An integrated approach to discriminate the quality markers of Traditional Chinese medicine preparation based on multi-dimensional characteristic network: Shenqi Jiangtang Granule as a case.

BACKGROUND: Due to the complexity of traditional Chinese medicine (TCM), the current quality evaluation of TCM are difficult to associate with clinical efficacy. Shenqi Jiangtang Granule (SJG), a classical TCM formula, is proven as a therapy for treatment of type II diabetes mellitus (DM) and complications while the substantial basis of the therapeutic effects is not clear. PURPOSE: The present study proposed an integrated approach to discriminate the quality markers (Q-markers) based on multi-dimensional characteristic network for quality control of TCM. METHODS: The multi-dimensional characteristic network was established by "Spider-web" mode, which was comprehensively integrating "compatibility-content-activity- efficiency-stability" of the candidate ingredients. The activity dimension was evaluated by the inhibitory activity of SJG on α-glucosidase and aldose reductase. The efficacy dimension was assessed through the association between the compounds and the target pathway of diabetic nephropathy (DN) based on integrated pharmacology platform. Each dimension for the feature network was quantified by multivariate statistical analysis, and regression area of the candidate compounds was constructed in the network. Finally, the candidate compounds were sorted comprehensively by the regression area. RESULTS: A total of 30 chemical compounds with effective hypoglycemic activity were identified as the potential Q-markers. From the data analysis, three dimensions of activity, efficacy and content performed a greater impact on the regression area of the characteristic network. Among these compounds, ginsenoside Re, ginsenoside Rd, ginsenoside Rg1, calycosin, ginsenoside Rb1, formononetin, astragaloside IV, ginsenoside Rf, ginsenoside Rc, notoginsenoside Fe, schisandrol A, gomisin D were screened out as the candidate Q-markers of SJG. CONCLUSION: The multi-dimensional characteristic network integrating compatibility, content, activity, efficiency and stability is efficient to discriminate the potential Q-markers of TCM prescription. Our results demonstrated that 12 candidate compounds from Panax Ginseng, Radix Astragali and Schisandrae Chinensis might select as Q-markers for qualitative evaluation of SJG.

Practical aspects of usage of insulin in India: Descriptive review and key recommendations.

BACKGROUND AND AIMS: Insulin therapy is an integral part of diabetes management. However, reliable and easily accessible information on a number of basic facts concerning insulin therapy, including storage of insulin, managing insulin therapy during travel, nuances of insulin use while driving, and dose adjustments during sick days is lacking. This document aims to make readily available, reliable, and easy to implement information on these essential but relatively less discussed aspects of insulin therapy. METHOD: Literature search was performed using PubMed and Cochrane Library from inception till 1st of July 2019. The relevant topics were reviewed by a panel of 5 specialists and 23 contributing physicians and endocrinologists, who had assembled at Bengaluru, India for the 13th National Insulin Summit. After a thorough review of the literature, and following detailed discussions, the committee arrived at these recommendations. RESULTS: Unopened vials and cartridges of insulin should be stored at 2 °C-8 °C in a refrigerator and protected from direct sunlight. For opened vials and in-use cartridges, manufacturer's instructions must be followed at all times. While traveling by air, dose adjustments are required only when flying across more than five time zones in the east or west directions. Insulin therapy should not be omitted or stopped during an acute illness; rather the doses need careful adjustments based on self-monitoring of blood glucose. CONCLUSION: Recommendations and guidelines, covering many common aspects of insulin therapy are readily available. This consensus document aims to make recommendations for those essential aspects of insulin therapy that are crucial for its success but are relatively less known and less discussed.

Determinants of treatment modification before and after implementation of the updated 2015 NICE guideline on type 2 diabetes: A retrospective cohort study.

