Management of autoimmune haemolytic anaemia in low-to-middle income countries: current challenges and the way forward.

Autoimmune haemolytic anaemia (AIHA) is a common term for several disorders that differ from one another in terms of aetiology, pathogenesis, clinical features, and treatment. Therapy is becoming increasingly differentiated and evidence-based, and several new established and investigational therapeutic approaches have appeared during recent years. While this development has resulted in therapeutic improvements, it also carries increased medical and financial requirements for optimal diagnosis, subgrouping, and individualization of therapy, including the use of more advanced laboratory tests and expensive drugs. In this brief Viewpoint review, we first summarize the diagnostic workup of AIHA subgroups and the respective therapies that are currently considered optimal. We then compare these principles with real-world data from India, the world's largest nation by population and a typical low-to-middle income country. We identify major deficiencies and limitations in general and laboratory resources, real-life diagnostic procedures, and therapeutic practices. Incomplete diagnostic workup, overuse of corticosteroids, lack of access to more specific treatments, and poor follow-up of patients are the rule more than exceptions. Although it may not seem realistic to resolve all challenges, we try to outline some ways towards an improved management of patients with AIHA.

Mounting Stroke Crisis in India: A Systematic Review.

Stroke, a neurological disorder, has emerged as a formidable health challenge in India, with its incidence on the rise. Increased risk factors, which also correlate with economic prosperity, are linked to this rise, including hypertension, diabetes, obesity, sedentary lifestyle, and alcohol intake. Particularly worrisome is the impact on young adults, a pivotal segment of India's workforce. Stroke encompasses various clinical subtypes and cerebrovascular disorders (CVDs), contributing to its multifaceted nature. Globally, stroke's escalating burden is concerning, affecting developing nations. To combat this trend effectively and advance prevention and treatment strategies, comprehensive and robust data on stroke prevalence and impact are urgently required. In India, these encompass individuals with elevated BMIs, and those afflicted by hypertension, diabetes, or a familial history of stroke. Disparities in stroke incidence and prevalence manifest across India, with differences in urban and rural settings, gender-based variations, and regional disparities. Early detection, dietary changes, effective risk factor management, and equitable access to stroke care are required to address this issue. Government initiatives, like the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases, and Stroke (NPCDCS) 2019, provide guidelines, but effective implementation and awareness campaigns are vital. Overcoming barriers to stroke care, especially in rural areas, calls for improved infrastructure, awareness campaigns, and support systems. Data standardization and comprehensive population studies are pivotal for informed public health policies.

The double burden of malnutrition in individuals: Identifying key challenges and re-thinking research focus.

The 'double burden of malnutrition' is a global health challenge that increasingly affects populations in both low- and middle-income countries (LMICs). This phenomenon refers to the coexistence of undernutrition and overweight or obesity, as well as other diet-related non-communicable diseases, in the same population, household or even individual. While noteworthy progress has been made in reducing undernutrition in some parts of the world, in many of these areas, the prevalence of overweight and obesity is increasing, particularly in urban areas, resulting in greater numbers of people who were undernourished in childhood and have overweight or obesity in adulthood. This creates a complex and challenging situation for research experts and policymakers who must simultaneously address the public health burdens of undernutrition and overweight/obesity. This review identifies key challenges and limitations in the current research on the double burden of malnutrition in individuals, including the need for a more comprehensive and nuanced understanding of the drivers of malnutrition, the importance of context-specific interventions and the need for greater attention to the food environment and food systems. We advocate for the re-evaluation of research strategies and focus, with a greater emphasis on multidisciplinary and systems approaches and greater attention to the synergistic relationship between the biological, environmental, commercial and socio-economic determinants of malnutrition. Addressing these key challenges can enable us to better comprehend and tackle the multifaceted and dynamic issues of the double burden of malnutrition, particularly in individuals and work towards more effective and sustainable solutions.

Cultural adaptation of an intervention for caregivers of young autistic children: Community members' perspectives.

