Consumption and adverse reaction reporting of herbal medicines among people living with HIV at University teaching hospitals in Blantyre, Malawi and Ibadan, Nigeria.

Background: Consumption of herbal medicines among people living with HIV is a common practice in Sub-Saharan Africa. The utilization of herbal medicines was at 17.5% and 67.9% in Malawi and Nigeria, respectively. There is inadequate data on use and adverse reactions (ADRs) reporting of herbal medicines among people living with HIV (PLWHIV). This study was designed to investigate use and ADRs reporting of herbal medicines among PLWHIV at the University Teaching Hospitals in Blantyre, Malawi and Ibadan, Nigeria. Methodology: A cross-sectional study was conducted among PLWHIV attending Antiretroviral Therapy (ART) clinic at Queen Elizabeth Central Hospital, Blantyre, Malawi and University College Hospital, Ibadan, Nigeria. A structured questionnaire was administered to 360 and 370 participants in Blantyre and Ibadan respectively, through face-to-face interviews after obtaining their informed consent. Results: The prevalence of herbal medicines use among PLWHIV in Malawi and Nigeria was at 80.6% and 55.7% (p<0.001), respectively. The most frequently used herbal medicines in Malawi were Aloe vera (14.0%), Moringa oleifera (14.0%), Zingiber officinale (13.0%) and Allium sativum (7.0%). Likewise, in Nigeria, the most commonly used herbal medicines were Zingiber officinale (15.0%), Vernonia amygdalina (14.0%), Moringa oleifera (9.0%), and Allium sativum (11.0%). The major reason for herbal medicines' use in Malawi was ready availability (42.1%) and perception that it boosts immunity (44.6%) in Nigeria. The PLWHIV reported experiencing suspected herbal medicine ADRs in Malawi (3.9%) and in Nigeria (8.0%). Conclusion: A higher percentage of people living with HIV are using herbal medicines in Malawi as well as in Nigeria. In both countries, a few participants reported experiencing suspected ADRs related to herbal medicines.

NMDAR autoimmune encephalitis and fulminant relapse of multiple sclerosis: a rare overlap syndrome.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease that has been rarely associated with AQP4-IgG and MOG-IgG demyelinating diseases, and even more rarely with multiple sclerosis. We present the case of a woman in her 40s with confirmed NMDAR encephalitis and coexistent fulminant relapse of multiple sclerosis treated with alemtuzumab 6 years prior, who had a favourable outcome following treatment with ocrelizumab. We proceed to systematic review of similar reported cases, finding a lower than anticipated prevalence of underlying malignancy compared with isolated NMDAR encephalitis, in this rare overlap syndrome.

Analysis of Longitudinal Patterns and Predictors of Medicine Use in Residential Aged Care Using Group-Based Trajectory Modeling: The "MEDTRAC-Cardiovascular" Longitudinal Cohort Study.

AIM: Cardiovascular diseases are the leading cause of death globally. Ensuring ongoing use of medicines-medication persistence-is crucial, yet no prior studies have examined this in residential aged care facilities (RACFs). We aimed to identify long-term trajectories of persistence with cardiovascular medicines and determine predictors of persistence trajectories. METHOD: A longitudinal cohort study of 2837 newly admitted permanent residents from 30 RACFs in New South Wales, Australia. We monitored weekly exposure to six cardiovascular medicine classes-lipid modifiers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs), beta-blockers, diuretics, calcium channel blockers (CCB), and cardiac therapy-over 3 years. Group-based trajectory modeling was employed to determine persistence trajectories for each class. RESULTS: At baseline, 76.6% (n = 2172) received at least one cardiovascular medicine with 41.2% receiving lipid modifiers, 31.4% ACEI/ARBs, 30.2% beta-blockers, 24.4% diuretics, 18.7% CCBs, and 14.8% cardiac therapy. The model identified two persistence trajectories for CCBs and three trajectories for all other classes. Sustained high persistence rates ranged from 68.4% (ACEI/ARBs) to 79.8% (beta-blockers) while early decline in persistence and subsequent discontinuation rates ranged from 7.6% (cardiac therapy) to 25.3% (CCBs). Logistic regressions identified 11 predictors of a declining persistence across the six medicine classes. CONCLUSION: Our study revealed varied patterns of cardiovascular medicine use in RACFs, with 2-3 distinctive medicine use trajectories across different classes, each exhibiting a unique clinical profile, and up to a quarter of residents discontinuing a medicine class. Future studies should explore the underlying reasons and appropriateness of nonpersistence to aid in identifying areas for improvement.