AIMS: To identify patient-specific factors associated with early metformin treatment modification among type 2 diabetes patients before and after implementation of the updated 2015 NICE (National Institute for Health and Care Excellence) guideline. METHODS: We conducted a population-based cohort study using data from the Clinical Practice Research Datalink GOLD database (2009-2016). Patients ≥ 18 years, newly treated with metformin only, during the period of valid data collection were included. The first prescription defined start of follow-up. Determinants of treatment modification in two cohorts (before and after implementation of the updated guideline) were studied by time-dependent Cox proportional hazards regression. RESULTS: After implementation of the updated guideline, patients were less likely to receive sulphonylureas (62.3% vs 41.3%) or thiazolidediones (4.7% vs 2.2%) and more likely to receive dipeptidyl peptidase-4 inhibitors (15.8% vs 27.1%) or sodium-glucose cotransporter-2 inhibitors (0.8% vs 9.9%). Some determinants influenced general practitioners' prescribing differently after implementation of the updated guideline compared to before, including a high body mass index and heart failure. CONCLUSIONS: Our results indicate that a first step towards tailored prescribing has been made. However, not all determinants that are important to consider when prescribing second-line glucose-lowering agents were of influence on general practitioners' prescribing.

Patient safety and public health concerns: poor dissolution rate of pioglitazone tablets obtained from China, Myanmar and internet sites.

BACKGROUND: Poor quality medicines have serious implications for public health. The aim of this study was to explore the quality of the antidiabetic pioglitazone, using samples collected in China and Myanmar, and samples purchased online. METHODS: In this cross-sectional study, we examined samples (n = 163) collected from hospitals in Shanghai, China in 2012 (n = 44), products purchased via the internet and imported into Japan in 2013 (n = 59), and samples purchased in shops in Yangon, Myanmar in 2015 (n = 60). Collected samples were subjected to visual inspection, authenticity investigation and quality testing (potency, content uniformity and dissolution test) by high-performance liquid chromatography. Samples were rated as compliant or non-compliant based on the relevant pharmacopoeial acceptance criteria. RESULTS: Visual inspection of all samples revealed compliant products. However, responses from manufacturers during authenticity investigation were poor. Among the n = 44 samples from China, one was non-compliant in the potency test. Among the n = 59 samples personally imported into Japan, 38% of generic samples were found to be non-compliant. In Myanmar, 13.3% of samples were non-compliant. Non-compliant samples predominantly failed in the dissolution test. All non-compliant samples were generic. CONCLUSIONS: Despite the apparent satisfactory outcome on the samples from China, pioglitazone samples collected in Myanmar and purchased online for personal import into Japan included many substandard products, which failed quality assessment predominantly because of poor dissolution. Internet providers did not comply with Japanese regulations in various respects.

Efficacy and safety of metformin in the treatment of gestational diabetes: A protocol for systematic review and meta-analysis.

BACKGROUND: The incidence of gestational diabetes is increasing, which not only cause adverse pregnancy outcomes, but also increases the risk of diabetes for pregnant women and their children. Insulin is the gold standard for the treatment of gestational diabetes, but there are some disadvantages, such as poor patient compliance. Metformin has been used in the treatment of gestational diabetes, but the evaluation of its efficacy and safety is lack of reliable evidence-based medicine evidence. The purpose of this study was to systematically investigate the efficacy and safety of metformin in the treatment of diabetic gestational diabetes. METHODS: Computer searches China National Knowledge Infrastructure, Wanfang, Vipu Information Chinese Journal Service Platform and China Biomedical Database, PubMed, Embase, Web of Science, the Cochrane Library from the establishment of the database to November 2020, randomized controlled clinical trials of metformin in the treatment of gestational diabetes mellitus were conducted in English and Chinese. Two researchers independently carried out data extraction and literature quality evaluation on the quality of the included study, and the included literature was analyzed by Meta using RevMan5.3 software. RESULTS: In this study, the efficacy and safety of metformin in the treatment of diabetic gestational diabetes were investigated by evaluating the outcome indicators of pregnant women and newborn babies respectively. CONCLUSION: This study will provide reliable evidence for the clinical application of metformin in the treatment of diabetic gestational diabetes. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/ OSF.IO / 7RB95.

Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.