Caregivers of autistic children in low-to-middle-income countries experience many barriers to access resources to support their child's development. Caregiver training is considered an evidence-based practice and may be a cost-effective way to support caregivers of autistic children in such settings. This study focuses on the cultural adaptation of Parents Taking Action (PTA; Magaña et al., Family Process, 56, 57-74, 2017) to support caregivers of autistic children in Paraguay. We conducted focus groups and individual interviews with 28 caregivers, autistic individuals, and professionals in Paraguay to understand caregivers' needs and to explore needed cultural adaptations of PTA to achieve contextual fit. Participants identified caregivers' need for accurate and reliable information, strategies to support children's growth, and emotional support and strategies to manage stress. Additionally, participants provided recommendations for adapting PTA considering the dimensions within the Cultural Adaptation Checklist (Lee et al., International Journal of Developmental Disabilities, 2023). This study is the first step in the iterative process of culturally adapting an intervention and the process described in this study may be appropriate for culturally adapting other interventions.

Mechanical valve replacement for patients with rheumatic heart disease: the reality of INR control in Africa and beyond.

The majority of patients requiring heart valve replacement in low- to middle-income countries (LMICs) need it for rheumatic heart disease (RHD). While the young age of such patients largely prescribes replacement with mechanical prostheses, reliable anticoagulation management is often unattainable under the prevailing socioeconomic circumstances. Cases of patients with clotted valves presenting for emergency surgery as a consequence of poor adherence to anticoagulation control are frequent. The operative mortality rates of reoperations for thrombosed mechanical valves are several times higher than those for tissue valves, and long-term results are also disappointing. Under-anticoagulation prevails in these regions that has clearly been linked to poor international normalised ratio (INR) monitoring. In industrialised countries, safe anticoagulation is defined as >60%-70% of the time in the therapeutic range (TTR). In LMICs, the TTR has been found to be in the range of twenty to forty percent. In this study, we analysed >20,000 INR test results of 552 consecutive patients receiving a mechanical valve for RHD. Only 27% of these test results were in the therapeutic range, with the vast majority (61%) being sub-therapeutic. Interestingly, the post-operative frequency of INR tests of one every 3-4 weeks in year 1 had dropped to less than 1 per year by year 7. LMICs need to use clinical judgement and assess the probability of insufficient INR monitoring prior to uncritically applying Western guidelines predominantly based on chronological age. The process of identification of high-risk subgroups in terms of non-adherence to anticoagulation control should take into account both the adherence history of >50% of patients with RHD who were in chronic atrial fibrillation prior to surgery as well as geographic and socioeconomic circumstances.

Respiratory syncytial virus immunoprophylaxis: Novel opportunities and a call for equity.

With the approval of the first vaccines against respiratory syncytial virus (RSV) and a novel RSV-neutralizing antibody, 2023 has been perceived as a game-changing year in preventing severe outcomes of RSV infections in infants and the elderly. However, the costs of these pharmaceuticals are high, while RSV disproportionately impacts populations of low-to-middle-income regions, which may continue to suffer from a lack of pharmaceutical measures for RSV prevention under health and socioeconomic disparities. This paper presents an overview of the characteristics, clinical results, and approval status of various RSV vaccines and anti-RSV antibodies. It posits that wealthy nations cannot monopolize RSV immunoprophylaxis and should work jointly to make it available to lower-income countries. An approach toward RSV immunoprophylaxis equity based on five points is offered: (1) integration of RSV vaccines and antibodies into the existing global humanitarian distribution systems, (2) using affordable RSV vaccine pricing models, (3) enforcing equity as a part of national and global public health strategy, (4) implementing equitable allocation frameworks for RSV immunoprophylaxis, and (5) promoting local manufacturing. Such a plan needs to be put into action as soon as possible to avoid delays in serving the populations with the highest needs related to RSV burden.

Building capacity for network meta-analysis in Sub-Saharan Africa: reflections and future direction.

