The efficacy of Carbamylglutamate impacts the nutritional management of patients with N-Acetylglutamate synthase deficiency.

BACKGROUND: The autosomal recessive disorder N-acetylglutamate synthase (NAGS) deficiency is the rarest defect of the urea cycle, with an incidence of less than one in 2,000,000 live births. Hyperammonemic crises can be avoided in individuals with NAGS deficiency by the administration of carbamylglutamate (also known as carglumic acid), which activates carbamoyl phosphatase synthetase 1 (CPS1). The aim of this case series was to introduce additional cases of NAGS deficiency to the literature as well as to assess the role of nutrition management in conjunction with carbamylglutamate therapy across new and existing cases. METHODS: We conducted retrospective chart reviews of seven cases of NAGS deficiency in the US and Canada, focusing on presentation, diagnosis, medication management, nutrition management, and outcomes. RESULTS: Five new and two previously published cases were included. Presenting symptoms were consistent with previous reports. Diagnostic confirmation via molecular testing varied in protocol across cases, with consecutive single gene tests leading to long delays in diagnosis in some cases. All patients responded well to carbamylglutamate therapy, as indicated by normalization of plasma ammonia and citrulline, as well as urine orotic acid in patients with abnormal levels at baseline. Although protein restriction was not prescribed in any cases after carbamylglutamate initiation, two patients continued to self-restrict protein intake. One patient experienced two episodes of hyperammonemia that resulted in poor long-term outcomes. Both episodes occurred after a disruption in access to carbamylglutamate, once due to insurance prior authorization requirements and language barriers and once due to seizure activity limiting the family's ability to administer carbamylglutamate. CONCLUSIONS: Follow-up of patients with NAGS deficiency should include plans for illness and for disruption of carbamylglutamate access, including nutrition management strategies such as protein restriction. Carbamylglutamate can help patients with NAGS deficiency to liberalize their diets, but the maximum safe level of protein intake to prevent hyperammonemia is not yet known. Patients using this medication should still monitor their diet closely and be prepared for any disruptions in medication access, which might require immediate dietary adjustments or medical intervention to prevent hyperammonemia.

The relationship between working memory and anxiety in individuals with early treated phenylketonuria (PKU).

OBJECTIVE: Although early diagnosis and treatment prevent the severe impairments associated with untreated phenylketonuria (PKU), individuals with early treated PKU (ETPKU) nonetheless experience significant neurocognitive and psychological sequelae, including difficulties in working memory (WM) and increased risk of anxiety. The primary objective of the present study was to examine the extent to which anxiety may moderate the relationship between ETPKU and WM performance. METHOD: A sample of 40 adults with ETPKU and a demographically comparable sample of 40 healthy adults without PKU completed a comprehensive assessment of WM performance and anxiety symptomatology. Data were collected using a variety of remote assessment methods (e.g., web-based neurocognitive tests, semistructured interview, report-based measures). RESULTS: The ETPKU group demonstrated significantly poorer WM performance as compared to the non-PKU group. The groups did not differ significantly in anxiety; however, high anxiety was more common in the ETPKU group (53% of sample) than the non-PKU group (33%). A significant interaction between anxiety, metabolic control (as reflected by Phe levels), and WM performance was observed for the ETPKU group. Individuals with high anxiety and/or high Phe levels (> 360 µmol/L) performed poorer than the non-PKU group. Individuals with low anxiety and relatively low Phe levels (< 360 µmol/L) performed comparably to the non-PKU group. CONCLUSIONS: Anxiety was found to moderate the relationship between Phe levels and WM performance in individuals with ETPKU. This finding underscores the importance of accounting for anxiety when evaluating neurocognitive performance in individuals with ETPKU whether for research or clinical purposes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells.