BACKGROUND: Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19. Our main objective was to examine the association between in-hospital death and each routine at-home glucose-lowering drug both individually and in combination with metformin in patients with type 2 diabetes mellitus admitted for COVID-19. We also evaluated their association with the composite outcome of the need for ICU admission, invasive and non-invasive mechanical ventilation, or in-hospital death as well as on the development of in-hospital complications and a long-time hospital stay. METHODS: We selected all patients with type 2 diabetes mellitus in the Spanish Society of Internal Medicine's registry of COVID-19 patients (SEMI-COVID-19 Registry). It is an ongoing, observational, multicenter, nationwide cohort of patients admitted for COVID-19 in Spain from March 1, 2020. Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs in a 1:1 manner by propensity scores. In order to assess the adequacy of propensity score matching, we used the standardized mean difference found in patient characteristics after matching. There was considered to be a significant imbalance in the group if a standardized mean difference > 10% was found. To evaluate the association between treatment and study outcomes, both conditional logit and mixed effect logistic regressions were used when the sample size was ≥ 100. RESULTS: A total of 2666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin. After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected. No at-home glucose-lowering drugs showed a significant association with in-hospital death; the composite outcome of the need of intensive care unit admission, mechanical ventilation, or in-hospital death; in-hospital complications; or long-time hospital stays. CONCLUSIONS: In patients with type 2 diabetes mellitus admitted for COVID-19, at-home glucose-lowering drugs showed no significant association with mortality and adverse outcomes. Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed.

Glyburide Use in Older Adults: Pharmacy Claims Data Analysis of a Regional Healthcare Organization.

BACKGROUND/OBJECTIVES: Glyburide was added to the 2012 American Geriatrics Society (AGS) Beers Criteria® due to the risk of hypoglycemic events in older adults. The objective of this study was to evaluate trends of glyburide use in persons aged 65 and older with diabetes mellitus, type II, before, during, and after the 2012 AGS Beers Criteria® Update. DESIGN: Multicenter retrospective cohort study comparing pharmacy claims data from four Sharp Rees-Stealy clinic regions over 5 years (2010-2015). SETTING: Pharmacy claims database. PARTICIPANTS: A total of 3,005 patients with diabetes mellitus, type II, aged 65 and older. MEASUREMENTS: Prescription fill history of the sulfonylureas glyburide, glipizide, and glimepiride were collected along with comorbidity (Elixhauser) and demographic information. Odds of glyburide prescribing were stratified by year, clinic region, and by prescriber type. RESULTS: Glyburide use decreased across each study year (35.8%, 27.7%, and 4.2% in 2011, 2013, and 2015, respectively; P < .01). Adjusted odds of glyburide use indicated that regions A and D were 24% (P = .045) and 11% (P < .01) less likely to prescribe glyburide in 2011, regions A and D were 37% (P < .01) and 8% (P = .03) less likely to prescribe glyburide in 2013, respective to the overall average, whereas region B was 41% (P = .04) more likely. No significant regional site variations remained in 2015. Internists were 47% more likely to prescribe glyburide than family medicine providers in 2013; P < .01), but not in any other study years. CONCLUSION: Rates of glyburide use decreased after release of the 2012 AGS Beers Criteria® demonstrating successful adoption of evidence-based medicine at a large multiregional site. However, regional differences may affect timing of implementation. Education, system-level initiatives, and strong professional support may help enhance more uniform adoption. J Am Geriatr Soc 68:2354-2358, 2020.

Substandard and Falsified Antibiotics and Medicines against Noncommunicable Diseases in Western Cameroon and Northeastern Democratic Republic of Congo.

