Risk factors for labour induction and augmentation: a multicentre prospective cohort study in India.

Background: Guidelines for labour induction/augmentation involve evaluating maternal and fetal complications, and allowing informed decisions from pregnant women. This study aimed to comprehensively explore clinical and non-clinical factors influencing labour induction and augmentation in an Indian population. Methods: A prospective cohort study included 9305 pregnant women from 13 hospitals across India. Self-reported maternal socio-demographic and lifestyle factors, and maternal medical and obstetric histories from medical records were obtained at recruitment (≥28 weeks of gestation), and women were followed up within 48 h after childbirth. Maternal and fetal clinical information were classified based on guidelines into four groups of clinical factors: (i) ≥2 indications, (ii) one indication, (iii) no indication and (iv) contraindication. Associations of clinical and non-clinical factors (socio-demographic, healthcare utilisation and lifestyle related) with labour induction and augmentation were investigated using multivariable logistic regression analyses. Findings: Over two-fifths (n = 3936, 42.3%, 95% confidence interval [CI] 41.3-43.3%) of the study population experienced labour induction and more than a quarter (n = 2537, 27.3%, 95% CI 26.4-28.2%) experienced augmentation. Compared with women with ≥2 indications, those with one (adjusted odds ratio [aOR] 0.50, 95% CI 0.42-0.58) or no indication (aOR 0.24, 95% CI 0.20-0.28) or with contraindications (aOR 0.12, 95% CI 0.07-0.20) were less likely to be induced, adjusting for non-clinical characteristics. These associations were similar for labour augmentation. Notably, 34% of women who were induced or augmented did not have any clinical indication. Several maternal demographic (age at labour, parity and body mass index in early pregnancy), healthcare utilization (number of antenatal check-ups, duration of iron-folic acid supplementation and individuals managing childbirth) and socio-economic factors (religion, living below poverty line, maternal education and partner's occupation) were independently associated with labour induction and augmentation. Interpretation: Although decisions about induction and augmentation of labour in our study population in India were largely guided by clinical recommendations, we cannot ignore that more than a third of the women did not have an indication. Decisions could also be influenced by non-clinical factors which need further research. Funding: The MaatHRI platform is funded by a Medical Research Council Career Development Award (Grant Ref: MR/P022030/1) and a Transition Support Award (Grant Ref: MR/W029294/1).

Economic evaluations of neglected tropical diseases interventions in low- and middle-income countries: a systematic review protocol.

OBJECTIVE: The objective of this systematic review is to provide an overview of economic evaluation studies of interventions for neglected tropical diseases in low- and/or middle-income countries. INTRODUCTION: The majority of people most susceptible to neglected tropical diseases reside in low- and middle-income countries and suffer significant economic impact due to these diseases. The World Health Organization suggests utilizing a systematic and cross-cutting approach with multiple interventions to lessen the neglected tropical disease burden. INCLUSION CRITERIA: Studies will be eligible for inclusion if they include economic evaluations of interventions for neglected tropical diseases and are conducted in low- and/or middle-income country settings. METHODS: A preliminary search of MEDLINE (PubMed) was undertaken using MeSH terms, such as neglected tropical disease, economic evaluation, therapeutics, low- and/or middle-income countries. Two reviewers will screen titles and abstracts independently, followed by a full-text review against the inclusion criteria. Disagreements will be resolved by discussion or with a third reviewer. To assess methodological quality, the JBI checklist for economic evaluations will be used. For economic evaluations, data will be extracted using the standardized JBI data extraction form. The Dominance Ranking Matrix will be used to summarize and compare the results of different types of economic evaluations. Cost per quality adjusted life year gained and cost per disability adjusted life year averted will be measures for economic evaluation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to assess the certainty of economic evidence, such as resource use and costs. REVIEW REGISTRATION: PROSPERO CRD42017070386.

Women's awareness of perinatal mental health conditions and the acceptability of being asked about mental health in two regions in India: a qualitative study.