TROP2 is a powerful cancer driver in colorectal cancer cells. Divergent epigenetic regulation mechanisms for the corresponding TACSTD2 gene exist such as miRNAs or DNA methylation. However, the role of TACSTD2 promoter hypermethylation in colorectal cancer has not been investigated yet. In this study, TROP2 expression strongly correlated with promoter methylation in different colorectal tumor cell lines. Treatment with 5-Azacytidine, a DNMT1 inhibitor, led to demethylation of the TACSTD2 promoter accompanied by an increase in TROP2 protein expression. TROP2 expression correlated with promoter methylation in vivo in human colon tumor tissue, thereby verifying promoter methylation as an important factor in the regulation of TROP2 expression in colorectal cancer. When performing a ChIP-Seq analysis in HCT116 and HT29 cells, we found that TACSTD2 promoter demethylation was accompanied by tri-methylation of H3K4. In silico analysis of GSE156613 data set confirmed that a higher binding of histone mark H3K4me3 around the TACSTD2 promoter was found in TACSTD2 high expressing tumors of colon cancer patients compared to the corresponding adjacent tumor tissue. Moreover, the link between TROP2 and the H3K4me3 code was even evident in tumors showing high intratumoral heterogeneity for TROP2 staining. Our data provide novel evidence for promoter demethylation and simultaneous gains of the active histone mark H3K4me3 across CpG-rich sequences, both being complementary mechanisms in the transcriptional regulation of TACSTD2 in colon cancer. The functional consequences of TROP2 loss in colorectal cancer needs to be further investigated.

Total choline intake and working memory performance in adults with phenylketonuria.

BACKGROUND: Despite early diagnosis and compliance with phenylalanine (Phe)-restricted diets, many individuals with phenylketonuria (PKU) still exhibit neurological changes and experience deficits in working memory and other executive functions. Suboptimal choline intake may contribute to these impairments, but this relationship has not been previously investigated in PKU. The objective of this study was to determine if choline intake is correlated with working memory performance, and if this relationship is modified by diagnosis and metabolic control. METHODS: This was a cross-sectional study that included 40 adults with PKU and 40 demographically matched healthy adults. Web-based neurocognitive tests were used to assess working memory performance and 3-day dietary records were collected to evaluate nutrient intake. Recent and historical blood Phe concentrations were collected as measures of metabolic control. RESULTS: Working memory performance was 0.32 z-scores (95% CI 0.06, 0.58) lower, on average, in participants with PKU compared to participants without PKU, and this difference was not modified by total choline intake (F[1,75] = 0.85, p = 0.36). However, in a subgroup with complete historical blood Phe data, increased total choline intake was related to improved working memory outcomes among participants with well controlled PKU (Phe = 360 µmol/L) after adjusting for intellectual ability and mid-childhood Phe concentrations (average change in working memory per 100 mg change in choline = 0.11; 95% CI 0.02, 0.20; p = 0.02). There also was a trend, albeit nonsignificant (p = 0.10), for this association to be attenuated with increased Phe concentrations. CONCLUSIONS: Clinical monitoring of choline intake is essential for all individuals with PKU but may have important implications for working memory functioning among patients with good metabolic control. Results from this study should be confirmed in a larger controlled trial in people living with PKU.

Healthcare Professionals' Knowledge of and Attitudes Towards the Use of Time in Range in Diabetes Management: Online Survey Across Seven Countries.

INTRODUCTION: Time in range (TIR) is a metric of glycaemic target management derived from continuous glucose monitoring (CGM) data. This study aimed to understand knowledge of and attitudes towards use of TIR among healthcare professionals (HCPs), and gain insights into benefits and barriers to its use in clinical practice. METHODS: An online survey was disseminated across seven countries. Participants were sampled from online HCP panels and were aware of TIR (defined as amount of time in, below, and above target range). Participants were HCPs classified as specialists (SP), generalists (GP), or allied HCPs (AP; diabetes nurse specialists, diabetes educators, general nurses, nurse practitioners/physician assistants). RESULTS: Respondents included 741 SP, 671 GP and 307 AP. Most HCPs (approximately 90%) agreed TIR is likely/somewhat likely to become the standard of diabetes management. Perceived benefits of TIR included helping to optimise medication regimen (SP, 71%; GP, 73%; AP, 74%), giving HCPs the knowledge and insights to make informed clinical decisions (SP, 66%; GP, 61%; AP, 72%), and empowering people with diabetes with information to successfully manage their diabetes (SP, 69%; GP, 77%; AP, 78%). Barriers to wider adoption included limited CGM access (SP, 65%; GP, 74%; AP, 69%) and lack of HCP training/education (SP, 45%; GP, 59%; AP, 51%). Most participants considered integration of TIR into clinical guidelines, recognition of TIR by regulators as a primary clinical endpoint, and recognition of TIR by payers as a parameter for diabetes treatment evaluation as key factors for increased use. CONCLUSIONS: Overall, HCPs agreed on the benefits of using TIR for diabetes management. Besides raising awareness among HCPs and people with diabetes, more training and healthcare system updates are needed to facilitate increased TIR use. In addition, integration into clinical guidelines and recognition by regulators and payers are needed.