Robust, relevant, comprehensive, and up-to-date evidence syntheses are the cornerstone for evidence-informed healthcare decisions. When considering multiple treatment options, network meta-analysis (NMA) systematic reviews play a key role in informing impactful decisions and clinical practice guidelines. However, the capacity and literacy to conduct NMA systematic reviews and interpret its results remains out of reach for many clinicians and review authors, especially in low-to-middle-income countries. Despite ample resources and guides, NMA capacity and training opportunities remain limited to non-existent in Sub-Saharan Africa. Towards solutions and strengthening evidence synthesis and NMA capacity in the Sub-Saharan African region, we describe and reflect on two courses that build NMA capacity and aim to address NMA literacy in Sub-Saharan Africa.The Primer in NMA systematic reviews aimed for participants to be able to find, appraise, interpret, and consider the use of NMA SRs of intervention effects. It is a 6-week online course for clinicians, policy-makers, and researchers wanting to learn more about using NMA systematic reviews. The Global NMA Masterclass workshop aimed for participants to be able to understand and apply pairwise and NMA in STATA and R, evaluate NMA assumptions and confidence in NMA results, and appropriately report NMA results. This course was offered over 5 weeks to clinicians, biostatisticians, and researchers with basic knowledge of epidemiology and biostatics. Although the bulk of learning occurred through self-study, we had weekly, synchronous question-and-answer sessions for both courses. Using relevant examples throughout the courses helped to enable an authentic learning environment.This was the first NMA training developed in Africa for Africa. Development of the courses was a collaborative effort from a multi-disciplinary team. Both NMA courses were well received and attended by a diverse group of participants spread across Sub-Saharan African countries. Participants felt the courses were applicable to their setting. Although most participants appreciated the benefits of online learning, we also experienced some challenges. There is great potential to conduct NMA systematic reviews in Sub-Saharan Africa. The NMA Primer and NMA workshop can play an essential role in expanding and developing NMA SR capacity and literacy in SSA.

Enhancing Quality of Congenital Heart Care Within Resource-Limited Settings.

Over 90% of the world's children with congenital heart disease (CHD) are born in the resources poor settings of low- to middle-income countries (LMICs). The shortfall in human and material resources and dysfunctional health systems leads to poor quality of care (QoC) which contributes substantially to suboptimal outcomes of patients with CHD in LMICs. Notwithstanding these challenges, it is possible to develop a quality improvement (QI) framework that can have a significant impact on outcomes and prevent a number of deaths. In this review, we examine the common barriers to implementing effective QI processes in LMICs. Using examples of successful QI initiatives in LMIC, we propose a broad framework that focuses on simple, yet effective measures involving cohesive efforts of all key participants guided and nurtured by a leadership that strongly values QoC.

Ongoing Healthcare Disparities in neuroHIV: Addressing Gaps in the Care Continuum.

PURPOSE OF REVIEW: We aim to review the neurological complications of HIV and the social, cultural, and economic inequalities that contribute to disparities in neuroHIV care. RECENT FINDINGS: Disparities in diagnostics and care of patients with neurological infections and non-infectious conditions associated with HIV in both high-income and low-to-middle-income countries (LMIC) are common. The COVID-19 pandemic has exacerbated these disparities. Factors, such as HIV-related stigma, may deter people from accessing HIV treatment. First-line recommended treatments for neurological infections are not available in many LMICs, leading to inadequate treatment and exposure to agents with more harmful side effect profiles. Access-related factors, such as lack of transportation, lack of health insurance, and inadequate telehealth access, may increase the risk of HIV-related neurological complications. Further research is needed to increase awareness of neurological complications among providers and PWH, and regional guidelines should be considered to better address these complications.

Treatment Challenges of Acquired Thrombotic Thrombocytopenic Purpura in Pediatric Patients From a Low-Income Country.

This study presents a comprehensive analysis of two cases of acquired thrombotic thrombocytopenic purpura (aTTP) observed in pediatric patients from a low-income country. In the instances described, both patients underwent a treatment regimen involving plasma exchange and immunosuppressive therapy conducted without the use of caplacizumab. Caplacizumab, an approved drug for adults known for its limited availability and high cost, has exhibited efficacy in reducing response time and recurrence frequency in aTTP cases. This approach resulted in significant clinical improvement and eventual remission of symptoms in one of the cases. These cases underscore the urgent necessity for a more inclusive approach in national health programs and international treatment guidelines. Specifically, there is a call to expand the existing comprehensive treatment algorithms to accommodate countries lacking access to caplacizumab. This adaptation aims to ensure the availability of suitable and effective treatment options for aTTP patients in regions facing limited pharmaceutical accessibility.

Anesthesia Services in Low- and Middle-Income Countries: The Fragile Point for Safe Surgery and Patient Safety.