The impact of global falsified medicines regulation on healthcare stakeholders in the legitimate pharmaceutical supply chain: a systematic review.

Background: Falsified medicines and their international regulation impacts all healthcare sectors and their actors. These regulations aim to strengthen and protect the global pharmaceutical supply chain against falsified medicines. However, an evaluation of the impacts of these regulations on key stakeholders within the legitimate supply chain have not been explored. Objective: This research aimed to evaluate both the positive and negative impacts of falsified medicines regulation on key stakeholders within the global pharmacy sector including including manufacturers, wholesalers, hospital pharmacies, community pharmacy and patients. Design: This research consists of a systematic review and thematic analysis concerning falsified medicines regulation and the subsequent impacts of existing global regulations on healthcare. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and checklist were utilized for reporting in this systematic review. Data sources and methods: A search of three databases, Embase, ProQuest and PubMed, was undertaken to determine studies applicable to the research question. The Mixed Methods Appraisal Tool (MMAT) was used to assess methodological quality and risk of bias for all included studies. Results: From the initial 657 studies, a final set of 13 relevant studies were identified. The most frequently reported falsified medicines regulation was the Falsified Medicines Directive (FMD) [n = 11]. The impact of falsified medicines regulation in the literature related to four areas: (1) Financial, (2) Social, (3) Organizational, and (4) Pharmacy Practice. These common themes across the included studies frequently relate to challenges and/or concerns associated with falsified medicines regulation implementation as well as both the logistics and practicality of incorporating falsified medicines regulations into daily operations. Conclusion: Implementation and enforcement of falsified medicines regulation does not yet appear to categorically fulfill the primary aim of the regulations, to strengthen the drug supply chain. However, in recent years, such regulations have challenged the legitimate pharmaceutical supply change actors as they attempt to successfully implement these regulations. Studies mainly detail the negative impacts of regulation during the implementation phase but with the overall benefit pertaining to the prioritization and enhancement of patient care and safety within the healthcare sector.

Access to essential medicines used in the management of noncommunicable diseases in Southern Ethiopia: Analysis using WHO/HAI methodology.

Objectives: This study aims to assess access to essential medicines used in the management of noncommunicable diseases through analysis of the availability, prices, and affordability of these essential medicines in Arba Minch town, Gamo Zone, Southern Ethiopia. Methods: A cross-sectional design was carried out using the World Health Organization/health action international methodology between 2 March and 2 May 2023, within public and private healthcare facilities located in Arba Minch town, Southern Ethiopia. The median price ratio served as a metric. Statistical tests like the Shapiro-Wilk and Kolmogorov-Smirnov were utilized to assess the normal distribution of price data. The Wilcoxon-Mann-Whitney U test was also employed to compare median buyer's prices (patient prices) between public and private healthcare institutions. Treatment affordability was determined by estimating the number of days' wages required by the lowest-paid government employee in Ethiopia to afford the prescribed medication regimen. Results: Among 23 health facilities surveyed, the pooled availability of essential medicine used in the management of noncommunicable diseases was 18.7% (range: 0%-30.1%), with the public and private facilities contributing 16.3% and 38.3%, respectively. The overall percentage of availability originator brand versions was 1.1% for overall health sectors, 0.6% for public sectors, and 1.2% for private sectors. The overall percent availability of lowest price generics was 36.2% (range: 0%-26.2%; public: 32.0%; private: 37.1%). Only seven lowest price generics satisfied the World Health Organization target of 80% and above. The overall median price of lowest price generic medicines in private was two times higher than in public sectors. The top five median price scorers were amlodipine, furosemide, insulin, beclomethasone, and salbutamol. The Mann-Whitney U test showed that 11.6% of lowest price generics medicines had a statistically significant median price disparity between the public and private sectors (p < 0.05). The overall percent of unaffordability was found to be 100.0%, (public: 70.4; private: 100.0%). Conclusions: This study revealed the limited availability and potential financial burdens on patients seeking essential noncommunicable disease medications. Limited availability suggests the need for better supply chain management and consistent stock availability. The price disparities and affordability challenges identified underscore the necessity for policy interventions such as price regulation and subsidized programs to ensure equitable access to essential noncommunicable disease medications in Arba Minch town, Southern Ethiopia.