BACKGROUND: Mental health conditions are common during pregnancy and the first year after childbirth. Early detection allows timely support and treatment to be offered, but identifying perinatal mental health conditions may be challenging due to stigma and under-recognition of symptoms. Asking about symptoms of mental health conditions during routine antenatal and postnatal appointments can help to identify women at risk. This study explores women's awareness of perinatal mental health conditions, their views on the acceptability of being asked about mental health and any preference for specific assessment tools in two regions in India. METHODS: Focus group discussions (FGDs) were conducted with pregnant, post-partum and non-perinatal women in Kangra, Himachal Pradesh (northern India) and Bengaluru, Karnataka (southern India). Settings included a hospital antenatal clinic and obstetric ward, Anganwadi Centres and Primary Health Centres. FGDs were facilitated, audio-recorded and transcribed. Narratives were coded for emerging themes and analysed using thematic analysis. RESULTS: Seven FGDs including 36 participants were conducted. Emerging themes were: manifestations of and contributors to mental health conditions; challenges in talking about mental health; and the acceptability of being asked about mental health. Difficult familial relationships, prioritising the needs of others and pressure to have a male infant were cited as key stressors. Being asked about mental health was generally reported to be acceptable, though some women felt uncomfortable with questions about suicidality. No preference for any specific assessment tool was reported. CONCLUSIONS: Women face many stressors during the perinatal period including difficult familial relationships and societal pressure to bear a male infant. Being asked about mental health was generally considered to be acceptable, but questions relating to suicidality may be challenging in a community setting, requiring sensitivity by the interviewer. Future studies should assess the acceptability of mental health assessments in 'real world' antenatal and postnatal clinics and explore ways of overcoming the associated challenges in resource-constrained settings.

Diagnosis of rabies using reverse-transcription polymerase chain reaction on post-mortem skin tissue specimens of the nasolabial plate in a rabies suspected cow: a case study.

In India, rabies in cattle is under-reported. Religious sentiments hamper its diagnosis, discouraging post-mortem examination, particularly opening the cranium. Specimens of peripheral tissue innervated by the cranial nerves could potentially be used as alternative diagnostic specimens to the brain. Herein, we present a case study of a novel approach for diagnosing rabies in a cow suspected of having rabies, using skin tissue specimens of the nasolabial plate obtained post-mortem. Brain and nasolabial tissue specimens tested positive for rabies using conventional reverse-transcription polymerase chain reaction. This approach has been previously shown to have a high diagnostic sensitivity in animals. We encourage further studies with more nasolabial plate skin specimens for both post- and antemortem diagnosis of rabies in cattle.

Reply to Kapur, V. Is Pre-Exposure Prophylaxis a Cost-Effective Intervention to Avert Rabies Deaths among School-Aged Children in India? Comment on "Royal et al. A Cost-Effectiveness Analysis of Pre-Exposure Prophylaxis to Avert Rabies Deaths in School-Aged Children in India. Vaccines 2023, 11, 88".

Thank you so much for forwarding the critical analysis the author (VK) conducted on our recently published modelling study 'A Cost-Effectiveness Analysis of Pre-Exposure Prophylaxis to Avert Rabies Deaths in School-Aged Children in India' in your reputed journal [...].

Multilevel Comparison of Indian Naja Venoms and Their Cross-Reactivity with Indian Polyvalent Antivenoms.

Snake envenoming is caused by many biological species, rather than a single infectious agent, each with a multiplicity of toxins in their venom. Hence, developing effective treatments is challenging, especially in biodiverse and biogeographically complex countries such as India. The present study represents the first genus-wide proteomics analysis of venom composition across Naja species (N. naja, N. oxiana, and N. kaouthia) found in mainland India. Venom proteomes were consistent between individuals from the same localities in terms of the toxin families present, but not in the relative abundance of those in the venom. There appears to be more compositional variation among N. naja from different locations than among N. kaouthia. Immunoblotting and in vitro neutralization assays indicated cross-reactivity with Indian polyvalent antivenom, in which antibodies raised against N. naja are present. However, we observed ineffective neutralization of PLA2 activities of N. naja venoms from locations distant from the source of immunizing venoms. Antivenom immunoprofiling by antivenomics revealed differential antigenicity of venoms from N. kaouthia and N. oxiana, and poor reactivity towards 3FTxs and PLA2s. Moreover, there was considerable variation between antivenoms from different manufacturers. These data indicate that improvements to antivenom manufacturing in India are highly desirable.

ICMR task force project- survey of the incidence, mortality, morbidity and socio-economic burden of snakebite in India: A study protocol.