Falsified and substandard medicines may undermine the progress toward the Sustainable Development Goals. The present study investigated the quality of 13 essential medicines in Cameroon and the Democratic Republic of Congo (DR Congo). Five hundred six medicine samples were collected from the government and faith-based health facilities, private pharmacies, and informal vendors (total 60 facilities). Collected samples were analyzed according to the U.S. Pharmacopeia (USP) for identity, content, and dissolution of their active pharmaceutical ingredients (APIs) and for uniformity of dosage units. Three samples (0.6%) were identified as falsified. Overall, 8.5% of the samples failed USP specifications for the content of the API and 11.7% failed dissolution testing. Medicines from informal vendors showed a higher out-of-specification rate (28.2%) than other types of drug outlets (12.3%; P < 0.0001). All three falsified medicines had been sold by informal vendors. The failure rate of medicines stated to be produced in Europe (5.1%) was lower than that for medicines from Asia (17.7%; P = 0.0049) and Africa (22.2%; P = 0.0042). Medicines against noncommunicable diseases showed a higher failure rate than antibiotics (25.3% versus 12.1%; P = 0.0004). Four hundred fifty-one of the samples were analyzed in Cameroon and the DR Congo with the Global Pharma Health Fund Minilab (thin-layer chromatography and disintegration testing). The three falsified medicines were readily detected in Minilab analysis. However, substandard samples were detected with low sensitivity. A well-enforced ban of medicine sales by informal vendors and increased attention to supplier qualification in the procurement process may reduce the prevalence of substandard and falsified medicines.

9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Reducing Hypoglycemia in Critical Care Patients Using a Nurse-Driven Root Cause Analysis Process.

BACKGROUND: Successful blood glucose control is associated with improved outcomes of critically ill patients. However, insulin treatment can cause hypoglycemia, an important patient safety concern. The Joint Commission has recommended that all episodes of hypoglycemia be evaluated with a root cause analysis. OBJECTIVE: To reduce episodes of hypoglycemia through the analysis of data related to each episode. METHODS: The interdisciplinary team of the 16-bed critical care unit of a university-affilited teaching hospital developed a process to analyze, in real time, each episode of hypoglycemia (blood glucose level <60 mg/dL), including evaluation of patient risk factors and nursing interventions. The nursing staff integrated the root cause analysis into daily practice. The preimplementation period encompassed 2429 consecutive admissions, and the implementation period encompassed 2608 consecutive admissions. RESULTS: The percentage of patients with hypoglycemia decreased substantially during the implementation period among those without (from 6.15% to 3.78%; P = .001) and with diabetes (from 13.14% to 7.23%; P = .002). Mean blood glucose level decreased during the implementation period among patients without diabetes (P < .001), and did not change significantly among patients with diabetes (P = .23). The coefficient of variation, reflecting glucose variability, decreased during the implementation period among patients without and with diabetes (P < .001 for each). CONCLUSION: The nurse-driven root cause analysis was associated with a substantial reduction in hypoglycemia, with concomitant decreases in mean blood glucose level among patients without diabetes and glucose variability in patients without and with diabetes.

Role of ultrafast-acting insulin analogues in the management of diabetes.

To control both fasting and prandial plasma glucose levels in people with diabetes, insulin therapy must mimic "normal" physiological insulin secretion as much as possible. This is achieved with a long-acting insulin injected once or twice daily and a bolus of insulin injected before every meal. Prandial (bolus) insulin can either be regular human insulin (RHI) or a rapid-acting insulin analogue (RAIA). Although the efficacy of RHI has been established over approximately 35 years of clinical use, RAIAs offer several clinical advantages over RHI, namely that they have been engineered with a reduced tendency to aggregate as hexamers, which allows for rapid dissociation and absorption after a subcutaneous injection. Conventional RAIAs include insulin lispro, insulin aspart, and insulin glulisine. The more recently developed fast-acting insulin aspart (faster aspart) is an ultrafast-acting mealtime insulin that contains the conventional insulin aspart in a new formulation with the excipients niacinamide and L-arginine to achieve faster insulin absorption than RHI and the conventional insulin aspart formulation. This article reviews the clinical evidence supporting the use of RAIAs as part of a basal-bolus regimen in patients with diabetes, with a focus on new formulations whose pharmacological profiles more closely mimic the endogenous prandial insulin secretion pattern that is seen in individuals without diabetes. This review also provides a clinical perspective to help guide health care professionals in the use of RAIAs.