'Time in range' is the proportion of time in a day that a person's glucose level is within a particular range. The purpose of this study was to understand knowledge of and attitudes towards use of TIR among healthcare professionals. The study was carried out using an online survey and participants from seven countries were included. Participants were healthcare professionals classified as specialists (SP), generalists (GP), or allied healthcare professionals (AP; diabetes nurse specialists, diabetes educators, general nurses, nurse practitioners, or physician assistants). Overall, 1719 participants were included in the study. Most healthcare professionals (approximately 90%) agreed that time in range is likely/somewhat likely to become the standard of diabetes management. Participants reported the following benefits of time in range: helping to optimise medication regimen, giving healthcare professionals the knowledge and insights to make informed clinical decisions, and empowering people with diabetes with information to successfully manage their diabetes. The most common barrier to wider time in range adoption was limited access to continuous glucose monitoring (SP, 65%; GP, 74%; AP, 69%), followed by lack of healthcare professionals' training/education (SP, 45%; GP, 59%; AP, 51%). Most participants considered integration of time in range into clinical guidelines, recognition of time in range by regulators as a primary clinical endpoint, and recognition of time in range by payers as a parameter for evaluation of diabetes treatment as key factors for the increased use of time in range.

Nutrition management of PKU with pegvaliase therapy: update of the web-based PKU nutrition management guideline recommendations.

BACKGROUND: The web-based GMDI/SERN PKU Nutrition Management Guideline, published before approval of pegvaliase pharmacotherapy, offers guidance for nutrition management of individuals with phenylketonuria (PKU) treated with dietary therapy and/or sapropterin. An update of this guideline aims to provide recommendations that improve clinical outcomes and promote consistency and best practice in the nutrition management of individuals with PKU receiving pegvaliase therapy. Methodology includes: formulation of a research question; review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature; expert input through Delphi surveys and a Nominal Group process; and external review by metabolic experts. RESULTS: Recommendations, summary statements, and strength of evidence are included for each of the following topics: (1) initiating a pegvaliase response trial, (2) monitoring therapy response and nutritional status, (3) managing pegvaliase treatment after response to therapy, (4) education and support for optimal nutrition with pegvaliase therapy, and (5) pegvaliase therapy during pregnancy, lactation, and adolescence. Findings, supported by evidence and consensus, provide guidance for nutrition management of individuals receiving pegvaliase therapy for PKU. Recommendations focus on nutrition management by clinicians, as well as the challenges for individuals with PKU as a result of therapy changes. CONCLUSIONS: Successful pegvaliase therapy allows the possibility for individuals with PKU to consume an unrestricted diet while still maintaining the benefits of blood phenylalanine control. This necessitates a perspective change in education and support provided to individuals in order to achieve healthy nutrient intake that supports optimal nutritional status. The updated guideline, and companion Toolkit for practical implementation of recommendations, is web-based, allowing for utilization by health care providers, researchers, and collaborators who advocate and care for individuals with PKU. These guidelines are meant to be followed always taking into account the provider's clinical judgement and considering the individual's specific circumstances. Open access is available at the Genetic Metabolic Dietitians International ( https://GMDI.org ) and Southeast Regional Genetics Network ( https://managementguidelines.net ) websites.

Characterization of Choline Nutriture among Adults and Children with Phenylketonuria.

Choline is an essential nutrient for brain development and function that is attained through high-protein foods, which are limited in the phenylalanine-restricted diet of people with phenylketonuria (PKU). This study compared choline consumption among individuals with PKU to a reference sample from the National Health and Nutrition Examination Survey (NHANES), and identified treatment and diet-related factors that may modulate choline needs. Participants were individuals with PKU (n = 120, 4-61 years) managed with dietary therapy alone (n = 49), sapropterin dihydrochloride for ≥1 year (n = 38), or pegvaliase for ≥1 year with no medical food (n = 33). NHANES participants were not pregnant or nursing and came from the 2015-2018 cycles (n = 10,681, 4-70 years). Dietary intake data were used to estimate total usual intake distributions for choline, and mean probability of adequacy (MPA) was calculated as a summary index of nutrient adequacy for four methyl-donor/co-factor nutrients that impact choline utilization (folate, vitamin B12, vitamin B6, and methionine). Only 10.8% (SE: 2.98) of the total PKU sample (14.7% [SE: 4.03] of children; 6.8% [SE: 2.89] of adults) achieved the adequate intake (AI) for choline, while 12.2% (SE:0.79) of the NHANES sample met the recommended level. Adults receiving pegvaliase were the most likely to exceed the AI for choline (14.82% [SE: 4.48]), while adults who were on diet therapy alone were the least likely (5.59% [SE: 2.95]). Without fortified medical foods, individuals on diet therapy and sapropterin would not be able to achieve the AI, and MPA for other methyl donor/co-factor nutrients would be reduced. More frequent monitoring of choline intake and increased choline fortification of medical foods could benefit this population.