BACKGROUND: Snakebite is possibly the most neglected of the NTDs (Neglected Tropical Diseases). Half of the global deaths due to venomous snakebites, estimated at 100,000 per year, occur in India. The only representative data on snakebite available from India is the mortality data from the RGI-MDS study (Registrar General of India- 1 Million Death Study) and another study on mortality from the state of Bihar. Incidence data on snakebite is available for 2 districts of the state of West Bengal only. Hospital-based data on snakebite admissions and use of ASV are gross underestimates as most snakebite victims in rural India depend more on alternate treatment methods which do not get represented in National registries. The proposed study is a multi-centric study to determine the incidence, morbidity, mortality and economic burden of snakebites in India covering all 5 geographical zones of the country. PROTOCOL: A community level surveillance for snakebite covering 31 districts in 13 states of India in order to obtain annual incidence of snakebites from the community. Frontline health workers will be trained to gather information on new cases of snakebite over the study period of 1-year, from "wards "(smallest administrative subunit of a village or town) that they represent in the study districts. Dedicated field officers would collect data on snakebites, victim characteristics, outcomes, utilization of health facilities on a questionnaire sheet designed for this purpose. The study duration is for 18 months from April 2022 to October 2023. DISCUSSION: The study would be the first of its kind in India looking prospectively at the incidence of snakebite covering 13 states in 5 zones of India and a population of 84 million. Our study covers 6.12% of the total population of the country as compared to the incidence study conducted in Sri Lanka which covered 1% of the total population.

Venom of several Indian green pit vipers: Comparison of biochemical activities and cross-reactivity with antivenoms.

Green pit vipers, a name that can refer to several unrelated species, comprise a large group of venomous snakes found across the humid areas of tropical and sub-tropical Asia, and are responsible for most of the bite cases across this region. In India, green pit vipers belonging to several genera are prevalent in the northern and north-eastern hilly region, unrelated to species present in the peninsular region. In the present study, crude venom of representative species of green pit vipers present in the north and north-eastern hilly region of India (Trimeresurus erythrurus, T. septentrionalis, Viridovipera medoensis, and Popiea popieorum) were characterized to elucidate venom composition and venom variation. Profiling of crude venoms using SDS-PAGE and RP-HPLC methods revealed quantitative differences among the species. Further, in vitro biochemical assays reveal variable levels of phospholipase activity, coagulation activity, thrombin-like activity, fibrinogenolytic and haemolytic activity. This correlates with the pseudo-procoagulant effects on the haemostatic system of victims, which causes consumptive coagulopathy, frequently observed in patients bitten by green pit vipers. The immunoreactivity of Indian polyvalent antivenom and Thai green pit viper antivenom towards crude venoms were also evaluated by western blotting and inhibition of biochemical activities. The results exhibited poor efficacy of Indian polyvalent antivenom in neutralizing the venom toxins of crude venoms; however, Thai green pit viper antivenin (raised against the venom of Trimeresurus allbolabris, not present in India) showed higher immunoreactivity towards congeneric venoms tested. Analysis of green pit viper bite patients records from a community health centre in Assam, India, further revealed the inability of Indian polyvalent antivenom to reverse the extended coagulopathy featured.

A Cost-Effectiveness Analysis of Pre-Exposure Prophylaxis to Avert Rabies Deaths in School-Aged Children in India.

Children contribute to one-half of the total painful rabies mortalities in India. The state-of-the-art rabies mortality averting strategies need exploration for the effective implementation of pre-exposure prophylaxis (PrEP) in India. This study reports on the economic evaluation of various PrEP and post-exposure prophylaxis (PEP) strategies to avert rabies mortalities in school-aged children in India. A decision tree model has been developed for children in the age group of 5-15 years to evaluate various PrEP + PEP and PEP only regimens. The 2-site intradermal regimen administered on day zero and seven was chosen as the intervention [PrEP (I)]. ICER was calculated from the quasi-societal and quasi-health systems' perspectives for the base case analysis, along with one-way sensitivity, and scenario analyses for each regimen. The incremental DALYs averted per million population with the implementation of PrEP (I) ranged between 451 and 85,069 in 2020. The ICER was reported in the range of USD 384-352/DALY averted (non-dominant) in comparison to PEP regimens from a quasi-societal perspective. PrEP (I) is reported to be 'very cost effective' in comparison with PEP regimens from the quasi-societal and quasi-health systems' perspectives and reduce deaths by up to 89.9%. This study concludes that the PrEP (I) regimen is a cost-effective and life-saving strategy to avert painful mortalities due to rabies in school-aged children in India.

