Static Postural Stability in Women during and after Pregnancy: A Prospective Longitudinal Study

This longitudinal study aimed to compare static postural stability in women between early pregnancy, advanced pregnancy, and at 2 and 6 months postpartum. Forty-five pregnant women were enrolled and 31 completed the protocol. Data were collected at 7–16 and 34–39 weeks gestation, and at 6–10 and 26–30 weeks postpartum. For each subject, the center of foot pressure path length and mean velocity (with directional subcomponents) were computed from 30-s long quiet-standing trials on a stationary force plate with eyes open or closed. The body mass, stance width, and sleep duration within 24 h before testing were also recorded. Static postural stability was not different between pregnancy and postpartum, except for the anterior posterior sway tested in the eyes-closed condition, which was significantly increased in late pregnancy compared to that at 2 and 6 months postpartum. Pregnant/postpartum women’s body mass weakly positively correlated with anterior-posterior sway in the eyes-closed condition and their stance width weakly positively correlated with the anterior-posterior sway in the eyes-open condition. No effect of sleep duration on postural sway was found. Our findings indicate that under visual deprivation conditions women in advanced pregnancy may have decreased static stability compared to their non-pregnant state.     

Pulse Wave Velocity Testing in the Baltimore Longitudinal Study of Aging

Carotid-femoral pulse wave velocity is considered the gold standard for measurements of central arterial stiffness obtained through noninvasive methods¹. Subjects are placed in the supine position and allowed to rest quietly for at least 10 min prior to the start of the exam. The proper cuff size is selected and a blood pressure is obtained using an oscillometric device. Once a resting blood pressure has been obtained, pressure waveforms are acquired from the right femoral and right common carotid arteries. The system then automatically calculates the pulse transit time between these two sites (using the carotid artery as a surrogate for the descending aorta). Body surface measurements are used to determine the distance traveled by the pulse wave between the two sampling sites. This distance is then divided by the pulse transit time resulting in the pulse wave velocity. The measurements are performed in triplicate and the average is used for analysis.     

Chikungunya Virus-associated Long-term Arthralgia: A 36-month Prospective Longitudinal Study

Background

Arthritogenic alphaviruses, including Chikungunya virus (CHIKV), are responsible for acute fever and arthralgia, but can also lead to chronic symptoms. In 2006, a Chikungunya outbreak occurred in La Réunion Island, during which we constituted a prospective cohort of viremic patients (n = 180) and defined the clinical and biological features of acute infection. Individuals were followed as part of a longitudinal study to investigate in details the long-term outcome of Chikungunya.

Methodology/Principal Findings

Patients were submitted to clinical investigations 4, 6, 14 and 36 months after presentation with acute CHIKV infection. At 36 months, 22 patients with arthralgia and 20 patients without arthralgia were randomly selected from the cohort and consented for blood sampling. During the 3 years following acute infection, 60% of patients had experienced symptoms of arthralgia, with most reporting episodic relapse and recovery periods. Long-term arthralgias were typically polyarthralgia (70%), that were usually symmetrical (90%) and highly incapacitating (77%). They were often associated with local swelling (63%), asthenia (77%) or depression (56%). The age over 35 years and the presence of arthralgia 4 months after the disease onset are risk factors of long-term arthralgia. Patients with long-term arthralgia did not display biological markers typically found in autoimmune or rheumatoid diseases. These data helped define the features of CHIKV-associated chronic arthralgia and permitted an estimation of the economic burden associated with arthralgia.

Conclusions/Significance

This study demonstrates that chronic arthralgia is a frequent complication of acute Chikungunya disease and suggests that it results from a local rather than systemic inflammation.     

Longitudinal Analysis of Maternal Plasma Apolipoproteins in Pregnancy: A Targeted Proteomics Approach

Minimally invasive diagnostic tests are needed in obstetrics to identify women at risk for complications during delivery. The apolipoproteins fluctuate in complexity and abundance in maternal plasma during pregnancy and could be incorporated into a blood test to evaluate this risk. The objective of this study was to examine the relative plasma concentrations of apolipoproteins and their biochemically modified subtypes (i.e. proteolytically processed, sialylated, cysteinylated, dimerized) over gestational time using a targeted mass spectrometry approach. Relative abundance of modified and unmodified apolipoproteins A-I, A-II, C-I, C-II, and C-III was determined by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in plasma prospectively collected from 11 gravidas with uncomplicated pregnancies at 4–5 gestational time points per patient. Apolipoproteins were readily identifiable by spectral pattern. Apo C-III₂ and Apo C-III₁ (doubly and singly sialylated Apo C-III subtypes) increased with gestational age (r²>0.8). Unmodified Apo A-II, Apo C-I, and Apo C-III₀ showed no correlation (r² = 0.01–0.1). Pro-Apo C-II did not increase significantly until third trimester (140 ± 13% of first trimester), but proteolytically cleaved, mature Apo C-II increased in late pregnancy (702 ± 130% of first trimester). Mature Apo C-II represented 6.7 ± 0.9% of total Apo C-II in early gestation and increased to 33 ± 4.5% in third trimester. A label-free, semiquantitative targeted proteomics approach was developed using LTQ-Orbitrap mass spectrometry to confirm the relative quantitative differences observed by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in Apo C-III and Apo C-II isoforms between first and third trimesters. Targeted apolipoprotein screening was applied to a cohort of term and preterm patients. Modified Apo A-II isoforms were significantly elevated in plasma from mothers who delivered prematurely relative to term controls (p = 0.02). These results support a role for targeted proteomics profiling approaches in monitoring healthy pregnancies and assessing risk of adverse obstetric outcomes.The maternal physiology during pregnancy is characterized by inflammation and hyperlipidemia. Plasma protein composition fluctuates dynamically throughout gestation to reflect these physiological changes. Apolipoproteins, a diverse subset of triglyceride transport proteins, contribute to the hyperlipidemia of pregnancy by modulating lipid homeostasis in maternal plasma (1–3). Exaggerated hyperlipidemia and peripheral apolipoprotein burden are associated with inflammatory insult and signal obstetric complications (4–5). Numerous post-translationally modified apolipoprotein isoforms are reported in plasma, but it is unclear how these modifications affect apolipoprotein function and plasma distribution. For example, changes in the glycosylation status of apolipoprotein variants predate the onset of clinical symptoms in patients with preeclampsia, a hypertensive disorder of pregnancy with clinical features in common with cardiovascular disease (6–8). The identification and functional characterization of plasma apolipoprotein isoforms and their post-translationally modified subtypes may reveal important diagnostic and/or therapeutic targets for hypertensive disorders of pregnancy (6).Mass spectrometry and targeted proteomics analyses afford unprecedented sensitivity and specificity for detecting apolipoproteins and their numerous isoforms and subtypes (9–12). Mass spectrometry approaches overcome limitations inherent in biochemical approaches (e.g. ELISA [enzyme-linked immunosorbant assays] and Western blot analysis), especially the lack of specificity of antibodies for post-translationally modified variants of plasma proteins. The objective of this study was to longitudinally evaluate maternal plasma apolipoprotein profile over gestational time by SELDI-TOF-MS (surface-enhanced laser desorption/ionization-time of flight-mass spectrometry)¹ analysis of intact proteins and a complementary targeted LTQ-Orbitrap XL MS approach. We evaluate changes in 13 post-translationally modified subtypes of the plasma apolipoproteins A-II, C-I, C-II, and C-III over gestational time.     