Enhancing Hospital Accreditation Practices: Building and Implementing a Continuous Readiness Model.

Accreditation Canada is moving from a three-to-five-year assessment cycle to a continuous assessment program. As our organization shifted to a culture of continuous readiness, we aimed to develop a model that would support a seamless transition. To develop our model, we completed a literature review, environmental scan and an organizational needs assessment. Grounded in quality management theory, our continuous readiness model includes overarching supporting infrastructure and tasks, tools and initiatives to embed the principles of continuous readiness across the organization. Our model provides organizations with a practical, evidence-informed process to support a state of continuous readiness for accreditation.

Lagophthalmos: An etiological lookout to frame the decision for management.

Purpose: To describe the etiology, clinical profile, duration of lagophthalmos cases and thereby, framing a decision for the management based on the severity of Exposure keratitis (EK), Facial palsy (FP) with each etiology and to describe the outcome of the management options. Methods: The method was a prospective review of 120 lagophthalmos cases treated at a single tertiary center from January 2018 to January 2019. The main outcome measures were analysing the association between age, etiology, duration and management of lagophthalmos. Results: Of the 120 patients studied, paralytic etiology was noted in 86 and eyelid etiology in 34 patients. The percentage of various lagophthalmos etiology documented were Bell's palsy (35.83%), lagophthalmos in ICU patients (15%), traumatic facial palsy(FP) (10.80%), stroke associated FP (6.67%), infection associated FP (6.67%), iatrogenic FP, cicatricial lagophthalmos (5%), lagophthalmos post eyelid surgeries (5%), neoplastic FP(3.33%), congenital FP (1.67%), proptosis induced lagophthalmos (1.67%), floppy eyelid syndrome induced lagophthalmos (0.83%) and lid coloboma associated lagophthalmos (0.83%). A statistically significant correlation was noted between exposure keratitis and age, with an increased prevalence age advances. The management showed significant variation with individual etiology, with some etiologies unquestionably requiring surgical management. Surgical management is crucial as the duration of lagophthalmos increases more than 6 weeks, EK involving pupillary axis and poor FP recovery. Conclusion: This study concludes that the conservative management was sufficient in all cases when the duration is less than 1 week, Exposure keratitis not involving the pupillary axis (EK< Grade II) and FP with good functional recovery ( FP < Grade III). The predominant causes being Bell's palsy, lagophthalmos in ICU patients and vascular FP. Whereas, cases with poor functional recovery of facial palsy(FP) and permanent eyelid deformation require definitive surgical management like Traumatic FP & cicatricial lagophthalmos.

Breastfeeding practices for infants with inherited metabolic disorders: A survey of registered dietitians in the United States and Canada.

Background: Breast milk is considered the optimal first food for infants. Breastfeeding infants with inherited metabolic disorders (IMDs) is complex due to the critical need to manage intake of specific macronutrients depending on the type of IMD. Objective: To describe current practices of registered dietitians (RD) who treat patients with IMDs regarding the incorporation of breastmilk into disease management. Design: Cross-sectional survey.Participants/setting:online survey conducted in December 2020 of 66 RDs who treat patients with IMDs in the United States and Canada.Main outcome measures:the survey focused on personal demographics, clinic characteristics, institutional feeding protocols for infants with IMDs, confidence in working with breastfeeding parents of infants with IMDs, and knowledge about breastfeeding with questions derived from the Iowa Infant Feeding Attitudes Scale.Statistical analysis performed:.Fisher's exact test was used for comparisons. Results: Most RDs were confident or very confident in their ability to provide nutritional guidance for breastfeeding infants with IMDs. Half of the participants reported that they had received training on breastfeeding of infants of IMDs. For infants with phenylketonuria (PKU), most RDs include breastfeeding as part of nutritional management. Breastfeeding is less likely to be used in the management of infants with other aminoacidopathies and fatty acid oxidation disorders. Use of measured expressed breastmilk was preferred, including for aminoacidopathies other than PKU, organic acidemias, and fatty acid oxidation disorders. Knowledge about breastfeeding varied. Less than half of RDs referred mothers to a lactation specialist somewhat regularly or frequently. Conclusions: Our survey found variation in experience, training, and use of breastfeeding-related nutritional management protocols in IMDs. A lack of formal training programs for the nutritional management of IMDs may account for some of this variation. Future research, including the collection of more detailed disorder-specific data, could help contribute to the development of clinical practice guidelines.