Epidemiological, humanistic and economic burden of dog-mediated rabies in India: a systematic review protocol.

Background: Rabies is a neglected zoonotic disease. It is transmitted through the bite of a rabid animal and dog bites are responsible for around 95% of human cases. The disease is almost always fatal after the onset of symptoms. It is an endemic and major public health problem in India with one-third of the global deaths reported from this country. Protocol: This systematic review aims to estimate the epidemiological, humanistic and economic burden of dog-mediated rabies in India. Initially the existence of controlled descriptors in MeSH terms (such as 'Epidemiology', 'Rabies', 'Cost', 'Dog bite', 'Quality of Life', 'India' etc), and their synonyms (key words) was identified in MEDLINE, and were later combined with Boolean operators 'AND' and 'OR' to develop a detailed search strategy. Two independent reviewers will screen the titles and abstracts and select the studies as per the inclusion criteria. The selected studies will be assessed for their quality and risk of bias. Data will be extracted using standardized data extraction tools and will be synthesized for analysis. Disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Discussion: This systematic review will be performed to critically examine relevant literature and report the epidemiological, humanistic and economic burden of dog-mediated rabies in Indian context. The findings will help in estimation of burden of the disease in India and expected to contribute in policy making and planning of the program and interventions in the country. Protocol registration: PROSPERO ID: CRD4202021326.

Reviewing Solutions of Scale for Canine Rabies Elimination in India.

Canine rabies elimination can be achieved through mass vaccination of the dog population, as advocated by the WHO, OIE and FAO under the 'United Against Rabies' initiative. Many countries in which canine rabies is endemic are exploring methods to access dogs for vaccination, campaign structures and approaches to resource mobilization. Reviewing aspects that fostered success in rabies elimination campaigns elsewhere, as well as examples of largescale resource mobilization, such as that seen in the global initiative to eliminate poliomyelitis, may help to guide the planning of sustainable, scalable methods for mass dog vaccination. Elimination of rabies from the majority of Latin America took over 30 years, with years of operational trial and error before a particular approach gained the broad support of decision makers, governments and funders to enable widespread implementation. The endeavour to eliminate polio now enters its final stages; however, there are many transferrable lessons to adopt from the past 32 years of global scale-up. Additionally, there is a need to support operational research, which explores the practicalities of mass dog vaccination roll-out and what are likely to be feasible solutions at scale. This article reviews the processes that supported the scale-up of these interventions, discusses pragmatic considerations of campaign duration and work-force size and finally provides an examples hypothetical resource requirements for implementing mass dog vaccination at scale in Indian cities, with a view to supporting the planning of pilot campaigns from which expanded efforts can grow.

Mean corpuscular volume/mean corpuscular hemoglobin values are not reliable predictors of the ß-thalassemia carrier status among healthy diverse populations of Himachal Pradesh, India.

BACKGROUND: Himachal Pradesh is a hill state in North India in the Western Himalayas. ß-thalassemia is a genetic disorder of hemoglobin inherited in an autosomal recessive manner that results in defective globin production leading to the early destruction of red blood cells. ß-thalassemia has long been neglected in Himachal Pradesh due to popular belief that it runs along "Lahore-Gujarat-Punjab" belt in India. Therefore, there is no ß-thalassemia testing facility currently in the state. METHODS: To estimate the prevalence of ß-thalassemia carriers, we calculated the sample size based on probability proportional to size self-weighing design. In each of 20 selected colleges, 111 students having an age of 18-25 were tested for high-performance liquid chromatography (HPLC) and complete blood count. Some were further tested for the mutations. We computed sensitivity, specificity, positive predictive value (PPV) and negative predictive value, and receiver operating characteristic curve for mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) red cell parameters. RESULTS: Of the 2220 students, 57 were found to be ß-thalassemia carrier by HPLC. The overall prevalence rate was 2.6% which translates to probable 180,000 ß-thalassemia carriers in Himachal Pradesh. Six districts bordering highly endemic Punjab had a higher prevalence. Hemoglobin D-Punjab, Heterozygous-Iran Trait, and raised fetal hemoglobin were found. Thalassemia major and sickle cell disease were not found. Anemic status or MCV/MCH parameters were not found to be reliable predictors of thalassemia carrier status among the healthy populations of HP. The predominant mutation found was IVS 1-5 G > C. CONCLUSION: Popular ongoing strategy for screening with MCV and MCH has low-PPV and can miss upto 37% of true thalassemia carriers. HPLC is better strategy for screening carriers and reduces further spread of thalassemia.