The Safe Surgery Saves Life campaign of the World Health Organization advocates patient safety best practices during surgical procedures. Anesthesia service is indivisible from the patient safety best practices. Although anesthesia services are safer than ever before, safe delivery of anesthesia service and patient safety depends significantly on the availability of qualified anesthesiologists, the knowledge and competency of anesthesiologists, the work environment, and the availability of essential equipment and monitoring facilities. Despite anesthesiologists being the midstream of perioperative care, their role and service are often underacknowledged, especially in low- and middle-income countries (LMICs). Anesthesia services in LMICs face myriad challenges such as a shortage of skilled personnel, inadequate resources, limited training opportunities, and minimal administrative say, which act as the fragile point in the chain of safe surgery delivery. Specific solutions should focus on strengthening the anesthesia workforce, providing fair remuneration and incentives, advocating for anesthesia autonomy, and facilitating access to educational resources. Nevertheless, managing these problems requires a collaborative effort involving governments, healthcare organizations, and international stakeholders to develop sustainable solutions and prioritize the well-being of both anesthesia providers and patients. This editorial focuses on it briefly, emphasizing the anesthesia of rural healthcare service and patient safety.

ChatGPT: promise and challenges for deployment in low- and middle-income countries.

In low- and middle-income countries (LMICs), the fields of medicine and public health grapple with numerous challenges that continue to hinder patients' access to healthcare services. ChatGPT, a publicly accessible chatbot, has emerged as a potential tool in aiding public health efforts in LMICs. This viewpoint details the potential benefits of employing ChatGPT in LMICs to improve medicine and public health encompassing a broad spectrum of domains ranging from health literacy, screening, triaging, remote healthcare support, mental health support, multilingual capabilities, healthcare communication and documentation, medical training and education, and support for healthcare professionals. Additionally, we also share potential concerns and limitations associated with the use of ChatGPT and provide a balanced discussion on the opportunities and challenges of using ChatGPT in LMICs.

Placental inflammation and pregnancy outcomes: A prospective, observational study in South Asia: The PURPOSe study.

OBJECTIVE: To examine inflammatory lesions in placentas of stillbirths, preterm neonatal deaths and term controls in India and Pakistan. DESIGN: Prospective, observational study. SETTING: Three hospitals in India and a large maternity hospital in Pakistan. POPULATION: The enrolled participants with placentas available for histology evaluation included stillbirths (n = 814), preterm live births who died within 28 days of birth (n = 618) and term live birth controls (n = 201). From this same population, polymerase chain reaction (PCR) analysis for pathogens was performed on 809 stillbirth placentas, 614 neonatal death placentas and the placentas of 201 term controls. Placentas from preterm infants who lived beyond day 28 (n = 1432) were only available from India. METHODS: A prospective observational study of placental inflammatory lesions defined by the Amsterdam criteria and on the same placentas, multiplex PCR evaluation for 75 pathogens using TaqMan Array Cards. MAIN OUTCOME MEASURES: Any placental inflammatory lesions, including chorioamnionitis, funisitis, villitis and intervillitis and their association with various pathogens. RESULTS: In the Indian liveborn preterm infants, placental inflammation of any kind was present in 26.2% of those who died versus 16.6% of those who lived (p = 0.0002). Chorioamnionitis was present in 25.8% of those who died versus 16.3% of those who lived (p = 0.0002) and funisitis was present in 4.1% of those who died versus 1.5% of those who lived, (p = 0.005). Across all three sites, in the placentas of the 201 term controls, 18.9% had any inflammation, 16.9% had chorioamnionitis, 5.5% had funisitis, 0.5% had intervillitis and none had villitis. Overall, for stillbirths, any inflammation was observed in 30.2%, chorioamnionitis in 26.9%, funisitis in 5.7%, intervillitis in 6.0% and villitis in 2.2%. For the neonatal deaths, any inflammation was present in 24.9%, chorioamnionitis in 23.3%, funisitis in 8.1%, intervillitis in 1.9% and villitis in 0.5%. Compared with the placentas of term controls, in neonatal deaths, only chorioamnionitis was significantly increased (23.3% versus 16.9%, p = 0.05). Among stillbirths, the rates of any inflammation, chorioamnionitis, intervillitis and villitis were similar across the birthweight groups. However, funisitis was more common in the placentas of stillborn fetuses weighing 2500 g or more (13.8%) compared with 1.0% for those weighing less than 1000 g and 4.8% for stillborn fetuses weighing 1000-2499 g. In the PCR studies, Ureaplasma spp. were by far the most common pathogens found and generally were more commonly found in association with inflammatory lesions. CONCLUSIONS: Chorioamnionitis was the most common type of placental inflammatory lesion regardless of whether the placentas evaluated were from term controls, stillbirths or neonatal deaths. For stillbirths, inflammation in each inflammation category was more common than in the term controls and significantly more so for any inflammation, chorioamnionitis, intervillitis and villitis. For neonatal deaths, compared with the placentas of term controls, all inflammation categories were more common, but only significantly so for chorioamnionitis. Ureaplasma spp. were the most common organisms found in the placentas and were significantly associated with inflammation.