Cross-sectional survey on primary care medical doctors' practices on oral health care in pregnancy and its association with knowledge and attitude.

INTRODUCTION: Oral health care is an important indicator of the overall wellbeing of pregnant women. Optimizing the utilisation of dental care during pregnancy goes a long way in ensuring an improved and optimal pregnancy outcome. OBJECTIVE: This study aimed to assess the practices of primary care doctors on oral health care in pregnancy and its association with the level of knowledge and attitude. MATERIALS AND METHODS: This cross-sectional study was conducted among primary care doctors in nine public health clinics in Petaling District. A self-administered questionnaire consisting of socio-demographic characteristics, knowledge, attitude, and practices related to oral health care in pregnancy was used. RESULTS: A total of 138 primary care doctors participated in this study with a response rate of 98.0%. Most primary care doctors frequently advised patients not to delay dental visits until after pregnancy (84.8%), advised patients to see dentists (69.7%), and referred patients to dentists during pregnancy (63.6%). However, only 18.9% perform assessments routinely to detect oral health issues. The median (IQR) score for knowledge was 17(4) (range score: 0-23) and attitude was 23(3) (range score: 6-30). Knowledge median score (p:0.026) and practices of referring patients to dentists (p:0.017) were significantly associated. There was a positive correlation between overall practices of primary care doctors and their age, years of experience, and knowledge. CONCLUSION: Most primary care doctors frequently advise and refer pregnant patients to see dentist. Primary care doctors with higher knowledge score, who were older and had more experience, had better overall practices on oral health care in pregnancy.

Using Informatics to Build a Digital Health Footprint of Patients Living With Inherited Metabolic Disorders Identified by Newborn Screening.

Newborn screening is a process identifying people with inherited metabolic disorders (IMDs) at birth, but these patients are often lost to follow-up, and limited data on their long-term needs are available to advocate for policies that will help this vulnerable community. Using informatics best practices, the Medical Nutrition Therapy for Prevention (MNT4P) program and the Public Health Informatics Institute successfully deployed a minimally viable product-that is, the most basic working version that is scalable-allowing for lifelong patient follow-up and outcome and needs tracking, and that can address national data gaps. The new system offers a HIPAA-compliant, efficient record-keeping system that allows data standardization and harmonization. MNT4P staff have transitioned completely away from former manual processes and are relying on this system to log and track patient information. Other programs serving patient populations burdened with rare, marginalized diseases also may benefit from this work.

Plasma metabolomic profile changes in females with phenylketonuria following a camp intervention.

BACKGROUND: There remains a limited understanding of the metabolic perturbations, beyond phenylalanine (Phe) metabolism, that contribute to phenotypic variability in phenylketonuria (PKU). OBJECTIVES: This study aimed to characterize changes in the PKU plasma metabolome following a 5-d metabolic camp intervention and to compare PKU profiles with those of matched healthy controls. METHODS: In 28 females (aged 12-57 y), fasting plasma samples were collected on the first (day 1) and final (day 5) days of camp to measure metabolic control and to complete untargeted metabolomic profiling. Three-day dietary records were collected to assess changes in dietary adherence and composition. Univariate (Wilcoxon signed-rank and Mann-Whitney U test) and multivariate (random forest, hierarchical clustering) analyses were performed to identify clinical and metabolic features that were associated with the intervention and disease state. RESULTS: Relative to healthy controls, Phe catabolites, ketones, and carnitine- and glycine-conjugated fatty acids were elevated in females with PKU at baseline, whereas fatty acylcholine metabolites were substantially lower. After the camp intervention, plasma Phe concentrations decreased [median change: -173 µmol/L (IQR: -325, -28 µmol/L)] and 70% of PKU participants demonstrated improved dietary adherence by decreasing Phe intake and/or increasing medical food consumption. This was accompanied by a shift in abundance for 223 metabolites (q < 0.05). Compounds associated with the metabolism of Phe, fatty acids, and choline contributed most to profile differences between camp days 1 and 5. CONCLUSIONS: In females with PKU, untargeted metabolomics identified prominent perturbations in amino acid and lipid metabolites associated with bioenergetic impairment and oxidative stress. Choline-conjugated lipids could have fundamental roles in these pathways and they have not been previously evaluated in PKU. A short-term camp intervention was effective for improving or fully normalizing the abundance of the identified discriminatory metabolites.

