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https://doi.org/10.24304/kjcp.2022.32.4.336
Evaluating the Efficacy of Pharmacological Therapy for Prader-Willi Syndrome: A Systematic Review and Meta-analysis
Korean J Clin Pharm 2022;32(4):336-351
Published online December 31, 2022
© 2022 Korean College of Clinical Pharmacy.
Alim Yoo#, Sohyeon Park#, and Heeyoung Lee*
Department of Clinical Medicinal Sciences, Konyang University, Nonsan 32992, Republic of Korea
Correspondence to: Heeyoung Lee, Department of Clinical Medicinal Sciences, Konyang University, Nonsan 32992, Republic of Korea
Tel: +82-41-730-5685, Fax: +82-41-730-5349, E-mail: pharmdlee1@konyang.ac.kr
#These two authors contributed equally to this work.
Received October 1, 2022; Revised December 19, 2022; Accepted December 21, 2022.
This is an Open Access journal distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
Background: Prader-Willi Syndrome (PWS) is a rare genetic disorder. To improve the health deterioration of PWS, investigating optimal treatment options for PWS is required. Thus, we aimed to evaluate the efficacy of pharmacotherapies compared with supportive care or placebos in patients with PWS. Methods: PubMed and EMBASE databases were used to search for randomized controlled trials (RCTs) evaluating the efficacy of pharmacotherapy in PWS patients. Only RCTs that evaluating the efficacy of pharmacotherapy in PWS patients were retrieved. Results: A total of 26 studies were included to evaluate body composition, hormones, glucose levels and hyperphagia behavioral status. Pharmacological treatment group showed a significant decrease of body fat (mean difference (MD): -6.32, 95% confidence interval (CI): -10.58 to -2.06, p=0.004), a significant increase of lean body mass (LBM) (MD: 1.86, 95% CI: 1.43 to 2.30, p<0.00001) and insulin-like growth factor 1 (IGF-1) levels (MD: 241.62, 95% CI: 68.59 to 414.64, p=0.006) compared with the control group. Nevertheless, based on other outcomes evaluated by the current systematic review, pharmacological options showed different efficacy in treating PWS. Conclusion: Pharmacological therapies were effective to decrease significantly in body fat and increase significantly on LBM and IGF-1 levels in patients with PWS. However, still, individualized therapies should be considered in real-world practice in PWS treatment.
Keywords : Prader-Willi syndrome, pharmacological therapy, systematic review, meta-analysis, efficacy
Body Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
Prader-Willi Syndrome (PWS) is a rare genetic disability with a prevalence rate of 1 in 10,000-30,000 live births.1,2) PWS is a complex developmental disability caused by a deficiency of genes expressed on chromosomes 15q11-q13,3,4) resulting in growth hormone (GH) deficiency, hypogonadism, reproductive dysfunction, behavioral problems, hyperphagic problems, and obesity.5,6) The cause of the abnormal body composition in PWS is not completely known. However, a unique pattern of body composition with increased body mass index (BMI) or total body fat mass (FM) and a decrease in lean body mass (LBM) has been observed in patients with PWS.7) Individuals with PWS may have pathological obesity resulting from excessive weight gain or severe hyperphagia.8) Physical deterioration and weight gain in patients with PWS can cause negative consequences such as metabolic dysfunction, cardiovascular disease, and early death.8)
There are pharmacological and non-pharmacological methods for treating these complications in patients with PWS. Non-pharmacological methods, such as dietary restriction or bariatric surgery, have limitations in improving the condition of patients with PWS.8) In contrast, although they are non-pharmacological treatments, dietary interventions have been reported to be effective in preventing excessive weight gain.9) However, another study has reported that nutritional intervention does not contribute significantly to weight loss.10) Especially in patients with PWS, food restriction was not associated with appetite reduction or the patient's ability to live independently because they needed help from their families.11) Although non-pharmacological treatments for PWS have been ineffective, the efficacy of pharmacological treatment for PWS is supported by various studies. There is currently no standard therapy for treating PWS. In addition, there is limited evidence to prove the efficacy of pharmacological options. Hence, an evaluation of the benefits of pharmacological treatment in patients with PWS is needed.8)
In previous systematic reviews and meta-analysis, the effects of pharmacological treatments on body composition variables such as height, BMI, and FM have evaluated.12-15) As a result of previous meta-analysis, increased LBM and decreased FM were consistently observed.12-15) Since previous studies have investigated randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs) simultaneously,12-15) biases were unpreventable. Moreover, there are additional studies that have been investigated the efficacy of pharmacological treatment in PWS patients but are not included in the previous meta-analysis. These studies need to be included in the analysis.
Hence, the current meta-analysis aimed to assess the efficacy of pharmacological therapies compared to supportive care or placebos in PWS patients with RCTs.
Methods Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
The current meta-analysis was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PRISMA checklist was indicated in Supplementary Table 1. The study protocol was registered in the International Prospective Register of Systematic Reviews database with registration number: CRD42022320845.
Search Strategy
PubMed and EMBASE databases were used for searching relevant studies published before 18 March 2022. The search was conducted using the keywords combined with "PWS", "pharmacological treatment", and relevant Medical Subject Headings (MeSH) terms. The detailed search strategy was indicated in Supplementary Table 2 and Supplementary Table 3. The search strategy was targeted at published studies that estimated the efficacy of pharmacological treatments for PWS and was limited to full-text articles written in English. In order to limit to retrieve only full-text English articles, the three investigators manually reviewed the articles. References in the collected articles and systematic reviews were manually browsed to identify additional studies.
Three independent investigators assessed the titles and abstracts of the retrieved articles to identify potentially related articles. This review included (1) all RCTs that registered patients with PWS to evaluate the efficacy of pharmacological treatments and (2) studies that providing outcomes of body composition, hormones, and glucose levels, and hyperphagic status in patients with PWS. We excluded the studies following four reasons: (1) inappropriate outcome measure, (2) non-pharmacological intervention, (3) full-text records not retrieved and (4) not placebo or untreated controls. All disagreements between the three investigators were resolved through discussion.
Changes in body composition parameters, such as LBM, FM, body fat percentage, BMI, weight, and height were assessed. In addition, changes in glucose levels and hormones such as insulin, insulin-like growth factor binding protein 3 (IGFBP-3), insulin-like growth factor 1 (IGF-1), glucose and adiponectin levels were evaluated. Additionally, the hyperphagic status was assessed.
Data extracted from the retrieved studies included sample size, intervention, type of control group, study design, registration number, study period, body composition, hormone & glucose levels and hyperphagia behavior. Three investigators performed data extraction and assessment of internal study validity and quality. The risk of bias assessment tool developed by the Cochrane Collaboration was used to evaluate quality of RCTs.16) The evidence for the included study was assessed as a Grading of Recommendations, Assessment, Development and Evaluations profiler (GRADEpro) approach; classified as high, moderate, low, or very low.17) All disagreements between the three investigators were resolved through discussions.
We determined the overall changes in body composition, hormone, glucose levels and hyperphagic status after pharmacological treatment. We extracted the change of the measurements. In the case of articles that show only baseline and final levels, the change was calculated through those levels. Net changes were quantified as differences between baseline and final measures. We assumed a correlation of r= 0.5 to calculate the standard deviation (SD) of the change. To perform meta-analysis on several studies, only studies in which the level of each outcome expressed as mean±SD were analyzed. Hence, we excluded the studies that each outcome level expressed as median with range or interquartile range in meta-analysis. The overall effect size for the studies represented as the mean difference (MD) and 95% confidence interval (CI). We equalized the units for each outcome to analyze with MD and used them as follows; BMI (kg/m2), LBM (kg), body fat (%), weight (kg), IGF-1 (ng/mL) and fasting insulin (mIU/L). Since other outcomes did not have enough number of articles to analyze with mean±SD, meta-analysis performed on only these six outcomes. Statistical significance was set at p<0.05.