Comparison of Three Regional Medicines Regulatory Harmonisation Initiatives in Africa: Opportunities for Improvement and Alignment.

BACKGROUND: The African Medicines Regulatory Harmonisation (AMRH) Initiative was formed in 2009 and subsequently, three regional initiatives (East African Community Medicines Regulatory Harmonisation [MRH], Southern African Development Community [SADC]/ZaZiBoNa MRH, and the Economic Community of West Africa States MRH) were established. As these initiatives serve as a foundation for the African Medicines Agency (AMA), the aim of this study was to compare their operating models, successes and challenges to identify opportunities for improvement and alignment. METHODS: A mixed method approach was used for the data collection using a questionnaire, the Process, Effectiveness and Efficiency Rating (PEER), developed by the authors specifically for this study and semi-structured interview techniques. There were 23 study participants (one from each agency of the member countries of the three regions). It was hoped that data generated from this study would lead to a series of recommendations, which would then be ratified by the regulatory authorities. RESULTS: Most respondents stated that AMRH contributed to the strengthening of regulatory systems and harmonising regulatory requirements across economic regions of Africa, potentially resulting in improved access to quality-assured medicines. Although established at different times and at the discretion of each region, the marketing authorisation application review processes are largely similar, with a few differences noted in the eligibility and submission requirements, type of procedures employed, the timelines and fees payable. The challenges identified in the three regions are also similar, with the most noteworthy being the lack of a binding legal framework for regional approvals. CONCLUSION: In this study, we compared the process, successes and challenges of these three regional harmonisation initiatives in Africa addressing the areas of legal frameworks, information management systems, the accessibility and affordability of medicines and reliance that will bring greater alignment and efficiency in their operating models, thereby strengthening the foundation of the soon-to-be-operationalised AMA.

A qualitative exploration of the impact of a hospital electronic prescribing and medicines administration (HEPMA) protocol on junior doctor confidence and competence to prescribe end-of-life care medicines.

BACKGROUND: With hospital electronic prescribing and medicines administration (HEPMA) systems now in widespread use across hospital inpatient clinical services, work is underway to measure the benefits of HEPMA on healthcare systems and patient care. HEPMA functionality enables users to prescribe medicines by 'bundle' or 'protocol'. Although it is assumed that this is a significant system benefit, there are few qualitative studies supporting this conclusion. AIM: To explore the impact of an electronic anticipatory care medicines protocol on junior doctor perceptions of their confidence and competence to prescribe opioids and midazolam for patients at the end of life. METHOD: Between May and August 2022, one-to-one semi-structured interviews were conducted at a 570-bed District General Hospital with junior doctors who had experience of prescribing on both HEPMA and paper-based systems. Audio recordings of the interviews were transcribed verbatim and underwent thematic analysis. RESULTS: Ten junior doctors participated (median age 23 years). Analysis generated five main themes that described perceptions and attitudes towards confidence and competence. These were prescribing safety benefits; information technology infrastructure, interoperability and system design concerns; clinical knowledge and training needs; cultural and social factors and risks of automation in prescribing. CONCLUSION: This study suggests that junior doctors experienced an overall increase in their confidence and perceived competence to prescribe anticipatory medicines post-implementation of a HEPMA protocol. Further studies are required to detail the impact of HEPMA/CPOE protocols on clinical practice.