Natural history of children and adults with phenylketonuria in the NBS-PKU Connect registry.

PURPOSE: Phenylalanine hydroxylase deficiency, or phenylketonuria (PKU), is a rare autosomal recessive metabolic disorder. Early diagnosis via newborn screening (NBS) and initiation of treatment prevent the development of cognitive impairment and other co-morbidities. The purpose of this study is to describe the natural history of PKU in the United States, including prevalence of co-morbidities and predictors of outcomes. METHODS: We analyzed data from a self-report survey in the NBS-PKU Connect online registry. We describe the participants' nutrition management strategies, barriers to management, outcomes of bone disorders, skin, and psychological co-morbidities, and the use of special education or other special services. Predictors of outcomes were identified and assessed, including the impact of sex, age, age at diagnosis, blood phenylalanine concentration, use of sapropterin, use of medical food, adherence to prescribed diet, use of low protein modified foods, whether they had ever been off-diet, and use of tyrosine supplementation. RESULTS: The 219 respondents included individuals with PKU or hyperphenylalanemia (n = 78), or their caregivers (n = 141). Most (84.3%) started treatment before the age of two weeks. About one-third indicated that they had been off-diet at some point in their lives, and 81.4% reported that they currently adhered to their prescribed diet, with adherence to prescribed diet decreasing with age. Blood phenylalanine concentration was under the recommended threshold of 360 µmol/L for 68.5% of participants. One-quarter of respondents reported psychological co-morbidities, with anxiety and ADD/ADHD being the most common. The incidence of psychological co-morbidities increased with age and with ever having been off diet. Special education or other special services were more likely to be reported by individuals who were diagnosed after one week of age. Skin disorders such as acne and eczema were more common in females than males, and a minority of participants reported bone disorders. CONCLUSIONS: Despite recommendations to maintain blood phenylalanine concentrations in the therapeutic range throughout life, it is not uncommon for adults with PKU to discontinue dietary management of their disorder. Early diagnosis was associated with reduced need for special education or other special services, and continuous treatment was associated with decreased psychological co-morbidities.

Effect of Amlodipine in Stroke and Myocardial infarction: A Systematic Review and Meta-analysis.

INTRODUCTION: Hypertension is a progressive cardiovascular condition arising from complex aetiologies. Progression is strongly associated with functional and structural abnormalities that lead to multi-organ dysfunction. Stroke and myocardial infarction are two of the major complications of hypertension in India. Various anti-hypertensive drugs, such as calcium channel blockers (CCBs), beta-blockers, diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, have been the medications of choice for disease management and are known to be effective in reducing the complications of hypertension. CCBs, such as amlodipine, are also currently being used and proven to be effective, although their beneficial effects in the management of complications of hypertension like stroke and myocardial infarction (MI) have yet to be proven. Therefore, the aim of this systematic review was to evaluate the effect of amlodipine on stroke and MI in hypertensive patients. METHODS: A systematic search of English electronic databases was performed for studies with sufficient statistical power that were published between 2000 andl 30 August 2020, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. A total of 676 papers were screened, and 13 were found eligible to be included in the meta-analysis. Studies that included patients who suffered from MI or stroke and were under amlodipine treatment were included in the analysis. The odds ratio and the risk ratio of amlodipine compared to active control/placebo were noted from the studies and statistically analyzed. RESULTS: Amlodipine had a significant effect in reducing stroke and MI in hypertensive patients. Similar to results published in reports, this systematic review proved that the hazard ratio for amlodipine was < 1 for stroke (0.69-1.04) and MI (0.77-0.98), showing that amlodipine accounted for better prevention of stroke and MI. CONCLUSION: In the pooled analysis of data from 12 randomised controlled trials and one double-blinded cohort study measuring the effect of CCBs, we found that the CCB amlodipine reduced the risk of stroke and MI in hypertensive patients. Superior results for amlodipine were found in ten of the 13 studies included in this meta-analysis.

Genetic Referral Patterns and Responses to Clinical Scenarios: A Survey of Primary Care Providers and Clinical Geneticists.