I2 statistics were used to decide the significance of heterogeneity among studies classified as low (<25%), moderate (25-50%) or high (>50%). If I2 <25%, meta-analysis was conducted with a fixed-effect model. Otherwise, meta-analysis was conducted with random-effect model. When I2> 50%, sensitivity analysis was performed by omitting each study individually. Sensitivity analysis was also performed when the meta-analysis results were affected by a specific study with a large weight. Due to less than 10 studies were included in each analysis, publication bias was not evaluated. The meta-analysis was conducted using Review Manager (RevMan [Computer Program]. Version 5.4, The Cochrane Collaboration, 2020), R (version 4.2.1) and Excel.
Results Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
We identified 241 potentially eligible studies extracted from PubMed and EMBASE databases (Fig. 1). Full-text screening reduced the number of studies to 90. 66 of 90 studies were excluded for the following four reasons: (1) inappropriate outcome measures (n=57), (2) non-pharmacological interventions (n=6), (3) full-text records not retrieved (n=2), and (4) not placebo or untreated controls (n=1). Two more articles were identified through a nonautomatic search of the reference lists of the retrieved studies. Ultimately, 26 studies were included in qualitative analysis.18-43) and 11 of them were included in quantitative analysis.18,20,22,25,26,30,32,37-40)
Fig. 1. The flowchart of the study selection process for the systematic review and meta-analysis.
Study characteristics
The basic characteristics of the total 26 studies were presented in Table 1.18-43 Body composition was evaluated in 21 studies,18-22,24-26,28,30,32-33,35-43) hormone and glucose levels were evaluated in 21 studies18,19,21-25,29-31,33-43) and status of hyperphagic behavior was evaluated in three studies.20,22,27) Most of the 26 studies used GH administration18,29-43) and 10 studies used the administration of additional drugs including 19-28): anticonvulsant,20) selective methionine aminopeptidase 2 inhibitor,21) unacylated ghrelin analog,22) glucagon-like peptide 1 receptor agonist,23) cannabinoid receptor CB1 inverse agonist,24) somatostatin receptor agonist,25) oxytocin,19,27,28) and serotonin releasing agent.26)
Characteristics of included studies
Research period
Patients age
Sode-Carlsen et al. (2010)42) 46 GH Placebo N/A 1 year 16-50 years
Festen et al. (2007)41) 20 GH (Genotropin) SC 1 mg/m2/day untreated N/A 2 years 4-9 years
Bakker et al. (2015)35) 47 GH (Genotropin) 0.035 mg/kg/day untreated ISRCTN 49726762 / NTR 628 2 years 6 month-14 years
Kuppens et al. (2016 a)40) 27 GH (Genotropin) SC 0.67 mg/m2/day Placebo NTR1038 2 years 17.2 (1.8) years a
Myers et al. (2000)30) 54 GH (Nutropin) 1 mg/m2/day untreated N/A 2 years 4-16 years
HAQQ et al. (2003)32) 12 GH (Genotropin) SC 0.043 mg/kg•d Placebo SC N/A 1 year 4.5–14.5 years
Carrel et al. (1999)18) 54 GH (Nutropin) 1 mg/m2/day untreated N/A 1 year 4-16 years
Hoybye et al. (2004)29) 17 GH (Genotropin) 0.8 → 1.6 IU (0.26 → 0.53 mg) daily Placebo N/A 18 months 17-32 years
Hauffa et al. (1997)34) 17 GH SC 0.15 IU/kg/day untreated N/A 1 year 3-12 years
Hoybye et al. (2003 a)39) 17 GH (Genotropin) SC 0.8 → 1.6 IU (0.26 → 0.53 mg) daily Placebo N/A 18 months (Placebo-controlled period: 6 months, Open label GH period: 1 year) 17-37 years
Hoybye et al. (2003 b)31) 17 GH (Genotropin) SC 0.8 → 1.6 IU (0.26 → 0.53 mg) daily Placebo N/A 18 months (Placebo-controlled period: 6 months, Open label GH period: 1 year) 17-32 years
De Lind van Wijngaarden et al. (2010)43) 85 GH (Genotropin) SC 1.0 mg/m2/day untreated N/A 2 years 6 month-14 years
Carrel et al. (2004)38) 29 GH (Genotropin) 1 mg/m2/day untreated N/A 1 year 4-37 months
Lindgren et al. (1998)37) 29 GH (Genotropin) SC 0.1 IU/kg/day untreated N/A 1 year 3-12 years
Lindgren et al. (1999)36) 19 GH (Genotropin) SC 0.1 - 0.2 IU/kg/day untreated N/A 2 years 3.8-12.7 years
Festen et al. (2008)33) 91 GH (Genotropin) SC 1 mg/m2/day untreated N/A 2 years 3-12 years
Non-GH
Anticonvulsunt
Consoli et al. (2019)20) 62 Topiramate 50–200 mg/day Placebo NCT02810483 8 weeks 12-45 years
Cannabinoid receptor CB1 inverse agonist
Motaghedi et al. (2011)24) 10 Rimonobant 20 mg Placebo N/A 6 months 19.5 - 36.3 years
Glucagon‐like peptide 1 receptor agonist
Sze et al. (2011)23) 8 Exenatide (Byetta) SC 10 μg Placebo SC (normal saline) N/A 4 weeks 30.0 (2.8) years a
Einfeld et al. (2014)27) 30 Intranasal oxytocin (11 participants: (13–15 years) 18 IU B.I.D, (16 years and over) 24 IU B.I.D 18 participants: (13–15 years) 32 IU B.I.D, (16 years and over) 40 IU B.I.D) Placebo ACTRN12609000982213 18 weeks 12-30 years
Kuppens et al. (2016 b)28) 25 Intranasal oxytocin (Syntocinon) twice daily (dose range: 24-48 IU/day) Placebo NTR4950 8 weeks 6-14 years
Damen et al. (2021)19) 26 Intranasal oxytocin (Syntocinon) twice daily (dose range: 16-40 IU/day) Placebo N/A 3 months 3-11 years
Selective methionine aminopeptidase 2 inhibitor
McCandless et al. (2017)21) 107 Beloranib 1.8 mg or 2.4 mg Placebo 0.45ml or 0.6ml NCT02179151 1 year (administer 26 weeks) 12–65 years
Serotonin releasing agents
Selikowitz et al. (1990)26) 15 Fenfluramine capsule >(5 to 7 years: 10 mg TID, 8 to 15 years: 10 mg → 20 mg TID, Over the age of 15: 20 mg TID → 40 mg TID) Placebo capsule (lactose) N/A 6 weeks 5.5-27 years
Somatostatin receptor agoinist
De Waele et al. (2008)25) 9 Octreotide (Sandostatin LAR) IM 30 mg Placebo IM (saline) NCT00175305 56 weeks 10.8–18.9 years
Unacylated ghrelin analog
Allas et al. (2018)22) 47 AZP-531 SC 3 or 4 mg Placebo N/A 2 weeks 18-40 years
ACTRN: Australian clinical trials registration number, AZP-531: unacylated ghrelin analog, BID: Bis In Die (=twice a day), GH: growth hormone, IM: intramuscular injection, ISRCTN: International Standard Randomised Controlled Trial Number, IU: International Unit, N/A: not available, NCT: National Clinical Trial (number), NTR: Netherlands Trial Register, SC: subcutaneous injection, TID: Ter In Die (=three times a day), a is indicated as Mean (Standard deviation)
The effects of pharmacological treatment on body composition including BMI, LBM, FM, body fat, weight and height were summarized in Table 2.18-22,24-26,28,30,32-33,35-43)
Effects of pharmacological treatments on body composition, hormone & glucose, and states of hyperphagic behavior
Hormone & glucose
States of hyperphagic behavior
Sode-Carlsen et al. (2010) 42) BMI (kg/m2) unchanged
LBM (kg) ↑
FM (kg) ↓ IGF-1 (ng/mL) ↑
Fasting glucose (mmol/L) unchanged
Fasting insulin (pmol/L) unchanged -
Festen et al. (2007) 41) BMI (kg/m2) ↓
Height SDS ↑ Glucose (mmol/L) ↓
Insulin (mU/L) ↑
Adiponectin (mg/L) ↑ -
Bakker et al. (2015) 35) LBM (kg) ↑
FM (kg) ↑
Body fat (%) ↓
Height (SDS) ↑ Fasting glucose ↑
Fasting insulin ↑
Fasting adiponectin (mg/L) ↑ -
Kuppens et al. (2016 a) 40) BMI (kg/m2) ↑
FM (kg), FM (%) ↑ Glucose (mmol/L) ↓
Insulin (pmol/L) ↓ -
Myers et al. (2000) 30) BMI (kg/m2) ↓
Body fat (%) ↓ IGF-1 (ng/mL) ↑
Fasting insulin (mIU/L) ↑ -
Haqq et al. (2003) 32) BMI (kg/m2) ↑
FM (kg) ↓
Height (SDS) ↑ - -
Carrel et al. (1999) 18) BMI (kg/m2) ↓
Height (SDS) ↑ IGF-1 (ng/mL) ↑
IGFBP-3 (mg/L) ↑
Hoybye et al. (2004) 29) - Adiponectin (mg/L) ↑ -
Hauffa et al. (1997) 34) - IGF-1 ↑
IGFBP-3 ↑ -
IGFBP-3 (ng/mL) ↑ -
Carrel et al. (2004) 38) LBM (kg) ↑
Height (SDS) ↑ IGF-1 (ng/mL) ↓
Lindgren et al. (1998) 37) Body fat (%) ↓
Height (SDS) ↑ IGF-1 (SDS) ↑
Hoybye et al. (2003 a) 39) BMI (kg/m2) ↑
Glucose (mmol/L) ↓
Insulin (pmol/L) ↑ -
Height (SDS) ↑ Insulin (mU/L) ↑ -
De Lind van Wijngaarden et al. (2010) 43) Height (SDS) ↑ Glucose (mmol/L) ↑
Insulin (mU/L) ↑ -
Hoybye et al. (2003 b) 31) - IGF-1 (ng/mL) ↑
Consoli et al. (2019) 20) BMI (kg/m2) ↓ - ↓
Motaghedi et al. (2011) 24) BMI (kg/m2) ↓
FM (g/cm2) ↓
Weight (kg) ↓ IGF-1 (ng/mL) ↑
Glucagon-like peptide 1 receptor agonist
Sze et al. (2011) 23) - Fasting glucose (mmol/L) ↓
Kuppens et al. (2016 b) 28) BMI (kg/m2) ↓
Weight (kg) ↑ - -
Damen et al. (2021) 19) BMI (kg/m2) ↑
Body fat (%) ↑
Weight (kg) ↑ Fasting glucose ↑
Fasting insulin ↑ -
Einfeld et al. (2014) 27) - - unchanged
McCandless et al. (2017) 21) LBM (kg) ↓
Weight (kg) ↓ Adiponectin (mg/L) ↑ -
Serotonin releasing agent
Selikowitz et al. (1990) 26) Weight (kg) ↓ - -
Somatostatin receptor agonist
De Waele et al. (2008) 25) BMI (kg/m2) ↑
Weight (kg) ↑
Height (cm) ↑ Fasting glucose (mg/dL) ↑ -
Allas et al. (2018) 22) FM (%) ↓
Weight (kg) ↓ Fasting glucose (mmol/L) ↓
Fasting insulin (pmol/L) ↑ ↓
BMI: body mass index, FM: fat mass, IGF-1: Insulin-like growth factor 1, IGFBP-3: Insulin-like growth factor-binding protein 3, LBM: lean body mass, mIU: milli international unit, SDS: standard deviation score, U: unit, ↑ = increased, ↓ = decreased
Thirteen studies evaluated the effects of pharmacological treatment on BMI18-20, 24, 25, 28, 30, 32-33, 39-42). BMI was reduced in seven studies18,20,24,28,30,33,41) and in the other six,19,25,32,39-40,42) it was either unchanged or slightly increased (Table 2). In the case of using GH, BMI showed inconsistent results because it was unchanged,42) increased32,39,40) or decreased.18,30,33,41) Similarly, in the case of using non-GHs such as oxytocin showed an inconsistent tendency with an increased BMI in one study19) and a decreased BMI in another study.28) Otherwise, BMI tended to decrease in non-GH treatments such as anticonvulsants20) and cannabinoid receptor CB1 inverse agonist24) except for an increase in somatostatin receptor agonist.25) Of the 13 studies,18-20,24,25,28,30,32-33,39-42) only six studies which BMI were expressed in mean±SD were analyzed.18,20,25,30,32,40) Patients who received pharmacological treatment showed a nonsignificant decrease in BMI compared to the control group (MD: −0.73, 95% CI:-1.95 to 0.50, p=0.25) (Fig. 2a). We performed a sensitivity analysis because of the large weight of De Waele et al. (2008), but there was no difference in I2.