Outcomes of Community Pharmacy Interventions on Patients with Medicines Under Additional Monitoring.

Purpose: Additional monitoring (AM) medicines include (i) medicines containing a new active substance; (ii) biological medicines; (iii) medicines with conditional approval or authorized in special situations; (iv) medicines which require further studies; (v) medicines that have specific requirements regarding the reporting of suspected adverse drug reactions (ADRs). When AM medicines are marketed, their most common ADRs are known, but safety information is limited because relatively rare ADRs are often not detected in clinical trials. Their AM status warrants real-world studies to identify other safety issues; however, such studies are lacking. Correct use and adherence to dosage regimen by patients are key factors for the evaluation of the safety and efficacy of medicines. The objective of this work was assessing the impact on safety, adherence, use and knowledge (U&K) about medicines and patient's quality of life (QOL), of community pharmacist (CP)-led interventions in a new service focused on AM medicines targeted at three prevalent chronic diseases: diabetes mellitus type 2, chronic obstructive pulmonary disease and cardiovascular disease. Patients and Methods: A prospective interventional cohort study was conducted with a 6-month follow-up in 27 community pharmacies (145 patients). Safety, adherence to treatment, patient U&K and QOL were assessed at follow-up visits (months 0, 3 and 6). Results: The number of detected ADRs was 163 with 41 patients referred to the doctor. At baseline, 24.1% of the patients were non-adherent, mainly due to unintentional causes. After six months and 130 interventions by CPs on adherence, a significant reduction to lower than 5.8% was achieved. The inadequate U&K of medicines also decreased, from 47.6% to 7.9% after 182 interventions. Also, the patient's QOL improved. Conclusion: A new patient-centered pharmacy service provides some evidence on the important role of CP in assisting the proper and safe use of AM medicines, improving patient health outcomes.

Capacity Assessment of the National Medicines Regulatory Authority in a Low -Income Country.

BACKGROUND: Access to medical products of the required efficacy, quality and safety is essential for everyone's health and wellbeing. To achieve this milestone, every country needs a robust and strong performing National Regulatory Authority (NRA) that is independent and outcome oriented. With the help of the World Health Organization (WHO), the global benchmarking tool is the gold standard used to assess the regulatory capacity of NRAs. OBJECTIVES: This study assessed the capacity of the National Medicines Regulatory Authority in Sierra Leone to perform its regulatory functions. METHODS: This descriptive cross-sectional study used both qualitative and quantitative approaches. A self-administered questionnaire was used for the quantitative approach, and the qualitative aspect consisted of a desk review looking at key regulatory documents such as laws, regulations, policies, guidelines, standard operating procedures and reports. The data collection tool used was the WHO global benchmarking tool (GBT) for "Evaluation of National Regulatory System of Medical Product Version VI. RESULTS: The majority of the participants had a postgraduate degree (60%), and 72% had over 10 years of experience working at the NRA. Out of 251 sub-indicators assessed, 85 (34%) sub-indicators were fully implemented. Of the eight (8) functions assessed, sub-indicators related to clinical trial oversight and vigilance were the most implemented, with 67% and 62%, respectively. Of the 9 indicators assessed, 79% of the sub-indicators that are related to quality and risk management were implemented. The results of this study showed that PBSL operates at maturity level 1. The absence of laws and regulations that give PBSL the mandate to perform its regulatory functions was a major challenge even though other indicators were met. The study reported other challenges toward effective functioning, including but not limited to a lack of sufficient staff, weak enforcement of the sale of medicines and a poorly equipped quality control laboratory.

Correction: A Survey of Availability and Affordability of Polypills for Cardiovascular Disease in Selected Countries.

[This corrects the article DOI: 10.5334/gh.1335.].

Microneedle system for tissue engineering and regenerative medicines: a smart and efficient therapeutic approach.