INTRODUCTION: Primary care physicians (PCPs) are considered the gatekeepers of genetic services, but they often underutilize or inappropriately utilize such services, leading to lack of early treatment, incorrect diagnoses, and unnecessary procedures. This study aims to delineate PCP referral patterns, including the frequency of, motivators for, and barriers to genetic referrals and testing in the present landscape of genomics. METHODS: A 34-item online survey was distributed to PCPs in the United States (US). PCP demographics, practice characteristics, and referral patterns, motivators, and barriers were analyzed. Six hypothetical clinical scenarios included in the survey also were presented to a cohort of clinical geneticists. We calculated PCPs' rates of ordering genetic tests and of referral to genetics services in the past year. Rates and responses to clinical scenarios were compared based on respondents' personal and practice characteristics. RESULTS: A total of 95 PCPs and 25 clinical geneticists participated. Among the PCPs, 79% reported referring and 50% reported ordering genetic testing in the last year. PCPs with genetic counselors (GCs) in their clinic referred at significantly higher rates than those without (P = .008). White PCPs referred at significantly higher rates compared to Black or African American PCPs (P = .009). The most commonly reported motivators for referring patients to genetic services were preference for specialist coordination, lack of knowledge, and family's desire for risk information. The most commonly reported barriers were patient refusal, provider concerns about costs to patients, and uncertainty of when a genetic referral is appropriate. In response to clinical scenarios, clinical geneticists were in agreement about the need for genetic testing or referral for 2 of the scenarios. For these 2 scenarios, only 48% and 71% of PCPs indicated that they would offer genetic testing or referral, respectively. CONCLUSIONS: Responses to clinical scenarios suggest that it is not clear to PCPs when referrals or testing are needed. Collaboration with GCs is one approach to reducing barriers to and improving PCPs' utilization of genetic services. Clear guidelines from clinical geneticists may help facilitate appropriate use of genetics services by PCPs. Additional research is needed to further describe barriers that PCPs face in genetic testing/referrals.

Efficacy of a Combination of Metformin and Vildagliptin in Comparison to Metformin Alone in Type 2 Diabetes Mellitus: A Multicentre, Retrospective, Real-World Evidence Study.

BACKGROUND: Early use of combination therapy in diabetes patients may lead to sustained glycemic control and thereby reduce the progression of diabetic complications. Given the limitation of the traditional stepwise intensification strategy, early combination therapy can be an effective approach. Therefore, this study aims to assess the real-world efficacy of a combination of metformin and vildagliptin in comparison to metformin alone in type 2 diabetes mellitus (T2DM) patients in India. METHODS: This was an observational, retrospective, non-interventional study based on electronic medical records (EMRs) of 2740 T2DM patients, retrieved from 2010 onwards from 22 diabetes centres across India. Adult drug naïve patients with a 5-year history of T2DM treated with either metformin or a combination of metformin and vildagliptin for at least 3 months were considered for this study. Efficacy assessment was done to evaluate the post-treatment HbA1c levels and patients requiring additional oral antidiabetic drugs (OADs) at the time of follow-up visit. Patients were also analyzed for the occurrence of adverse events. RESULTS: Out of the total, 2452 patients were in metformin only arm, and 288 patients were in metformin plus vildagliptin treatment arm. A more significant reduction in HbA1c level was observed in metformin plus vildagliptin arm than metformin only arm (median: -0.5% vs 0%, respectively; p<0.001). Patients requiring additional OAD at follow-up were significantly lesser in the metformin plus vildagliptin arm than the metformin only arm (15.6% vs 35.2%, respectively; p<0.001). The adverse events were comparable across the two arms, and commonly reported adverse events were giddiness, fatigue and gastric discomfort. CONCLUSION: The findings of this EMR-based real-world study emphasizes the need for early initiation of combination therapy (metformin plus vildagliptin) over metformin monotherapy for achieving better glycemic control.

The Use of Telemedicine and Other Strategies by Registered Dietitians for the Medical Nutrition Therapy of Patients With Inherited Metabolic Disorders During the COVID-19 Pandemic.