Fig. 2. Forest plots for the effects of pharmacological treatments on (a) BMI, (b) LBM, (c) body fat, (d) weight, (e) IGF-1 and (f) fasting insulin levels. Squares represent the effect size for each included studies and the size of the square represents the weight assigned to that study in the meta-analysis. Diamond indicated as meta-analyzed measure of effect. BMI: body mass index, IGF-1: Insulin-like growth factor 1, LBM: lean body mass
The effects of pharmacological treatment on LBM were evaluated in ten studies.18,19,21,30,32,35,38-40,42) Except for one study,21) the LBM increased in nine studies (Table 2).18,19,30,32,35,38-40,42)LBM increased in all studies that using GH.18,30,32,35,38-40,42) A study that using oxytocin, one of the non-GH treatments, also showed an increase in LBM.19) In contrast, LBM decreased when selective methionine aminopeptidase 2 inhibitor, another type of non-GH treatments, was used.21) Of the ten studies,18,19,21,30,32,35,38-40,42) only six studies which LBM were expressed in mean±SD were analyzed.18,30,32,38-40) Patients who received pharmacological treatment showed a significant improvement in LBM compared to the control group (MD: 1.86, 95% CI: 1.43 to 2.30, p<0.00001) (Fig. 2b). We conducted a sensitivity analysis because of the large weight of Carrel et al. (2004), but there was no difference in I2.
Eight studies evaluated the effects of pharmacological treatment on FM21,22,24,25,32,35,40,42) (Table 2). In the case of using GH, FM showed an inconsistent trend because each study showed an increased FM35,40) or a decreased FM.32,42) Except for somatostatin receptor agonist,25) FM was decreased in all non-GH treatments such as selective methionine aminopeptidase 2 inhibitor,21) cannabinoid receptor CB1 inverse agonist24) and unacylated ghrelin analog.22)
The effect of pharmacological treatments on body fat was evaluated in 11 studies.18,19,25,28,30,32,35-39) In nine studies, body fat was reduced,18,28,30,32,35-39) and in the other two, it was increased19,25) (Table 2). Body fat decreased in all studies that using GH.18,30,32,35-39) Body fat was increased when somatostatin receptor agonist, one of non-GH treatments, was used.25) In contrast, oxytocin, another type of non-GH treatments, showed an increased body fat in one study19) and a decreased body fat in another study.28) Of the 11 studies,18,19,25,28,30,32,35-39) only seven studies which body fat were expressed in mean±SD were analyzed.18,25,30,32,37-39) Patients who received pharmacological treatment showed a significant decrease in body fat compared to the control group (MD: −6.32, 95% CI:-10.58 to −2.06, p=0.004) (Fig. 2c). The analyzed results may actually be heterogeneous (I2=88%). In the case of omitting De Waele et al. (2008), I2 decreased from 88% to 68%. De Waele et al. (2008) is the main cause of heterogeneity.
Ten studies evaluated the effects of pharmacological treatment on height18,25,32,33,35-38,41,43) (Table 2). Increase of height was observed in all studies.18,25,32,33,35-38,41,43) Height has increased in all studies that using GH.18,32,33,35-38,41,43) In addition, a study that using somatostatin receptor agonist, one of non-GH treatments, also showed an increased height.25)
In addition, the effects of pharmacological treatments on weight were evaluated in seven studies.19,21,22,24-26,28) Weight loss was observed in four studies,21,22,24,26) and the other three reported weight gain19,25,28) (Table 2). Of non-GH drugs, cannabinoid receptor CB1 inverse agonist,24) selective methionine aminopeptidase 2 inhibitor,21) serotonin releasing agent26) and unacylated ghrelin analog showed a decrease in weight.22) Otherwise, in the case of using oxytocin or somatostatin receptor agonist,19,25,28) weight was increased. Of the seven studies,19,21,22,24-26,28) only three studies which weight were expressed in mean±SD were analyzed.22,25,26) Patients who received pharmacological treatment showed a nonsignificant increase in weight compared with the control group (MD: 0.31, 95% CI: −0.73 to 1.36, p=0.56) (Fig. 2d). We performed sensitivity analysis due to large weight of Allas et al. (2018), but there was no difference in I2.
The effects of drug treatment on hormones including IGF-1, IGFBP-3, insulin, adiponectin, and glucose levels were summarized in Table 2.18,19,21-25,29-31,33-43)
Ten studies evaluated the effects of pharmacological treatment on IGF-118,24,30,31,33,34,37-39,42) (Table 2). In the case of using GH,18,30,31,33,34,37-39,42) IGF-1 levels were increased,18,30,31,33,34,37,39,42) except for one study.38) Non-GH treatment such as cannabinoid receptor CB1 inverse agonist showed an increasing effect.23) Of the 10 studies,18,24,30,31,33,34,37-39,42) only three studies which IGF-1 levels were expressed in mean±SD were analyzed.18,38,39) IGF-1 showed a more significant increase in the pharmacological treatment group than in the control group (MD: 241.62, 95% CI: 68.59 to 414.64, p=0.006) (Fig. 2e). The analyzed results may actually be heterogeneous (I2=98%). In the case of omitting Carrel et al. (1999), I2 decreased from 98% to 60%. Carrel et al. (1999) is the main cause of heterogeneity.
The effects of pharmacological treatment on IGFBP-3 were evaluated in five studies.18,24,31,33,34) IGFBP-3 expression increased in all studies18,24,31,33,34) (Table 2). IGFBP-3 expression with GH treatments was increased in all studies18,31,33,34) (Table 2). The non-GH treatment cannabinoid receptor CB1 inverse agonist also showed an increase in IGFBP-3.24)
Four studies evaluated the effects of pharmacological treatment on glucose levels.39-41,43) Except for one study43) glucose levels with GH treatments decreased in three studies.39-41) In addition, the effects of pharmacological treatments on fasting glucose levels were evaluated in six studies.19,22,23,25,35,42) In the case of using GH drugs,35,42) fasting glucose has unchanged in one study42) and increased in another study35) (Table 2). In the case of using non-GH treatments,19,22,23,25) unacylated ghrelin analog and glucagon-like peptide 1 (GLP-1) receptor agonist showed a decreasing effect.22,23) In contrast, somatostatin receptor agonist and oxytocin showed an increase in fasting glucose level.19,25)
The effects of pharmacological treatments on insulin levels were evaluated in five studies36,39-41,43) (Table 2). All studies for insulin used only GH. Except for one study 40), insulin levels increased in four studies.36,39,41,43) In addition, there were nine studies evaluating the effects of pharmacological treatment on fasting insulin levels19,22,23,30,35-38,42) Studies that investigating fasting insulin levels with using GH, one study showed unchanged level,42) and another five studies showed increased levels.18,30,35,37,38) Non-GH treatments such as unacylated ghrelin analog, GLP-1 receptor agonist and oxytocin showed increased fasting insulin levels.19,22,23) Of the nine studies,19,22,23,30,35-38,42) only four studies which fasting insulin levels were expressed in mean±SD were analyzed.18,22,30,38) Patients who received pharmacological treatment showed a nonsignificant increase in fasting insulin levels compared with the control group (MD=2.87, 95% CI: −0.88 to 6.62, p=0.13) (Fig. 2f). The analyzed results may actually be heterogeneous (I2=71%). In the case of omitting Carrel et al. (1999), I2 decreased from 71% to 52%. Carrel et al. (1999) is the main cause of heterogeneity.
There were four studies evaluating the effects of pharmacological treatment on adiponectin levels.21,29,35,41) All studies that investigating adiponectin levels and fasting adiponectin levels with GH were showed an increase29,35,41)(Table 2). In the case of using selective methionine aminopeptidase 2 inhibitor,21) adiponectin levels were also increased.
Status of hyperphagic behavior
The effects of drug treatment on the status of hyperphagic behavior were summarized in Table 2.20,22,27) The status of hyperphagic behavior was measured using the Dykens Hyperphagia Questionnaire. The hyperphagic status was reduced in studies that using topiramate and unacylated ghrelin analog.20,22) In contrast, there was no change in study that using oxytocin.27)
Risk of Bias and Level of Evidence
A summary of the risk of bias evaluation is indicated in Fig. 3. In case of overall bias, five studies showed some concerns19,30,34,35,41) and one study showed high risk,24) but most studies showed low risk.18,20-23,25-29,31-33,36-40,42,43) Related to the bias arising from the randomization process, most studies showed low risk,19-29,31-34,39,40,42,43) but seven studies showed some concerns.18,30,35-38,41) In case of bias due to deviations from intended interventions, all studies except for one showed low risk.18-20,22-43) One study showed some concerns.21) Related to the bias due to missing outcome data, most of the studies showed low risk,18-23,25-33,35-43) but one study showed some concerns,34) and another study showed high risk.24) In case of bias in measurement of the outcome, most studies showed low risk,18-32,36-40,42,43) but four studies showed some concerns.33-35,41) Related to the bias in selection of the reported result, most studies showed low risk,18,20-23,25-33,36-43) but four studies showed some concerns.19,24,34,35)
Fig. 3. Risk of bias summary
Table 3 shows the level of evidence using the GRADEpro for the efficacy of pharmacological treatments in PWS patients compared to the control group.
GRADE evidence profile
No. of studies (No. of participants)
Certainty assessement
BMI 6 RCTs (238 participants) Not serious Not serious Serious Not serious None MD 0.73 lower (1.95 lower to 0.50 higher) ⨁⨁⨁◯ Moderate
LBM 6 RCTs (204 participants) Not serious Not serious Not serious Not serious None MD 1.86 higher (1.43 higher to 2.30 higher) ⨁⨁⨁⨁ High
Body fat 7 RCTs (223 participants) Not serious Very serious Not serious Not serious None MD 6.32 lower (10.58 lower to 2.06 lower) ⨁⨁◯◯ Low