The global demand for an enhanced quality of life and extended lifespan has driven significant advancements in tissue engineering and regenerative medicine. These fields utilize a range of interdisciplinary theories and techniques to repair structurally impaired or damaged tissues and organs, as well as restore their normal functions. Nevertheless, the clinical efficacy of medications, materials, and potent cells used at the laboratory level is always constrained by technological limitations. A novel platform known as adaptable microneedles has been developed to address the abovementioned issues. These microneedles offer a solution for the localized distribution of various cargos while minimizing invasiveness. Microneedles provide favorable patient compliance in clinical settings due to their effective administration and ability to provide a painless and convenient process. In this review article, we summarized the most recent development of microneedles, and we started by classifying various microneedle systems, advantages, and fundamental properties. Subsequently, it provides a comprehensive overview of different types of microneedles, the material used to fabricate microneedles, the fundamental properties of ideal microneedles, and their applications in tissue engineering and regenerative medicine, primarily focusing on preserving and restoring impaired tissues and organs. The limitations and perspectives have been discussed by concluding their future therapeutic applications in tissue engineering and regenerative medicines.

Differential times of submission and approval of CFTR modulators for the treatment of Cystic Fibrosis in the United States and the European Union.

BACKGROUND: The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU). METHODS: By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023. RESULTS: Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications. CONCLUSION: We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US.

Toward a Sociology of Plasma Products.

Over the past 20 years, plasma has become a medical treatment characterized as "liquid gold" to signal its lifesaving potential. Through a manufacturing process termed fractionation, plasma, collected through blood donation, is turned into Plasma Derived Medical Products (PDMPs). The World Health Organization (WHO) has underlined the importance of PDMPs for global health care, including a number of PDMPs on the WHO Model List of Essential Medicines. The process of collecting plasma from a donor, manufacturing plasma derived treatments, and distributing those treatments globally requires the coordination of multiple social actors operating in different social, political and economic contexts, but has received little attention in scholarly literature on public policy or the social sciences. This paper will introduce a set of analytic questions and concepts that can direct a sociology of plasma products. We build on the behavioral turn in the policy sciences to identify relevant policy questions emerging from this field and offer the analytic tools necessary to investigate how different social actors in this space make meaning of plasma. To do this, we will draw on key concepts in the sociology of health and illness.

Recovery from acute haemorrhagic leucoencephalitis secondary to COVID-19.

A man in his 50s presented with sudden onset expressive aphasia and right-sided facial droop after experiencing coryzal symptoms and malaise for 7 days prior to admission. A brain MRI showed a rapidly progressive mass effect across both hemispheres and cerebrospinal fluid analysis revealed neutrophil predominance with raised protein levels. Acute disseminated encephalomyelitis was provisionally diagnosed, and high-dose methylprednisone was initiated.On admission to the high dependency unit, the patient tested positive for COVID-19 and was treated with appropriate therapeutic agents for severe COVID-19. A subsequent brain biopsy confirmed a demyelinating process, strongly indicating a diagnosis of acute haemorrhagic leucoencephalitis when correlated with the presence of severe oedema on imaging. Nine sessions of plasma exchange were provided over 18 days.At the time of writing, the patient has made an excellent recovery. We urge clinicians to consider this diagnosis and these treatment options for an otherwise devastating condition.

The molecular and network mechanisms of antilipidemic potential effects of Ganfule capsules in nonalcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder characterized by hepatic steatosis, inflammation and fibrosis. Ganfule (GFL), a traditional Chinese medicine, has demonstrated therapeutic potential in the treatment of NAFLD but the mechanisms involved are not fully understood.To evaluate the biochemical mechanisms of GFL in treating NAFLD by examining its effects on biological networks, key therapeutic targets, histopathological changes and clinical implications. Methods: Chemical component screening, key target prediction, biological functional enrichment analysis, lipid profile localization analysis and complex network analysis were performed on GFL using multi-database mining, network analysis and molecular docking. An NAFLD rat model was then established and treated with different doses of GFL. Histopathological evaluation and western blotting were used to verify the expression levels of key target proteins in GFL-treated NAFLD rats. Results: Network analysis analysis identified 12 core targets, 12 core active ingredients and 7 core Chinese medicinal herbs in GFL potentially involved in the treatment of NAFLD. Biological functional enrichment analysis revealed the involvement of lipid metabolism, apoptosis and intracellular signaling pathways. Molecular docking confirmed a strong affinity between GFL's core compounds and certain target proteins. Histopathological examination of an NAFLD rat model showed reduced hepatocellular steatosis after GFL treatment. Western blotting revealed significant downregulation of PPARA and PPARD protein expression and upregulation of PIK3CG and PRKACA protein expression in NAFLD rats treated with lower doses of GFL. Conclusions: Our results suggest that GFL modulates key proteins involved in lipid metabolism and apoptosis pathways. GFL improved the histopathological features of NAFLD rats by regulating lipid metabolism as well as reducing hepatocyte apoptosis and hepatocellular steatosis. These findings offer insights into the biochemical mechanism of action of GFL and support its use in the treatment for NAFLD.

