sent on November 2015 to physicians and nurses at 383 clinics. DISCUSSION: Low metabolic reserve is common in people in Israel's peripheral districts aged ≥75 years. LIMIT may show whether alerting primary care staff is beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02476578 . Registered on June 11, 2015.

Mesodermal Wnt signaling organizes the neural plate via Meis3.

In vertebrates, canonical Wnt signaling controls posterior neural cell lineage specification. Although Wnt signaling to the neural plate is sufficient for posterior identity, the source and timing of this activity remain uncertain. Furthermore, crucial molecular targets of this activity have not been defined. Here, we identify the endogenous Wnt activity and its role in controlling an essential downstream transcription factor, Meis3. Wnt3a is expressed in a specialized mesodermal domain, the paraxial dorsolateral mesoderm, which signals to overlying neuroectoderm. Loss of zygotic Wnt3a in this region does not alter mesoderm cell fates, but blocks Meis3 expression in the neuroectoderm, triggering the loss of posterior neural fates. Ectopic Meis3 protein expression is sufficient to rescue this phenotype. Moreover, Wnt3a induction of the posterior nervous system requires functional Meis3 in the neural plate. Using ChIP and promoter analysis, we show that Meis3 is a direct target of Wnt/beta-catenin signaling. This suggests a new model for neural anteroposterior patterning, in which Wnt3a from the paraxial mesoderm induces posterior cell fates via direct activation of a crucial transcription factor in the overlying neural plate.

Randomized trial results of alerting primary clinicians to severe weight loss among older adults in the Low Indexes of Metabolism Intervention Trial part A.

AIM: To test whether alerting clinicians to severe weight loss in older patients leads to higher dietitian visit rates, to higher body mass index (BMI) levels and, mainly, to lower annual death risk. METHODS: The randomized controlled trial included patients aged ≥75 years, with BMI ≤23 kg/m2 that decreased ≥2 kg/m2 during the previous 2 years. All participants received usual care. Additionally, an email alert was sent only to clinicians of participants assigned to the email alert group. The follow-up period was 12 months. RESULTS: Among 706 participants (mean age 83 ± 6 years; mean baseline BMI 20.5 kg/m2 ), the BMI record was updated in 541 (77%) participants, and 123 participants died. Dietitian visits were reported for 22 patients (6%) in the email group (n = 362) and 14 patients (4%) in the control group (n = 344; OR 1.5, 95% CI 0.8-2.9; P = 0.24). Measured BMI were raised by a mean of 0.69 (95% CI 0.43-0.95) kg/m2 versus 0.79 (95% CI 0.48-1.1) kg/m2 (P = 0.63). A total of 77 patients (21%) died in the intervention group versus 47 (14%) in the control group (P = 0.008; number needed to harm = 13; 95% CI 7-43). CONCLUSIONS: In this trial, alerting clinical staff to severe weight loss in patients aged ≥75 years was not associated with higher visit rates to a dietitian or change in BMI, but was associated with a significantly higher death rate than usual clinical care. Geriatr Gerontol Int 2020; 20: 329-335.

A Randomized Trial of Alerting to Hypocholesterolemia Results of the Low Indexes of Metabolism Intervention Trial-C (LIMIT-C).