Weight 3 RCTs (93 participants) Not serious Not serious Serious Not serious None MD 0.31 higher (0.73 lower to 1.36 higher) ⨁⨁⨁◯ Moderate
IGF-1 3 RCTs (100 participants) Not serious Not serious Not serious Not serious None MD 241.62 higher (68.59 higher to 414.64 higher) ⨁⨁⨁⨁ High
Fasting insulin 4 RCTs (184 participants) Not serious Serious Serious Not serious None MD 2.87 higher (0.88 lower to 6.62 higher) ⨁⨁◯◯ Low
BMI: body mass index, CI: confidence interval, IGF-1: Insulin-like growth factor 1, LBM: lean body mass, MD: mean difference, RCT: randomized controlled trial
Discussion Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
We conducted systematic review and meta-analysis that evaluated the efficacy of pharmacological treatments for PWS patient care.
According to the current study, pharmacological treatment showed effects in increasing LBM and decreasing body fat. An increment in LBM was consistently shown in a previous meta-analysis treated with GH therapy.12,14) Increase of LBM is closely related to improving physical activity in PWS patients.44) Because increasing physical activity is related to increasing social activity and economic advantage.45) In addition to the improvement of LBM, higher body fat was also decreased with pharmacological treatment based on our study outcomes. Excessive body fat can cause various complications such as respiratory disorders, obstructive apnea, cardiovascular, and metabolic complications.46) The deaths caused by these complications are more than half of the total causes of death in PWS patients.47) Reducing body fat, it contributes to reducing complications and lowering mortality.47) In this study, drug with GH seemed to act on more significant reduction in body fat compared to other pharmacological therapies such as oxytocin. GH metabolizes fat through fat oxidation, increasing fat utilization and reducing fat.48) Since one of the relevant measures of body fat is BMI, this study analyzed both body fat and BMI.49,50) The increment in BMI is closely related to obesity.51,52) which accounts for 7% of the causes of death in patients with PWS.47) Previous meta-analysis or systematic review results for BMI were various,12-15) our study showed a nonsignificant decrease in BMI. These results may be caused by nonsignificant increments in weight and obvious increments in height. This may predict why BMI has not changed.
According to the types of hormone and glucose level measures, pharmacological treatment was differently associated with level change. The current study showed increased IGF-1 and fasting insulin levels after pharmacological treatment. As well, IGF-1 showed a significant increase in the previous meta-analysis,15) IGF-1 was significantly increased in our study. Low IGF-1 levels are associated with insufficient GH secretion,53) which results in linear growth impairment, abnormal body composition and hypothalamic dysfunction in PWS patients.54) High IGF-1 can improve the physical ability of PWS patients by maintaining improved body composition.44,55) Similar to low IGF-1 levels, patients with PWS show low insulin levels.56) As previous meta-analysis studies showed a significant increase in fasting insulin,15) in our study, both insulin levels and fasting insulin levels generally tended to increase in PWS patients through pharmacological treatment. PWS is a genetic syndrome characterized by relative hypoinsulinemia and normal or increased insulin sensitivity despite severe obesity.57) Some PWS patients have diabetes, which may be associated with pathological obesity and subsequent insulin resistance.58) Pharmacological treatment can prevent insulin resistance relatively, which is beneficial to the majority of GH-deficient PWS children.58) In addition, low insulin resistance can help the lower prevalence of non-alcoholic fatty liver disease (NAFLD) or coronary disease in PWS patients.59) The increase in insulin levels is generally associated with a decrease in glucose levels and our study also shows a tendency for glucose levels to decrease.60) Previous meta-analysis studies showed a nonsignificant increase in fasting glucose,14,15) whereas in this study, we could not ensure whether there was a particular tendency because the number of studies in which fasting glucose levels increased or decreased was similar. High glucose level is associated with signs of diabetes and the PWS group is at high risk for diabetes.5) Improved diabetes status improves one of the common causes of death in patients with PWS.47) In addition, it is possible to prevent deterioration of the quality of life due to complications.61,62) Nevertheless, the increase in fasting glucose showed a unique characteristic accompanied by increased fasting insulin. When GH or oxytocin was used to treat PWS patients, fasting glucose and fasting insulin increased simultaneously. This is because GH and oxytocin are drugs that increase metabolism.63,64) Glucose metabolism changes may occur due to the reverse regulatory effect of GH on insulin action through GH treatment.65) Since the increase in fasting insulin is a risk factor for subsequent atherosclerosis in epidemiological studies, insulin can also affect the development of atherosclerosis.66) In addition, fasting glucose reflects both basic insulin secretion and hepatic glucose production.66) Another hormone called adiponectin is an anti-inflammatory fat cytokine, which has an inverse relationship with insulin resistance, and is a fat-derived hormone that plays an important role in protecting against diabetes and atherosclerosis.67,68) The level of adiponectin increased in all studies. Increased adiponectin level through pharmacological treatment is consistent with the results of fat loss and can also contribute to increased insulin sensitivity.65) In addition, it can lead to protective effects related to type 2 diabetes and cardiovascular disease.68) Thus, pharmacological treatment was differently associated with level change, according to the types of hormone and glucose level measures.
Our study has some limitations. First, the current study did not investigate bone mineral density (BMD), one of the body-related indicators. The number of studies that investigated BMD was insufficient, so it is necessary to analyze it in other studies. Second, this study did not investigate other behavior-related problems except for hyperphagia behavior. Behavioral problems, such as compulsive behavior, were impossible for us to analyze because each study was measured using a different evaluation tool. Third, this study limited the control group to nonactive drug treatments, so we could not investigate the difference in efficacy between different medications. In the future, other studies need to analyze the differences in the effects of different drug treatments. Fourth, as recommended by the Cochrane Handbook for Systemic Reviews of Intervention, when less than 10 studies are included in meta-analysis, the power of the tests is low. There are less than 10 studies included in each meta-analysis, so we did not evaluate the publishing bias. Fifth, our study has a limitation in that various pharmacological treatments have been grouped into one intervention group. Although there were various treatment methods, these were collected according to the selection criteria that all of them were used as an intervention group to treat PWS. Sixth, this study included only GH drugs in meta-analysis of LBM and IGF-1. We found that their studies using only GH. Thus, we tried to include other treatments in meta-analysis. However, according to our inclusion criteria, studies included in LBM and IGF-1 meta-analysis did not exist any treatments except for GH. Finally, our study did not investigate safety indicators such as side effects. The purpose of this study was to investigate the efficacy of pharmacological treatments in PWS patient care, so we did not investigate safety-related outcomes. Therefore, research to analyze safety needs to be conducted.
Conclusion Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
In this study, the pharmacological treatment showed an efficacy in increased LBM, decreased body fat, and increased levels of IGF-1. Additional studies are necessary to accurately search for significant treatments for PWS patients by analyzing differences in effects between drugs.
Conflicts of Interest Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
The authors have no conflicts of interest to declare with regards to the contents of this study.
References Other SectionsAbstractBodyMethodsResultsDiscussionConclusionConflicts of InterestTableReference
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Let me start by saying it's very difficult to take a good photo from a moving train. Some of these are blurry, but I'm sharing them because I loved seeing these little gardens as we rolled through cities, towns, villages, and hamlets. I was particularly struck by the fact that, as always, no space goes unused.
Right next to the tracks often were gardens full of scarlet runner beans, zucchini, squash, tomatoes, eggplants, shiso, and heaps of cosmos, sunflowers, and petunias to name only a few. I was reminded a bit of the colorful patchwork of tiny backyard gardens I saw in London years ago from the train. These gardens, though, occurred in even the remotest of areas where it would seem there should be plenty of space elsewhere.
For more regular updates on our recent Hokkaido adventure, check out my Twitter page.
I love train travel; you see so much more from a train. Your photos gave us a short peek into a very different culture from a different angle. It must have been a very scenic ride. Thank you, again, for sharing.
I couldn't agree more. One of the things we really love about living in Japan is the ability to travel by train. Thanks for reading!