Minimal effects after a massive intravenous terbutaline overdose in a child.

A 22-kg female in early childhood with a history of reactive airway disease presented to a paediatric emergency department with acute shortness of breath, tachypnoea and wheezing. Despite treatment with albuterol and corticosteroids, her bronchospasm persisted, prompting the administration of terbutaline. The patient received 220 mcg (10 mcg/kg) terbutaline intravenously, followed immediately by an inadvertent supratherapeutic intravenous dose of 10 000 mcg (454.5 mcg/kg). The patient's laboratory results obtained minutes after the medication error were notable for: potassium, 3.1 mmol/L, lactate, 2.6 mmol/L and troponin I, 0.30 ng/mL (normal <0.03 ng/mL). Over the next 48 hours, serial serum troponin values decreased. The patient was discharged home approximately 72 hours after the initial presentation and she remained well based on follow-up calls over the next several months. Given the timing and trend of troponin concentrations, we do not believe the terbutaline overdose to be responsible for the myocardial injury.

The Impact of Additive PICOs in a European Joint Clinical Health Technology Assessment.

OBJECTIVES: To assess the potential number of EU PICOs based on EUnetHTA 21 guidance and to explore further evidence-based opportunities to produce more predictable and workable EU PICOs. METHODS: The consolidated EU PICOs of two future hypothetical medicines in first line non small cell lung cancer (1L NSCLC) and third line multiple myeloma (3L MM) were derived using published HTA reports of two recent medicines in similar indications based on EUnetHTA 21 proposed guidance. Sensitivity analysis assessed the impact of additional PICO requests. The number of analyses requested was estimated. RESULTS: In 1L NSCLC and 3L MM, six and nine EU Member States (MS), respectively, had published HTA reports. PICO consolidation resulted in 10 PICOs for 1L NSCLC and 16 PICOs for 3L MM, increasing to 14 and 18 PICOs respectively when England's NICE scope was included to proxy remaining MS. A minimum of 280 and 720 analyses would be requested, exponentially increasing as additional outcome measures and subgroups are requested. CONCLUSIONS: The PICO approach outlined by EUnetHTA 21 results in a significant number of analysis requests and substantial resources. Use of complementary analyses alongside evidence-based methods to derive PICOs and engaging with the health technology developer throughout the process, would create a workable EU PICO that is predictable and most impactful for the EU, resulting in a timely and high-quality assessment report that is more usable at a MS level.

Fremanezumab-associated injection site alopecia.

Calcitonin gene-related peptide (CGRP) inhibitors, in the form of injectable monoclonal antibodies, are a newer class of drugs for the prevention of migraine headaches. In clinical trials, they have been found to be effective with good tolerance and few adverse effects. Alopecia has been increasingly noted as a post-marketing event associated with CGRP inhibitor injectables. Of the case reports available on this topic, alopecia has commonly been localised to the scalp and associated with erenumab use; however, not as much has been reported for fremanezumab nor for injection site-related alopecia. We report an occurrence of persistent lower extremity localised injection site alopecia in a patient within our headache clinic who used fremanezumab. The possible mechanism of alopecia may be related to the failure of hair follicle immune privilege in the absence of CGRP immunomodulatory effects.