Antidiabetic Potential of Mangifera indica L. cv. Anwar Ratol Leaves: Medicinal Application of Food Wastes.

Background and objectives: Anwar Ratol is one of the most famous cultivar of mango in South Asia, especially Pakistan. Mango leaves are left as food waste. This study evaluated the potential of mango (Anwar Ratol) leaves for their use against diabetes mellitus. Material and Methods: In this study, hydro-alcoholic extract of the plant leaves was prepared and evaluated by electrospray ionization mass spectroscopy (ESI-MS) and high-performance liquid chromatography (HPLC) for the presence of phytochemicals. The plant extract was administered to Alloxan induced diabetic mice followed by evaluation through oral glucose tolerance test; determination of postprandial glucose, body weight, lipid profile and histopathological evaluation of pancreas. Results: Chemical evaluation revealed the presence of mangiferin, rhamnetin, catechin, epicatechin, iriflophenone 3-C-ß-D-glucoside, gallic acid and other phenolic and flavonoid compounds. The plant extract exhibited a decrease in postprandial blood glucose following seven days therapy in diabetic mice. The extract also prevented the rise in blood glucose level as determined by glucose tolerance test in diabetic mice. Furthermore, therapy of diabetic mice with the extract prevented a decrease in body weight and decline in beta-cell mass associated with alloxan and improved lipid profile. Conclusion: The findings of the study clearly suggested that the leaf extract of the plant might possess anti-diabetic activity possibly due to the presence of mangiferin and other phytochemicals such as phenolic and flavonoid compounds. This study will serve as a basis for the use of mango leaf extract against diabetes. Furthermore, this study will also provide basis for the bioassay-based fractionation and isolation of active principles responsible for the antidiabetic potential of mango leaves.

How often patients on insulin therapy measure postprandial glycemia and modify insulin doses accordingly? From an on-line survey in insulin-treated diabetes patients in Spain.

INTRODUCTION: Controlling postprandial glycemia (PPG) is important to achieve optimal glycemic control, but few studies have evaluated how often is measured and evaluated. OBJECTIVES: To evaluate how often patients on insulin therapy measure PPG and modify insulin doses accordantly. As secondary objectives, we evaluated the factors conditioning elevated PPG and associated issues. MATERIAL AND METHODS: Cross-sectional observational study based on a web-based survey from an unselected sample of adult insulin-treated patients. A p-value of < 0.05 was significant. RESULTS: 1251 patients (68% women, 38.9 ±â€¯13 years [mean ±â€¯SD], body mass index (BMI) 24.2 ±â€¯4.2 kg/m2, diabetes duration 17.4 ±â€¯12.8 years, insulin dose 38 ±â€¯18 IU) participated, 1104 with autoinmmune disease (AD) and 147 with non-autoinmmune diabetes (NAD). 59% of patients had HbA1c ≤ 7%, 92.7% of patients with AD and 55.8% with NAD were attended by specialists (p < 0.001). People with AD did more often blood glucose monitoring (BGM) (p < 0.0001) and used continuous glucose monitoring systems (CGMS) (p < 0.0001). 90.1% with AD and 68.0% with NAD received instructions on measuring PPG (p < 0.001), and more with AD received specific training to change the treatment (87% vs. 61.2%, p < 0.0001) and were more proactive. However, more with NAD discussed their postprandial glucose levels with their healthcare team during clinical visits (92.5% vs. 74.1%, p < 0.0001). Regarding bolus administration, 88.6% with AD and 68.7% with NAD injected the insulin bolus before meals (p < 0.001). CONCLUSIONS: Patients with AD determine PPG more frequently. Diabetes type, follow-up setting, number of injections and CGMS use were the most important predictive factors for PPG measurement. Diabetes education programs should address how to best monitor PPG and appropriate corrective actions.

Assessment of optimal insulin administration timing for standard carbohydrates-rich meals using continuous glucose monitoring in children with type 1 diabetes: A cross-over randomized study.