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Today is cloudy and chilly, colder than it has been. Tomorrow is supposed to be warm. I hope so as I need a sunny, warm day.
Every time I think I've seen the worse black and white science fiction movie I see another. The one I'm watching now is Robot Monster, The Original Version. The monster has the body of an ape and wears a space suit sort of hemet. Bubbles are a plot device. Why, I have no idea. There are dinosaurs appearing twice, the same scene of two attacking one another. I could go on, but I don't want to be a spoiler as I'm thinking this is a perfect film for a Saturday movie on the deck.
I need to be out today. Henry tested positive for Lyme so I need to pick up his pills, 28 days of pills. He has no symptoms so that's a good thing.
When I was a kid, our town had a Chinese Restaurant aptly named the China Moon but affectionally called The Moon. It was considered exotic. Once in a while my parents ordered Chinese food. They told us that Chinese food was not for kids. We believed them until we were a bit older and tasted Chinese food. The Moon is still there.
Hago Harrington's is a miniature golf course in my town. The course was built in 1950. I have played there many, many times, and I never seem to get any better. The lighthouse is my nemesis. There are three possible places at the bottom of the lighthouse for your ball to go through to the hole. I inevitably miss each of the three, and my ball bounces off the wood onto the walkway. I chase it down.
There used to be a big bowling alley. When I was in high school, a bunch of us would get together on a Friday or Saturday night to bowl. It was candlepin, three balls to a frame. We were all awful. I excelled at gutter balls. Despite my inability to bowl with any success, I was sorry when the bowling alley was replaced with a couple of businesses, one a Block Buster which also disappeared. A mostly take out place, The Liberty Bell Restaurant, is there now. The food is excellent.
Now, when I go to my hometown, I get a choice of restaurants including Chinese, Indian, Thai, Asian fusion and a few eclectic places. The town even has live theater. The Moon and the miniature golf course share a parking lot. A good afternoon is playing miniature golf and then eating Chinese at The Moon. The pleasure both bring is timeless.
Today is a lovely day, a bit chilly but sunny. It is a typical spring day on Cape Cod. Saturday is supposed to be a warm day. I'm hoping.
Henry doesn't have heartworm, but he did have a positive reading for Lyme disease. The vet said an additional blood test at $179.00 would determine whether or not he needs medication. I'll know tomorrow.
I get reflective at times. I remember all the neat things in my life all the way back to childhood. I remember the people most of all. My sixth grade teacher Miss Quilter wore thick glasses. She was probably the iconic spinster school teacher. I owe her. She awakened in me a love for learning. I always did well in school before her but after her I excelled. I wanted to know everything. I've told you about my classmate Marty Barrett, and I put him on the list because his travels to England made me want to travel the world. I still call this ache, this wanderlust, Barrett's disease. Most of all I will always owe my parents for their love and encouragement.
The Peace Corps recruiter, to whom I am totally indebted, came to my campus at the end of my junior year, and that was when I took the language test. In those days Peace Corps advertised on TV. Those ads cemented my long time desire to join the Peace Corps. I told no one. I remember my father saying what a waste of a good education. My application was sent in October. The only people who knew were my close friends. I waited and hoped. In January I received a special delivery letter welcoming me into the Peace Corps. Saying yes was easy, telling my father was not.
I became a teacher because of Peace Corps.
I have been retired for nearly fifteen years. I have had a remarkable time. My friends and I get together to celebrate anything we can. In the winter we have game night and in the summer movie night. I remember fondly our Cowboy Day celebration. I have traveled to Africa four times, three of those were to Ghana.
All in all I have been lucky.
When I woke up, it was cloudy. Now the sky is much lighter so there is sun behind those clouds. It is warmish, not quite warm and not quite cold, sort of a Goldilocks day. Rain is predicted for late in the afternoon, starting around five, so this glimpse of light will be gone.
I have an announcement. My forsythia has buds. I saw them this morning, tiny yellow buds. I also saw buds on my wild rose bush. Spring has officially arrived in my front garden.
When I was a kid, I loved when spring arrived. The mornings were glorious, filled with bright sun and the most wonderful smell of flowers. I even skipped to school sometimes. I felt joyful. Sunshine and flowers do that.
Our trip to the vets went far better than I expected. I did have to trap Henry to get his leash on him and sort of pull him to the car, but he rode well and even abided a stop at the bank window. He got a biscuit. He didn't want to go inside the vets. A man held the door for us as Henry wouldn't move. I sort of pushed him. When we got inside, he was far better than I expected. He didn't shake this time. He did pant a bit. Poor Henry did not want to go with the technician. She sort of dragged him. When he came out, he was a happy dog to see me. The tech said he was good when they took blood and cut his nails. Outside afterwards, he jumped into the car. He jumped out when we got home and raced to the front door. What was most surprising was he didn't hate me.
My mind's eye is filled with memories. I can see the hallway of my elementary school, the new school. I can walk down the main road in Bolga, and I can see places in the market like the vegetable auntie's stall, the egg man and the meat seller. I can remember the walk from my house to the classroom block I took every school day. I remember Bill, Peg, Kevin and I on our moto (motorcycle) trips. I remember dinner every night with my friends, and I remember the night sky ablaze with stars.
I am always been thankful for my sharp memory and especially thankful for the part which holds all my adventures.
Today is rainy but warm. The rain is light, mere drops. I can hear them dripping from the roof. It is one of my favorite sounds.
Last night I barricaded the plants by putting chairs in front of them to keep them from Henry. I'd move them if I had place to put them.
I love black jelly beans, but I don't like black licorice. Twizzlers are my favorite red licorice. I never refuse candy with peanut butter though at Easter my mother always bought me a fudge egg, my favorite. Dark chocolate is my first pick. Any other chocolate is my second pick. I loved my mother's brownies. She never used a package so I don't either. Just as she did, I frost them and put on jimmies, sprinkles to the rest of you.
My mother always made pea soup with the ham bone. She'd freeze some for me. I kept the last frozen soup for a long time. I didn't want to eat it knowing she'd never make any more, but I finally did and thought of my mother with each spoonful. She made the best pea soup.
My father used to keep his candy under the couch. He thought it was hidden, but we all knew where it was and helped ourselves. A candy dish was on the table beside where he always sat in the living room. My mother kept it filled usually with Hershey's Miniatures. Mr. Goodbar and Krackle were my favorites. Mr. Goodbar, though, always made me think of the novel Looking for Mr. Goodbar, not so weird an association I guess. When the candy dish was nearly empty, only the milk chocolates were left.
I'm going to the bank today, and this afternoon I'm taking Henry to the vets. He'll hate me for a while, but I haven't any choice. He needs a heart worm test, his nails clipped and more heart worm pills. Poor Henry! Poor me!
Today is a bit chillier than yesterday but is still a lovely day. Earlier I was out on the deck with Henry. He loves the deck and runs back and forth sliding on the wood. He did more plant damage last night. I saw the dirt and found an Africa violet on the floor. I replanted it and am hopeful it will survive. I'll put it on the counter tonight, but I'm thinking Henry might find a different plant.
Today is dump day. I like to go toward the late afternoon, just before 4 as that's when it closes. I loaded the car this morning. My father also always went on Sunday. He loved going to the dump. In those days it was a huge landfill with gulls circling the heaps. You could even see the tallest heaps from the highway. My father would think the current dump boring with all the recycle bins. He'd miss the seagulls.
We are a pet family. When I was a kid, we always had pets. We even had a turtle which lived a long time and some goldfish which lived a very short time. We had a dog and a cat. My sister has two cats but did have a dog, Lucky. My other sister also has two cats. My nephews have a dog and maybe a cat, but I don't remember if they have one or two. My niece has cats and a dog while another nephew has two dogs. This is the first time I've been without a cat, actually multiple cats. I even had one in Ghana I brought home with me. We spoil our pets. Henry knows where all the treats are, and he follows me there with a hopeful look on his face. I usually oblige.
I'm going to make a Sunday dinner for myself. I have some potatoes and vegetables and a pork roast. I'll also be eating it for the next few days, but I'm okay with that.
Today has a bit of spring about it. The wind is gone, the sky is clear blue and the sun brilliant. My dafs are all open, and the grape hyacinths are close. They are both shades of purple, one deeper than the other.
Henry did it again. The life of one house plant was snuffed all too soon. I found a stem and some leaves on the dining room floor, all that's left. The plant was a small one, an offshoot from a larger plant. It was repotted yesterday. Henry found it during his night maneuvers. I'm thinking to move a cactus into the now vacant pot. That plant has been within Henry's reach, but he's left it alone. Smart dog!
A Saturday like today would have had me biking all over town. I'd hit my usual spots, the dairy and maybe the zoo. It was free back then. My favorite at the zoo was the elephant, a baby elephant. I'd also stop at the field where the two horses grazed. They'd come over, and I'd give them some grass. I'd bike uptown and then to the library. I usually got home in the late afternoon.
I had three pairs of shoes when I was a kid. I had school shoes, Sunday shoes and shoes for everything else which were really not shoes but sneakers. I had over the shoe boots, but they were for snow. My Sunday shoes were dressy. My school shoes were utilitarian. One had straps, the other laces. I don't even know how many pairs of shoes I have now. They are stacked on my closet floor and shelf. Some are for winter only while others are for summer. I usually wear my slippers, even outside.
I could star in a last woman on Earth movie. I do hear cars and the mail is delivered, but I haven't seen any people. My dance card is empty and yellowed with age. Henry is my only companion. Strangely enough, though, I'm quite content.
Last night was cold, not chilly but downright cold, in the 30's. Mother Nature has to assert herself more. It's spring's turn.
Today is cloudy: the sky is filled with white, milky clouds. It will be in the low 40's. It's a stay home day. I have everything I need. I'm thinking I'll water the plants, fold my laundry and feed the birds, nothing monumental, nothing needing exertion.
In the small bookcase in my bedroom are the books of my childhood. My mother had saved them for me. Most are in good condition except the Whitman books with cardboard covers. They have split bindings. I think the glue gave up over time. Those books were 49¢. I have several Trixie Belden, Nancy Drew and Donna Parker. I have Heidi, Little Women and Treasure Island. I read all the time back then. Some things don't change.
When I was a kid, when the whole family was together in the car, we had the same seats every time. We mostly sat in the back seat. My brother was in the window seat behind my father. I was at the other window behind my mother. My sister had the hump seat in the middle. My youngest sister sat in the middle of the front seat which in those days was one long seat. The sister between my brother and me was the buffer. He and I fought even in the car. My father did the back swing to try to whack us while still holding on to the steering wheel with the other hand. His aim was never good. We always got out of his way. We quietly chuckled.
I remember going out to dinner with my parents at Mildred's in Hyannis. It was a grand restaurant which has been gone a long while, torn down. One dinner, when I was home from college, my father ordered me a drink, a daiquiri. I was amazed. I drank in college, but that wasn't something I shared with my parents. I'd never had a daiquiri before this. I guess my father thought it the perfect cocktail for me. I thought it was what the ladies in hats drank on the patio on a summer afternoon.
Henry is napping on the couch. He always leans against me.
The sun is bright. The morning air has a bit of a chill but the sort which will disappear as the day grows older. Every now and then the tops of the trees, the bare branches, sway. It is a winsome day.
Henry is a night marauder. He leaves my bed and goes downstairs and is up to no good. This morning it was dirt all over the kitchen floor and a bit on the dining room floor. He had attacked a plant. I also found some chewed paper. Where that came from I don't know. I'm thinking of barricading Henry.
When I was kid, Duke, our dog, wasn't allowed on furniture. He knew that but had ways around it. At night, he'd sleep on the couch and jump off in the morning when he heard footsteps. He'd stretch across the bed and leave only his toes on the floor. He was a sly one.
When I visited my parents for the weekend, I used to go with my father to visit my grandmother in what my father called wrinkle city, better known as apartments for the elderly. I never wanted to go, but I usually gave in to my father. On one visit he told me if I coughed it would be our signal to leave. Where she lived used to be woods when I was a kid. My turtle was buried in those woods. My grandmother was at the age where she repeated. On that visit she told us three times that my aunt had taken her to a restaurant where the Chinaman cut up and cooked dinner at the table. As she started to tell us for the fourth time, I coughed. My father started to laugh which caused him to cough. My grandmother wanted to know if he had a cold. We left shortly after that.
This morning was a lazy morning. Even Henry was quiet and he's now napping. I watered some plants, worked on jigsaw puzzles and looked through catalogs. I watched a couple of disaster movies. The first was a meteor strike which would destroy Earth. The movie on now is about the destruction of the Earth's crust. Lots of bursts of fire from the ground are killing people and destroying towns. I'm always reminded of Frost's poem Fire and Ice. Either will suffice.
Two of my front dafs are just about ready to bloom. The day lilies have sprouted. Everything is growing.
When I was a kid, the future was tomorrow except I knew I'd travel when I was grown. I knew that from the time I was eleven. I loved National Geographic which I read at the library. I have my own subscription now. When I was in grammar school, geography was one of my favorite subjects except I didn't care all that much about about crops and exports. The pictures in my books were beautiful. The Andes and Christ the Redeemer in Rio were in my seventh grade textbook. They stuck with me. I saw both of those. One of my neatest adventures was when I stood with a foot in each hemisphere in Ecuador. Back then there was no monument, no gift shop and no cameraman. I had to imagine the line. That was easy. Christ the Redeemer was huge. It towered on a hill overlooking the city. The Andes were snow covered. I remember flying over them on my way to Cusco. I could see the shadow of the plane on the rocky crags. I was so excited I could have been eleven again.
My dance card is empty for today and the rest of the week. I'm sure it is no surprise I have laundry to do. It is, as usual, leaning against the cellar door, maybe tomorrow.