OBJECTIVES: The benefit of alerting clinical staff to drug-induced hypocholesterolemia in patients aged 75 years and older remains uncertain. DESIGN, SETTING, AND PARTICIPANTS: The study included 1791 patients with serum cholesterol <160 mg/dL and on cholesterol-lowering drugs who were assigned to have an e-mail alert sent to their physician, and 1804 patients who were assigned to receive usual clinical care (control group). The primary outcome of the trial was annual death rate. Secondary outcomes included cholesterol-lowering drug dose reduction and emergency department (ED) visits. RESULTS: At 1 year, 58 patients (3.2%) in the intervention group and 61 (3.4%) in the control group had died [relative risk 0.94, 95% confidence interval (CI) 0.66-1.34; P = .74]. Quarter-averaged cholesterol-lowering drug defined daily doses were reduced by -13.5 ± 47.0 (-17% ± 60%) in the intervention group and by -5.1 ± 42.2 (-6%±54%) in the control group (difference -8.5 ± 1.5, 95% CI -5.5 to -11.4; P < .0001). Annual ED visit rates per 1000 patients were 291 in the intervention group and 336 in the control group (45 fewer visits per 1000 patients in the intervention group, 95% CI -1 to -89; P = .04). CONCLUSIONS AND IMPLICATIONS: In this trial, alerting clinical staff to hypocholesterolemia in patients aged 75 years and older being treated with cholesterol-lowering drugs was associated with mildly reduced cholesterol-lowering drugs doses and marginally reduced ED visit rates. This e-mail alert intervention was not associated with a significant difference in 1-year survival rate compared with usual clinical care.

A Randomized Trial of Alerting to Low Glycated Hemoglobin Level in Older Adults: Results of the Low Indexes of Metabolism Intervention Trial B (LIMIT-B).

OBJECTIVES: The benefit of alerting clinical staff to low plasma glycated hemoglobin (HbA1c) in patients aged 75 years and older who receive antidiabetic drugs remains uncertain. DESIGN, SETTING, AND PARTICIPANTS: In a randomized controlled trial, 1684 patients with HbA1c ≤ 6.5% who received antidiabetic drugs were assigned to have an e-mail alert sent to their physician, and 1643 were assigned to have no such alert (control group). The primary outcome of the trial was annual death. Secondary outcomes included antidiabetic drug dose reduction and HbA1c change. RESULTS: In the first quarter, antidiabetic drug-defined daily doses were reduced on average by 10.4 ± 35.8 (16% ± 55%) in the intervention group and by 6.4 ± 36.1 (10% ± 56%) in the control group (difference -4.1 ± 1.2, 95% confidence interval [CI] -6.5 to -1.6; P = .001). Measured HbA1c levels were raised by a mean (± standard deviation) of 0.28 ± 0.77 in the intervention group and by 0.18 ± 0.57 in the control group (difference 0.10 ± 0.02, 95% CI -0.15 to -0.059, P < .001). One year after the alerts, 121 patients (7.2%) died in the intervention group and 107 patients (6.5%) died in the control group (relative risk 1.1, 95% CI 0.86-1.42; P = .44). CONCLUSIONS AND IMPLICATIONS: In this trial, alerting clinical staff to low HbA1c in patients aged 75 years and older treated with antidiabetic medicines was associated with mildly reduced antidiabetic doses and increased HbA1c but was not associated with a significant difference in survival rate compared with usual clinical care.

Aggregation of maternal pigment granules is induced by the cytosolic discoidin domain of the Xenopus Del1 protein.

Xenopus oocytes generate pigment granules (melanosomes) that predominantly localize to the animal hemisphere cortex. During embryonic development, these granules are located near the membranes of outer layer ectoderm cells. We report a novel phenotype found during an expression cloning screen in Xenopus laevis embryos. The phenotype is characterized by dissociation of pigment granules from the cell membrane to form large central aggregates. This phenomenon was induced by a truncated form of the Xenopus Del1 (XDel1) protein that contains only the C-terminal discoidin (D2) domain. This truncated form of XDel1 localized to membranes as shown by a chimeric enhanced green fluorescent protein construct. Although a similar localization occurred in immature oocytes, dissociation of pigment granules was limited to the oocyte vegetal hemisphere. The full-length XDel1 cDNA was cloned, and XDel1 mRNA expression was found to be ubiquitous and continuous from early oocyte to tail bud stages, with a transient enrichment in the cement gland. Ectopic expression of various deletion or full-length constructs or antisense morpholino oligonucleotides did not induce any significant developmental phenotypes.