Quality of Life in Pediatrics With Intractable Epilepsy at King Abdulaziz Medical City, Jeddah, Saudi Arabia: A Cross-Sectional Study.

Objective The aim of this study was to assess the cognitive, emotional, social, and physical domains of quality of life (QoL) in pediatric patients with intractable epilepsy with an emphasis on depressed mood and suicidal ideation (SI). Methods This is a cross-sectional study conducted in pediatric neurology outpatient clinics in King Abdulaziz Medical City, Jeddah, Saudi Arabia. The sample consisted of 59 parents whose children aged 4-14 years of either sex had intractable epilepsy. The Quality of Life in Childhood Epilepsy Questionnaire - 55 (QOLCE-55) scale examined four domains of life: cognitive, emotional, social, and physical. Depressed mood and SI were part of the emotional domain. Results  The mean ± SD age of children was 8.2 ± 3.25. The mean ± SD of overall QoL was 43.02 ± 15.70, which reflected a poor QoL. Age was not related to the QoL. Female gender was significantly associated with a lower overall QoL (P = 0.0477). Patients with comorbidities had statistically insignificant lower QoL in the cognitive, social, and physical domains in addition to lower overall QoL. Seven of nine participants who reported feeling down reported having SI in the last four weeks (P < 0.001). Conclusions An intractable epilepsy-imposed burden negatively impacts all domains of QoL. Furthermore, females experience lower overall QoL compared to males. Children with comorbidities also tend to have lower QoL scores, although the differences were statistically insignificant. Additionally, a history of feeling down is associated with SI.

Identifying Challenges and Potential Solutions for Sustainable Kidney Nutrition Care Delivery in Selected Asian Countries.

BACKGROUND: Recent surveys highlight gross workforce shortage of dietitians in global kidney health and significant gaps in renal nutrition care, with disparities greater in low/low-middle income countries. OBJECTIVE: This paper narrates ground experiences gained through the Palm Tocotrienols in Chronic Hemodialysis (PaTCH) project on kidney nutrition care scenarios and some Asian low-to-middle-income countries namely Bangladesh, India, and Malaysia. METHOD: Core PaTCH investigators from 3 universities (USA and Malaysia) were supported by their postgraduate students (n = 17) with capacity skills in kidney nutrition care methodology and processes. This core team, in turn, built capacity for partnering hospitals as countries differed in their ability to deliver dietitian-related activities for dialysis patients. RESULTS: We performed a structural component analyses of PaTCH affiliated and nonaffiliated (Myanmar and Indonesia) countries to identify challenges to kidney nutrition care. Deficits in patient-centered care, empowerment processes and moderating factors to nutrition care optimization characterized country comparisons. Underscoring these factors were some countries lacked trained dietitians whilst for others generalist dietitians or nonclinical nutritionists were providing patient care. Resolution of some challenges in low-to-middle-income countries through coalition networking to facilitate interprofessional collaboration and task sharing is described. CONCLUSIONS: We perceive interprofessional collaboration is the way forward to fill gaps in essential dietitian services and regional-based institutional coalitions will facilitate culture-sensitive capacity in building skills. For the long-term an advanced renal nutrition course such as the Global Renal Internet Course for Dietitians is vital to facilitate sustainable kidney nutrition care.

Multilevel analysis identifying the factors associated with RSV detection in infants admitted for viral bronchiolitis in the era of the COVID-19 pandemic.