The clinical management of patients with inherited metabolic disorders (IMDs) includes medical nutrition therapy (MNT) by a registered dietitian (RD). We utilized an online quantitative and qualitative survey to characterize the practices of RDs treating patients with IMDs during the COVID-19 pandemic and to identify challenges and unmet needs. We received responses from 117 RDs. Results indicate that RDs are using alternate methods to engage this vulnerable population and provide MNT during the pandemic, including offering telemedicine appointments. Barriers to implementation of telemedicine include the limitations of virtual visits (inability to conduct physical exams and collect blood samples), time, patient knowledge of technology, audio problems, and patient access to internet, computers, or smartphones. RDs have addressed these barriers by extending prescriptions without a medical exam, relying on local facilities for blood draws, increasing the number of patients that use at-home filter papers for blood monitoring, and expanding the use of phone calls and emails. RDs identified patient education materials to facilitate telemedicine visits as a primary unmet need. Despite the reported barriers and limitations of telemedicine for MNT of IMDs, there was widespread satisfaction with the approach among RDs, with 96.9% reporting that they were somewhat or very satisfied with telemedicine. Although this survey focused on barriers, benefits of telemedicine for both RDs and patients were also reported. Identification of barriers and unmet needs can help clinics plan strategies to maximize telemedicine delivery models, to improve efficiency and patient outcomes, and to support sustained use of telemedicine post-pandemic.

Lipid changes in the metabolome of a single case study with maple syrup urine disease (MSUD) after five days of improved diet adherence of controlled branched-chain amino acids (BCAA).

BACKGROUND: Distinguishing systemic metabolic disruptions in maple syrup urine disease (MSUD) beyond amino acid pathways is under-investigated, yet important to understanding disease pathology and treatment options. METHODS: An adolescent female (15 years) with MSUD without liver transplant, attended 2 study visits, 5 days apart. Medical diet adherence was determined based on her 3-day diet records and plasma branched-chain amino acid (BCAA) concentrations at both study visits. Plasma from a single age- and sex-matched control (MURDOCK Study, Duke University) and the case patient were analyzed with UPLC/MS/MS for intensity (m/z), annotated, and normalized against a median of 1 (Metabolon, Morrisville NC). Differences between case/control and 5-day comparisons were defined as ≥ Ç€ 0.5 ǀ. RESULTS: 434 lipid metabolites were identified across samples; 90 (20.7%) were higher and 120 (27.6%) lower in the MSUD case at baseline compared with control. By study visit 2, plasma BCAA had declined, while 48 (53%) of elevated lipids and 14 (11.7%) of lower lipid values had moved to within ǀ 0.5 ǀ of control. Most shifts towards control by day 5 were seen in long-chain fatty acid intermediates (42%) and acylcarnitines (32%). Although androgenic (28%) and bile acid (23%) metabolites increased towards control, neither reached control level by day 5. DISCUSSION: This comparative metabolomics study in a single MSUD case and healthy control suggests intrinsic differences in MSUD lipid metabolism potentially influenced by therapeutic diet. Findings suggest influences on hormone regulation, fatty acid oxidation, and bile acid synthesis, but further studies are needed to confirm an association between MSUD and lipid dysregulation. SYNOPSIS: Within 5 days of improved dietary adherence, a single MSUD case experienced substantial changes in lipid markers potentially related to changes in plasma branched-chain amino acids.

Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature.

BACKGROUND: N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder affecting the urea cycle, leading to episodes of hyperammonemia which can cause significant morbidity and mortality. Since its recognition in 1981, NAGS deficiency has been treated with carbamylglutamate with or without other measures (nutritional, ammonia scavengers, dialytic, etc.). We conducted a systematic literature review of NAGS deficiency to summarize current knowledge around presentation and management. METHODS: Case reports and case series were identified using the Medline database, as well as references from other articles and a general internet search. Clinical data related to presentation and management were abstracted by two reviewers. RESULTS: In total, 98 cases of NAGS deficiency from 79 families, in 48 articles or abstracts were identified. Of these, 1 was diagnosed prenatally, 57 were neonatal cases, 34 were post-neonatal, and 6 did not specify age at presentation or were asymptomatic at diagnosis. Twenty-one cases had relevant family history. We summarize triggers of hyperammonemic episodes, diagnosis, clinical signs and symptoms, and management strategies. DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful. Management usually consists of treatment with carbamylglutamate, although the reported maintenance dose varied across case reports. Protein restriction was sometimes used in conjunction with carbamylglutamate. Supplementation with citrulline, arginine, and sodium benzoate also were reported. CONCLUSIONS: Presentation of NAGS deficiency varies by age and symptoms. In addition, both diagnosis and management have evolved over time and vary across clinics. Prompt recognition and appropriate treatment of NAGS deficiency with carbamylglutamate may improve outcomes of affected individuals. Further research is needed to assess the roles of protein restriction and supplements in the treatment of NAGS deficiency, especially during times of illness or lack of access to carbamylglutamate.