Study of a hepatitis E virus outbreak involving drinking water and sewage contamination in Shimla, India, 2015-2016.

BACKGROUND: Hepatitis E, caused by hepatitis E virus (HEV), accounts for 50% of acute hepatitis cases in India. We report an outbreak of hepatitis E in Shimla, India, in 2015-2016. METHODS: ICMR-National Institute of Virology (NIV), Pune, received two batches of water samples from Shimla in January 2016 to test for the presence of enterically transmitted hepatitis viruses. Subsequently, 57 icterus patients were tested for various markers of hepatotropic viruses, i.e. anti-HEV IgM/IgG, anti-hepatitis A virus (anti-HAV) IgM/IgG antibodies and HEV RNA. Water samples were screened for HEV and HAV RNA followed by phylogenetic analysis. RESULTS: Overall, 48/57 patients availing municipal water had evidence of HEV infection, detected by serology and RT-PCR. All the water samples tested positive for HEV and HAV RNA, while the patients were negative for anti-HAV IgM antibody, indicating no recent HAV infection. Phylogenetic analysis confirmed the aetiological agent of the current outbreak to be HEV genotype 1. CONCLUSIONS: Serology and RT-PCR confirmed HEV as the aetiology of the outbreak. The absence of new cases of hepatitis A, despite the presence of HAV in the water supply, could be due to previously acquired immunity. Sewage contamination of water leading to faecal-oral transmission of HEV still remains a concern, thus emphasising the need for a vaccination/control strategy.

Wound-only injection of rabies immunoglobulin (RIG) saves lives and costs less than a dollar per patient by "pooling strategy".

Since 2008, we in Himachal Pradesh have used a "pooling strategy" to help patients save money by pooling vials of antirabies vaccine at a centralized hospital and sharing them using the intradermal technique. In 2014, there was an acute shortage of rabies immunoglobulins (RIG) and two patients died after four injections of rabies vaccine were administered without RIG, which was not commercially available. After an extensive literature review and technical and ethical committee clearances, in June 2014 we started to infiltrate equine RIG (eRIG) into wound/s only without the recommended systemic intramuscular (IM) injection. WHO recommended this technique in 2018. During the four-year period June 2014 to June 2018, 7506 of 10,830 patients exposed to suspected rabid animals were injected with eRIG in and around the wounds in a single clinic at DDU Hospital Shimla without any adverse outcomes. The average volume of eRIG used per patient was 0.75 mL and cost US$ 0.75. Of the 80% of patients who were followed up, all were healthy at the end of a year, including 26 patients bitten by laboratory-confirmed rabid dogs. The reaction rate after PEP administration also declined significantly. Since February 2018, Himachal has started following the new WHO recommendations on PEP regimens of three intradermal antirabies vaccines instead of four, thereby saving hundreds of vaccine vials that became useful during shortages of rabies vaccine in India. To date, more than 700 vaccine vials have been saved in a single clinic at DDU hospital during the past 6 months alone. Not giving PEP to patients who have consumed raw milk from a suspected rabid cow has also saved 62 vials. Currently, 90 "pooling centers" have been established for sharing of vaccine and eRIG vials in Himachal State, generating huge savings that have enabled the government to provide PEP free of charge to all. The new WHO guidelines are a positive step towards a rabies-free world by 2030.

Using a modified rabies immunoglobulin protocol in a crisis of unavailability: Ethical and practical challenges.

Rabies is a dreaded disease of zoonotic origin, responsible for an estimated 55,000 deaths annually, of which 20,000 deaths are in India. Some animal bite patients need rabies immunoglobulin (RIG) for post exposure prophylaxis, in addition to the vaccine against rabies. The major reason for the high death rate in India is the high cost of RIG. Until 2017, the WHO-recommended protocol required a large amount of RIG. I describe how a cost-saving protocol for RIG was implemented in Himachal Pradesh. The published results contributed to the modification of the WHO's global recommendations on RIG use.