AIMS/INTRODUCTION: The present study was an assessment of postprandial glucose concentration after carbohydrates-rich meals using continuous glucose monitoring in 30 children with type 1 diabetes treated using continuous subcutaneous insulin infusion with a rapid-acting insulin analog. MATERIALS AND METHODS: Over a period of 3 days, participants administered simple boluses with different delay times between insulin administration and the beginning of carbohydrates-rich meal consumption (meal no. 1 containing 197 kcal, no. 2 containing 247 kcal and meal no. 3 containing 323 kcal; containing practically no protein and fat). In the present cross-over randomized study, we analyzed the average glucose concentration profiles in 5-min intervals, mean glucose at insulin administration, mean glucose after 120 and 180 min, mean and peak glucose, glucose peak time, areas under the glucose and glucose increase curves, and time period lengths with glucose <50, 70 mg/dL, and >140 and 200 mg/dL. RESULTS: For test meals at 20-min versus 0-min delay time, the study exposed a longer median time period to reach peak glucose (95 vs 65 min, P = 0.01) after meals. A tendency to the lowest peak and mean glucose, and the longest time with glucose within a normal range was observed in patients who administered bolus insulin 20 min before a meal. CONCLUSIONS: For carbohydrates-rich meals, administration of a proper dose of a rapid-acting insulin analog is crucial. The influence of rapid-acting insulin analog administration timing seems to be of minor importance in comparison with correct insulin dose adjustment; however, a tendency to achieve more balanced glucose profiles was found in a group who administered insulin 20 min before a meal.

[Towards personalized treatment of type 2 diabetes]. / Op weg naar een persoonsgerichte diabeteszorg.

The purpose of type 2 diabetes treatment is to reduce the risk of diabetic complications and, as a result, improve the quality and, possibly, quantity of life. This requires control of blood glucose levels and cardiovascular risk factor management in a patient-centred approach. Careful consideration of patient factors and preferences helps the process of individualising treatment strategies and goals. With respect to medication management, the Dutch College of General Practitioners (NHG) recently updated the practice guideline on how to reach these goals. Although this guideline promotes individualised glycaemic targets for patients based on comorbidities, propensity for hypoglycaemia, and capacity to carry out the treatment plan, a more profound shift seems necessary. Based on recent trials, optimal treatment should target specific complications and inherent risks besides glycaemic targets. Patients at high risk for cardiovascular disease may benefit from treatment with drugs that lower this risk.

Comparison of Toxic Metal Concentrations in Antidiabetic Herbal Preparations (ADHPs) Available in Bangladesh Using AAS and XRF Analytical Tools.

Widespread escalation of type 2 diabetes is a concern throughout the world. Developing countries are leading with patients suffering from diabetes-related complications. Plant-based therapeutic, antidiabetic herbal preparations (ADHPs) are being sought for long and the consumption is increasing in in Bangladesh. Plant-based antidiabetic preparations do not go through the screening procedure in terms of safety. Toxic metals in ADHPs have been investigated by two different methods: atomic absorption spectroscopy (AAS) and X-ray fluorescence (XRF). Then, metal concentrations obtained by AAS and XRF were compared. A total of eleven ADHPs were subjected to nondestructive XRF analysis and destructive AAS analysis. Results from the two methods were analyzed statistically by Pearson correlation coefficient (PCC), r xy . Pearson correlation coefficients were found to be -0.05, 0.94, and 1.00 for Mn, Cu, and Zn, respectively. Zn and Cu had significant strong positive correlation (r xy = 1.00 and 0.94, respectively); however, very weak negative correlation was observed in Mn (r xy = -0.05). The concentrations were regressed to observe the presence of linearity. Linear correlation was found for Zn and Cu which indicates a good agreement between AAS and XRF. However, very weak linear correlation in Mn indicates necessitating requirements for further investigation on getting scientific evidence of toxic metal assessment of the antidiabetic herbal preparations for searching and establishing instrumental agreement.