OBJECTIVES: To identify factors independently associated with respiratory syncytial virus (RSV) detection in infants admitted for viral bronchiolitis during 3 consecutive years, before and during the COVID-19 pandemic, in Bogota, Colombia, a middle-income country with a subtropical highland climate. METHODS: An analytical cross-sectional study was conducted before and during the COVID-19 pandemic, including patients with a diagnosis of viral bronchiolitis admitted to all the hospitals of the city between January 2019 and November 2021. We evaluated a set of a priori-selected predictor variables that included individual, healthcare system, meteorological, air pollutant, and COVID-19 variables. Since the variables analyzed are hierarchical in nature, multilevel modeling was used to identify factors independently associated with detection of RSV as the causative agent of viral bronchiolitis. RESULTS: A total of 13,177 patients were included in the study. After controlling for potential confounders, it was found that age (odds ratio [OR] 0.86; 95% confidence interval [CI] 0.76-0.97), a third level of medical care institution (OR 3.05; 95% CI 1.61-5.76), temperature (OR 1.60; 95% CI 1.24-2.07), rainfall (OR 1.003, 95% CI 1.001, 1.005), NO2 (OR 0.97; 95% CI 0.95-0.99), CO (OR 0.99; 95% CI 0.99-0.99), and COVID-19 pandemic period (OR 0.84, 95% CI 0.71-0.99) were independently associated with RSV detection in our sample of patients. CONCLUSIONS: The identified factors associated with RSV detection provide additional scientific evidence that may be useful in the development of specific interventions aimed at ameliorating or preventing the impact of RSV in Bogota and probably other similar low- to middle-income countries in high-risk infants.

High protein content in breast milk from South African mothers of preterm infants.

AIM: Macronutrient and energy content of human milk are largely assumed for fortification practices. The aim was to explore macronutrient and energy content of transition and mature human milk from South African mothers of preterm infants with a birth weight <1800 g. Secondary objectives compared day to night milk; and explored associations with selected innate factors. METHODS: In this single-centre, observational study macronutrient and energy content of day, night and mixed samples of transition (first 14 days of life) and mature (from Day 15 of life) human milk were analysed with mid-infrared spectroscopy. RESULTS: In total, 116 samples (38 days; 37 night; 41 mixed) from 47 mothers were retained for statistical analysis. Mean true protein, carbohydrate, fat and energy content of mixed samples per 100 mL were 1.5 ± 0.4 g, 7.2 ± 0.7 g, 3.5 ± 0.9 g and 69.4 ± 9.9 kcal, respectively. Mixed transition milk (n = 9) had 1.9 ± 0.3 g protein and 67.4 ± 9.6 kcal and mixed mature milk (n = 32) 1.4 ± 0.4 g protein and 70.0 ± 10.1 kcal, per 100 mL.The protein content of transition (p = 0.004) and mature (p = 0.004) milk were significantly higher than published data. Transition milk: 1.5 g protein, 65 kcal; mature milk: 1.2 g protein, 72 kcal per 100 mL. Night samples had less fat (p = 0.014) and energy (p = 0.033) than day samples. With increasing day of life protein content declined (p = 0.003). CONCLUSION: The protein content of human milk from South African mothers of preterm babies differs from published data and has implications for human milk fortification practises.

Effect of the postpartum hemorrhage intervention package implementation in a fourth-level hospital in Latin America.

OBJECTIVE: To evaluate the effectiveness of the implementation of intervention packages for postpartum hemorrhage (PPH) management in pregnant women hospitalized in a High Obstetric Complexity Unit in a Latin American country. METHODS: Retrospective cohort study including pregnant women with PPH attended between January 2011 to December 2019. Three periods of time were defined according to management strategies We performed univariate and multivariate robust Poisson regression logistic models for each of the outcomes derived from each period. RESULTS: We included 602 patients. There was a reduction in period 3 of the incidence of massive PPH (16% versus 12% P < 0.001, relative risk [RR] 0.61, 95% confidence interval [CI] 0.44-0.85; P = 0.003), major surgery (24%, 13%, 11%, P = 0.002, RR 0.54, 95% CI 0.33-0.883; P = 0.014), and admission to the intensive care unit (ICU) (14%, 7%, 6.1%, P = 0.0, RR 0.40, 95% CI 0.17-0.96 P = 0.00). CONCLUSION: The implementation of PPH intervention packages in a hospital in a middle-income country from Latin America, led to a significant decrease in the incidence of massive bleeding, the rate of major surgery, and the ICU stay of pregnant women affected by this condition.