text:
Welcome To Plathville
Seeking Sister Wife
My 600-lb Life
Teen Mom 2
Before the 90 Days
VIDEO Ultra-rare Merle Haggard prison performance surfaces
Darren O May 11, 2015 Johnny Cash, Johnny Paycheck, Law and Order, Merle Haggard
An astounding live clip by country music icon Merle Haggard of a song he wrote for friend and fellow star Johnny Paycheck has emerged online. This is believed to be the only known performance of the cut entitled "From Inside the Walls."
One of the most legendary and circulated stories in the history of country music involves Merle Haggard, Johnny Cash and San Quentin. Cash performed at the maximum-security California penitentiary and in the crowd, under incarceration for robbery, was a 20-year-old Haggard.
Merle has credited that performance with helping him to turn around his life and seek out a future in the music business. Merle said of Johnny, "He had the right attitude. He chewed gum, looked arrogant and flipped the bird to the guards — he did everything the prisoners wanted to do. He was a mean mother from the South who was there because he loved us. When he walked away, everyone in that place had become a Johnny Cash fan."
Many years later Merle looked to do another legendary artist a favor when he agreed to appear at a special concert by Johnny Paycheck to be filmed and recorded live at Chillicothe State Prison in Ohio. Paycheck, who passed away in 2003, was behind bars at the facility for a barroom fight that broke bad when the "Take This Job and Shove It" singer pulled out a pistol and fired it, grazing his opponent.
Merle made the trip and the show featuring Johnny Paycheck, performing for his fellow inmates, actually happened. Tragically the footage never saw the light of day as the project was shelved by Executive Producer and fellow country music legend Hank Cochran.
Producer, singer and songwriter Billy Don Burns talked in detail about the lost Paycheck performance in a fascinating post shared by TakeCountryBack.com:
"I know that this was one of the greatest events ever captured in recording history. I don't even know why it was me that was chosen to capture it, but it was me. It seemed like everyone in the industry was offended I did the project. It was like "who is this guy? Hell, he don't deserve a project of this magnitude."
The special was to be called Inside the Walls, and it got its name from a song Haggard penned, at Paycheck's request, for the show.
Thanks to hardcore Paycheck fan, Jeffery Allen Cropper, this believed to be one and only performance of "From Inside the Walls" has found its freedom so to speak via YouTube. Cropper was kind enough to share this terrific footage of a tune that stands beside many of Haggard's timeless prison-themed songs.
Merle Haggard "From Inside the Walls" Chillicothe State Prison 6.13.1989:
Merle Haggard "From Inside the Walls" lyrics:
Paid no mind to my momma's fair warning
Never listened to the things daddy said
Never listened to any good friend's advice
Made all the wrong moves instead
I never knew just how good I had it
Working in my bib overalls
I know I'm a loser but I can be a winner
And I'm learning from inside the walls
I'm learning from inside the walls
A man can't get up till he falls
Sometimes there's a light at the end of the tunnel
Sometimes there's no light at all
I know I'm a loser man but I can be a winner
Sometimes it burns ever so small
There are two other clips from the performance circulating online including a great duet by Paycheck and Haggard of Whitey Shafer's "I'll Break Out Again Tonight" (also shared by Cropper) and the rowdy opener "I'm The Only Hell (Momma Ever Raised)."
It's hard to imagine that this show is sitting on a shelf somewhere collecting dust. From what's been shared this is a recording begging to be released. You can get a great idea of what that would look like via the official website of Eric James – who was the production director for the event.
3 PHOTOS Evi Quaid and Randy Quaid Mug Shots
Phaedra Parks' husband Apollo Nida sentenced for fraud charges
MUG SHOTS Teen Mom's Kieffer Delp arrested again
Darren O
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redpajama_set_name: RedPajamaCommonCrawl