Failure of postexposure prophylaxis in a girl child attacked by rabid dog severing her facial nerve causing possible direct entry of rabies virus into the facial nerve.

On January 4, 2019 an eight-year-old girl child was bitten by a suspected rabid dog over the left parotid region. After a 17-h delay, the child was brought for rabies postexposure prophylaxis (PEP) at Civil Hospital Theog and was administered complete PEP. On January 29, 2019, the child was again brought to Theog Hospital with complaints of having fever, difficulty in walking, neck drop, and ptosis. On examination, pediatrician found photophobia, phonophobia, and hydrophobia and subsequently the patient died of cardiac arrest. On postmortem examination, the facial nerve was found dissected and injured at the inner end of the parotid gland. A severed end toward the brain was swollen and edematous. The entire brain was extracted and sent to Central Research Institute Kasauli for confirmation of rabies, where it tested positive for rabies by Fluorescent Antibodies Test and Biological Test. In situations where sensitive parts such as the face are involved, a thorough wound wash with soap and water and application of antiseptics along with immediate PEP may save some lives by not allowing the virus enough time to attach to and infect the nerve cells.

Modelling to inform prophylaxis regimens to prevent human rabies.

BACKGROUND: The Strategic Advisory Group of Experts (SAGE) Working Group on rabies vaccines and immunoglobulins was established in 2016 to develop practical and feasible recommendations for prevention of human rabies. To support the SAGE agenda we developed models to compare the relative costs and potential benefits of rabies prevention strategies. METHODS: We examined Post-Exposure Prophylaxis (PEP) regimens, protocols for administration of Rabies Immunoglobulin (RIG) and inclusion of rabies Pre-Exposure Prophylaxis (PrEP) within the Expanded Programme on Immunization (EPI). For different PEP regimens, clinic throughputs and consumables for vaccine administration, we evaluated the cost per patient treated, costs to patients and potential to treat more patients given limited vaccine availability. RESULTS: We found that intradermal (ID) vaccination reduces the volume of vaccine used in all settings, is less costly and has potential to mitigate vaccine shortages. Specifically, the abridged 1-week 2-site ID regimen was the most cost-effective PEP regimen, even in settings with low numbers of bite patients presenting to clinics. We found advantages of administering RIG to the wound(s) only, using considerably less product than when the remaining dose is injected intramuscularly distant to the wound(s). We found that PrEP as part of the EPI programme would be substantially more expensive than use of PEP and dog vaccination in prevention of human rabies. CONCLUSIONS: These modeling insights inform WHO recommendations for use of human rabies vaccines and biologicals. Specifically, the 1-week 2-site ID regimen is recommended as it is less costly and treats many more patients when vaccine is in short supply. If available, RIG should be administered at the wound only. PrEP is highly unlikely to be an efficient use of resources and should therefore only be considered in extreme circumstances, where the incidence of rabies exposures is extremely high.

Failure of Postexposure Prophylaxis in a Patient Given Rabies Vaccine Intramuscularly in the Gluteus Muscle, Himachal Pradesh, India.

A 48-year-old male was bitten by a dog on the forehead and on the RIGHT side of left eyebrow on November 26, 2017, at 2 pm. The patient was immediately rushed to a nearby private hospital where an MBBS doctor gave him immediate wound wash with soap and water and prescribed five doses of rabies vaccine intramuscularly (IM). Since the patient weight was 60 kg, he was also prescribed 2400 IU of equine rabies immunoglobulin (ERIG), but as eRIG was not available, it was not administered. All the four doses of rabies vaccine were given IM in gluteus muscle. On December 17, 2017, the patient was brought to the Government Regional Hospital Hamirpur with the symptoms of difficulty in swallowing water (Hydrophobia) for 2 days. He was given injection diazepam and referred to Rajinder Prasad Government Medical College Tanda, Kangra, Himachal Pradesh, India, where he died of suspected rabies on December 19, 2017. The explicit consent to publish this report and picture was taken from the relatives of the patient, so that others have a lesson from this case report.