text:
Torrubiella is a genus of fungi in the family Cordycipitaceae. The genus was circumscribed by mycologist Jean Louis Émile Boudier in 1885.

The genus name of Torrubiella is in honour of José Torrubia (1698–1761), who was a Spanish naturalist (Geology and paleontology) and clergyman. He was in 1721 a missionary in the Philippines and then Mexico.

Species

References

Hypocreales genera
Cordycipitaceae

redpajama_set_name: RedPajamaWikipedia


text:
China's First Space Station Is 'Out Of Control', And Could Crash Into Earth Any Minute
In 2011, China had ambitiously launched Tiangong-1, their first space station. The satellite station was scheduled for a controlled crash landing in an ocean.
According to an astronomer who spoke to News Australia, it could crash at any any moment
Its re-entry into Earth's atmosphere won't be a controlled landing, but a fiery, molten metal laden crash. Amateur satellite tracker Thomas Dorman told Space.com that he'd been following the satellite using telescopes and cameras, and had spotted a problem with the device.
He said: "If I am right, China will wait until the last minute to let the world know it has a problem with their space station."
"It could be a real bad day if pieces of this came down in a populated area, but odds are it will land in the ocean or in an unpopulated area."
China isn't saying anything – that's the scary bit.
Dean Cheng, a senior research fellow at the Asian Studies Center at the Heritage Foundation, said that China's silence on the matter could means it's already in freefall: "That would seem to suggest that it's not being deorbited under control. That's the implication.
Together 2016 aims to unify 1 million Christians in prayer on National Mall
Thousands Fasting After Russian President Putin Signs Law Banning Evangelism Outside of Churches
Artist releases video guiding Black Americans on how to NOT get shot at a traffic stop


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text:
Q: Inserting and searching data I have the following array:
Array
(
    [0] => &dwA-nTr&
    [1] => @nswt@
    [2] => *DI.2,8*
    [3] => dwA
    [4] => nTr
    [5] => sp
    [6] => fdw
    [7] => @jHj@
    [8] => *DI.2,9*
    [9] => jHj
    [10] => wr
    [11] => sA
    [12] => Hw,t-Hrw
    [13] => jrj
    [14] => sSS,t
    [15] => n
    [16] => mw,t
    [17] => =f
    [18] => wsr,t
    [19] => @nswt@
    [20] => *DI.2,10*
    [21] => nswt-bj,t.j

The goal is to insert this data in a mysql table. Each word starting with '&' is a SCENE; starting with '@' is a DIVINITE and starting with '*' is an ATTESTATION. the other words are regular words. The table has 5 Fields: ID (which is primary key), Word, Attestation, Scene, Divinite. So each regular word has to go in the 'Word' field en the other fields have to be filled with the corresponding info above. So the two first rows should look like this:
ID     Word    Attestation    Scene    Divinite
1      dwA      DI.2,8        dwA-nTr   nswt
2      nTr      DI.2,8        dwA-nTr   nswt
3      sp       DI.2,8        dwA-nTr   nswt
4      fdw      DI.2,8        dwA-nTr   nswt
5      jHj      DI.2,9        dwA-nTr   jHj
6      wr       DI.2,9        dwA-nTr   jHj
7      sA       DI.2,9        dwA-nTr   jHj
8      Hw,t-Hrw DI.2,9        dwA-nTr   jHj
9      jrj      DI.2,9        dwA-nTr   jHj
10     sSS,t    DI.2,9        dwA-nTr   jHj
11     n        DI.2,9        dwA-nTr   jHj
12     mw,t     DI.2,9        dwA-nTr   jHj
13     =f       DI.2,9        dwA-nTr   jHj
14     wsr,t    DI.2,9        dwA-nTr   jHj
15     nswt-bj,t.j  DI.2,10   dwA-nTr   nswt

for this i wrote the following:
mysql_select_db("my_db", $con);
$SceneTitle = $InitSceneTitle;
foreach($TextsansBracRenumer as $word)
{
if ($word[0] === "@")
        {
        $Divinite = str_replace("@", "", $word);
        }
if ($word[0] === "&")
        {
        $SceneTitle = str_replace("&", "", $word);
        }
if ($word[0] === "*")
        {
        $position = str_replace("*", "", $word);
        }
else
        {
        $SceneInfo = $position;
        $insert="INSERT INTO Words (Word, Attestation, Scene, Divinite) VALUES ('$word', '$position', '$SceneTitle', '$Divinite')";
        mysql_query($insert) OR die(mysql_error());
}

and this is working fine.
But when I want to search the data, trouble starts.
I wrote the following (table is called Words)
mysql_select_db("my_db", $con);
$search = "SELECT Word, Scene, Attestation, Divinite
    FROM Words
    WHERE Word = '$target'  ";

$retval = mysql_query($search, $con);
if(! $retval )
{
die('Could not get data: ' . mysql_error());
}
while($row = mysql_fetch_array($retval, MYSQL_ASSOC))
{
echo
     "{$row['Attestation']} <br> ";
}

So for word X  he will give me the attestation. So if I replace $target with the word 'dwA' he will give me 'DI.2,8'
And if I replace the last sentence "{$row['Attestation']} by "{$row['Divinite']} he will give me 'nswt'. and so on.
This works well, but when I want I replace the search
$search = "SELECT Word, Scene, Attestation, Divinite
    FROM Words
    WHERE Word = '$target'  ";

by
  $search = "SELECT Word, Scene, Attestation, Divinite
    FROM Words
    WHERE Scene = '$target'  ";

it doesn't work. So if I replace $target with dwA-nTr he should give me twice DI.2,8.
and it doesn't work for Attestation or for Divinite. In fact it only works for Word.
I try to insert the data manualy and than it works. So it seems not to be in the search program but rather in the way the data is put into the table.
Does anyone have an idea how to input the data in another manner? so that this would work
I think I found the problem but not the solution. I exported the database with SQL and this is what I get:
CREATE TABLE `Words` (
`ID` mediumint(15) NOT NULL AUTO_INCREMENT,
`Word` varchar(15) NOT NULL,
`Attestation` varchar(15) NOT NULL,
`Scene` varchar(15) NOT NULL,
`Divinite` varchar(15) NOT NULL,
PRIMARY KEY (`ID`)
) ENGINE=InnoDB  DEFAULT CHARSET=latin1 AUTO_INCREMENT=22 ;

--
-- Dumping data for table `Words`
--

INSERT INTO `Words` VALUES(3, 'dwA', 'DI.2,8\r', 'dwA-nTr\r', 'nswt\r');
INSERT INTO `Words` VALUES(4, 'nTr', 'DI.2,8\r', 'dwA-nTr\r', 'nswt\r');
INSERT INTO `Words` VALUES(5, 'sp', 'DI.2,8\r', 'dwA-nTr\r', 'nswt\r');
INSERT INTO `Words` VALUES(6, 'fdw\r', 'DI.2,8\r', 'dwA-nTr\r', 'nswt\r');
INSERT INTO `Words` VALUES(8, 'jHj', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(9, 'wr', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(10, 'sA', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(11, 'Hw,t-Hrw', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(12, 'jrj', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(13, 'sSS,t', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(14, 'n', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(15, 'mw,t', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(16, '=f', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(17, 'wsr,t\r', 'DI.2,9\r', 'dwA-nTr\r', 'jHj\r');
INSERT INTO `Words` VALUES(19, 'nswt-bj,t.j', 'DI.2,10\r', 'dwA-nTr\r', 'nswt\r');
INSERT INTO `Words` VALUES(21, 'Hnk', 'DI.9,8', 'Hnk-wnHr', 'jHj');

as you can see  after each 'Attestation', 'Scene' and 'Divinite' comes a \r. This explains problably why I can search for example the word 'dwA' but not the scene dwA-nTr. but searching on dwA-nTr\r doesn't work either.
BUt as you can see in 21, the row I inserted manualy, this \r is absent

A: I'm still studying your post, but can we start with this?:
foreach($TextsansBracRenumer as $word)
{ # changed to else..if since $word[0] is only one value, right? let me know
    if ($word[0] === "@")
    {
    $Divinite = str_replace("@", "", $word);
    }
    else if ($word[0] === "&")
    {
    $SceneTitle = str_replace("&", "", $word);
    }
    else if ($word[0] === "*")
    {
    $position = str_replace("*", "", $word);
    }
}
# just imagining pulling this out of your code, assuming that the foreach above handled the word-processing
$SceneInfo = $position;
$insert="INSERT INTO Words (Word, Attestation, Scene, Divinite) VALUES ('$word', '$position', '$SceneTitle', '$Divinite')";
mysql_query($insert) OR die(mysql_error());

I'd like to ask for more code, like:
what is the value of $InitSceneTitle ?
what is the value of $TextsansBracRenumer ?
[edit][based on new information : inserted row data]
Try replacing this:
$Divinite = str_replace("@", "", $word);

With this:
$Divinite = str_replace("\n",'', str_replace("\r",'', str_replace("@", "", $word)));

It seems that the data in your array contains new line and carriage return characters, represented by \n and \r respectively.. You'll have to replace those. What this brings to light is... How is the array populated with data? Because if we're not careful, then those two   (\n and \r) might have to or should remain in your data. If that's the case, then we will change our approach.
For now.. do the same for the word, scene, and attestation. And then perform your search again.. Let me know what happens...

redpajama_set_name: RedPajamaStackExchange


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A historic total solar eclipse arced across the United States from west to east Monday, as millions of people who gathered in its relatively narrow path of totality watched in awe.
The total solar eclipse was first visible in the U.S. over Lincoln City, Oregon. Crowds of people donning special solar filters cheered and roared as the moon completely blocked the sun and cast a 70-mile wide shadow that traveled from Oregon to South Carolina.
Briefly, various U.S. cities plunged into darkness, and temperatures dropped as much as 12 degrees. The sun's corona, or outer atmosphere, which is usually obscured by glare, appeared as a ring of ethereal white wisps around the moon while it blocked the sun.
In areas with clear skies, bright stars and planets appeared in the darkened daytime sky. And as the sun re-emerged from behind the moon, it created an astonishing diamond ring effect, with one bright spot of the sun shining at one end of the corona.
A total solar eclipse occurs when the moon moves directly between the sun and Earth, lasting up to three hours. Monday's total solar eclipse was particularly rare because it was the first time in 99 years that the path of totality exclusively crossed the continental United States. It was the first continent-wide eclipse to be visible only from the U.S. since 1776.
The last time the contiguous United States saw a total solar eclipse was Feb. 26, 1979, when the path of totality crossed the Pacific Northwest. ABC News' Frank Reynolds anchored a special report on the celestial phenomenon at the time and pledged that the network would cover the next total solar eclipse in 2017.
"So that's it, the last solar eclipse to be seen on this continent in this century. And as I said, not until Aug. 21, 2017, will another eclipse be visible from North America. That's 38 years from now. May the shadow of the moon fall on a world in peace. ABC News, of course, will bring you a complete report on that next eclipse 38 years from now," Reynolds said before signing off.
A total solar eclipse is visible only within a band called the path of totality. NASA estimated that more than 300 million people in the United States could have viewed Monday's total solar eclipse.
However, a partial solar eclipse was visible in every U.S. state. In fact, all of North America, as well as parts of South America, Africa and Europe, had a view of at least a partial eclipse, according to NASA.
The path of totality for Monday's solar eclipse crossed the United States from west to east, sweeping over portions of 14 U.S. states: Oregon, Idaho, Wyoming, Montana, Nebraska, Iowa, Kansas, Missouri, Illinois, Kentucky, Tennessee, Georgia, North Carolina and South Carolina.
The moon started to eclipse the sun over the West Coast just after 9 a.m. PT. From there, it raced across the country and left the East Coast just after 4 p.m. ET.
The exact times for partial and total phases of Monday's eclipse varied, depending on one's location.
With millions of people pouring into the U.S. cities within the path of totality, law enforcement, emergency personnel and hospitals there were on high alert.
Oregon alone anticipated a million visitors Monday, leading some local hospitals to cancel elective surgeries and call in extra help for emergency rooms. Some cities even pre-emptively declared a state of disaster, which allows the National Guard to help direct large crowds if needed.
"If a police department in a certain area is overwhelmed and they need us to help come and set up traffic control check points, we're ready to do that," Oregon National Guard spokesperson Leslie Reed told ABC News.
More than than 17,000 cars and SUVs were rented for Monday at Oregon's Portland International Airport — normally the number of rentals for an entire week.
In northeastern Georgia, the mountain town of Blairsville expected to host up to 200 percent more people than the number of residents. The town's hotels were fully booked, and camping sites were sold out for Monday.
The American Red Cross set up resources along the path of totality to help keep people safe during the rare celestial event.
"One thing is we really encourage folks to have in their cars an emergency go kit, and that should include things like water, nonperishable foods, a flashlight with batteries and an envelope with cash," said Josh Lockwood, the Greater New York regional CEO for the American Red Cross.
ABC News' Steve Osunami, Gina Sunseri and Ariella Weintraub contributed to this report.
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Q: Is there a typeguard syntax for restricting a class property to integer? I have an application which uses a lot of currency values, and several classes which reflect 'money' properties.
I plan on storing everything as integers and only converting to a decimal representation in views.
Is some property declaration guard syntax I can use to to ensure at compile time, that an error will be flagged by an attempt to assign a regular number which can't be certain isn't an integer to one of these fields?
For example:
 class Account {
     name: string
     private balance : integer = 0;
     maxWithdrawal: integer = 0;
     maxOverdraft : integer = 0;
     ...

     deposit(amount : number) {
         this.balance += deposit;   // flags some kind of "deposit may not be an integer" error.
     }

 }

A: BigInt currently is the only Integer type (apart from fixed sets like 1|2|3). What TS maintainers say:

BigInt seems like a "close enough" fit for these use cases and doesn't require us inventing new expression-level syntax.

Here are two possible solutions:
1.) BigInt
class AccountBigInt {
  private balance: bigint = 4n;

  deposit(deposit: bigint) {
    this.balance += deposit;
  }
}

const a = new AccountBigInt()
a.deposit(3n)
// a.deposit(3.3n) // error
// a.deposit(3.3)  // error

2.) Branded Integer type
type Integer = number & { __brand__: "__integer__" } // branded primitive type

// use this as the only way / factory method to create an Integer type
const int = (val: number): Integer => {
  if (Number.isInteger(val)) return val as unknown as Integer
  throw Error("val is not an integer.")
}

const i1 = int(3)
const i2 = int(3.3) // throws at run-time
const sum = int(3) + int(4) // works, Integer is a subtype of number

class AccountBranded {
  private balance: Integer = int(4);

  deposit(deposit: Integer) {
    // wrap with int(), because this.balance + deposit returns number
    // you also could create an add function for Integer
    this.balance = int(this.balance + deposit)
  }
}

const a2 = new AccountBranded()
a2.deposit(int(3)) // works
a2.deposit(3) // error, number not assignable to Integer (OK)

Code sample

Update: On BigInt support
Currently, BigInt isn't adopted widely (2020-01-10). As far as I know, there is no "real" polyfill library out there - it would have to change the core JS logic for operators like +, - and others. That would be a fairly sophisticated approach!
A well-known approach is to use JSBI library (see also here). Once BigInt support is better, you can transpile back to native BigInt without rewriting your code using a babel plugin.

A: No, there is no built-in type that restricts values to be integers in TypeScript.
As such, there is no way to catch such errors at compile time.
If you want, you can check for integers at run time.
You could make your own "boxed" integer, and use Number.isInteger() to ensure the boxed value is an integer. For example:
class BoxedInteger {
  public readonly value: number;

  public constructor(value: number) {
    if (!Number.isInteger(value)) {
      throw new Error(`Number is not an integer: ${value}`);
    }
    this.value = value;
  }
}

const a = new BoxedInteger(5).value; // ok, a = 5
const b = new BoxedInteger(5.5).value; // error!

[*] Note:
keep in mind the limitations of Number.isInteger()
For example: Number.isInteger(5.0000000000000001); // true
https://developer.mozilla.org/en-US/docs/Web/JavaScript/Reference/Global_Objects/Number/isInteger


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