Maternal Functional Hemodynamics in the Second Half of Pregnancy: A Longitudinal Study

Objective

Cardiovascular response to passive leg raising (PLR) is useful in assessing preload reserve, but it has not been studied longitudinally during pregnancy. We aimed to investigate gestational age associated serial changes in maternal functional hemodynamics and establish longitudinal reference ranges for the second half of pregnancy.

Materials and Methods

This was a prospective longitudinal study on 98 healthy pregnant women who were examined 3–5 times during 20–40 weeks of gestation (a total of 441 observations). Maternal cardiac function and systemic hemodynamics were assessed at baseline and 90 seconds after PLR using impedance cardiography (ICG). The main outcome measures were gestational age specific changes in ICG-derived variables of maternal cardiovascular function and functional hemodynamic response to PLR.

Results

Hemodynamic response to PLR varied during pregnancy. PLR led to an insignificant increase in stroke volume during 20⁺⁰ to 31⁺⁶ weeks, but later in gestation the stroke volume was slightly lower at PLR compared to baseline. PLR caused no significant change in cardiac output between 20⁺⁰ and 23⁺⁶ weeks and a significant decrease after 24⁺⁰ weeks. A decrease in heart rate, mean arterial pressure, and cardiac contractility was observed during PLR throughout the second half of pregnancy. Systemic vascular resistance was reduced by PLR up to 32⁺⁰ weeks, but increased slightly thereafter.

Conclusion

Healthy pregnant women appear to have limited preload reserve and reduced cardiac contractility, especially in the third trimester, which makes them vulnerable to fluid overload and cardiac failure.     

Pulse Wave Propagation in Elastic Tubes Having Longitudinal Changes in Area and Stiffness

The behavior of both step waves and sinusoidal waves in fluid-filled elastic vessels whose area and distensibility vary with distance is explored theoretically. It is shown that the behavior of these waves may be explained, to a large extent, by considering the effect of the continuous stream of infinitesimal reflections that is set up whenever any wave travels in a region of vessel where the local impedance, (that is, the ratio of elastic wavespeed to tube area) is not constant. It is found that in such vessels the behavior of sinusoidal waves over distances which are a fraction of a wavelength can be quite different from their average behavior over several wavelengths. Both behaviors are described analytically. The results are applied to the mammalian circulatory system, one of the most interesting results being that a longitudinal variation in the pressure and velocity amplitudes which has a wavelength roughly one-half that of standing waves is predicted. The treatment is essentially a linearized quasi-one-dimensional one, the major assumptions being that the fluid is inviscid, the mean flow is zero, and the vessel is perfectly elastic and constrained from motion in the longitudinal direction. As in the physiological situation, the ratio of fluid velocity to pulse propagation speed is assumed small. For comparison with the analytical results, the linearized equations are also solved numerically by computer.     

Maternal Health Factors as Risks for Postnatal Depression: A Prospective Longitudinal Study

Purpose

While previous studies have identified a range of potential risk factors for postnatal depression (PND), none have examined a comprehensive set of risk factors at a population-level using data collected prospectively. The aim of this study was to explore the relationship between a range of factors and PND and to construct a model of the predictors of PND.

Methods

Data came from 5219 women who completed Survey 5 of the Australian Longitudinal Study on Women’s Health in 2009 and reported giving birth to a child.

Results

Over 15% of women reported experiencing PND with at least one of their children. The strongest positive associations were for postnatal anxiety (OR = 13.79,95%CI = 10.48,18.13) and antenatal depression (OR = 9.23,95%CI = 6.10,13.97). Positive associations were also found for history of depression and PND, low SF-36 Mental Health Index, emotional distress during labour, and breastfeeding for less than six months.

Conclusions

Results indicate that understanding a woman’s mental health history plays an important role in the detection of those who are most vulnerable to PND. Treatment and management of depression and anxiety earlier in life and during pregnancy may have a positive impact on the incidence of PND.     

Risk of Vertical Transmission of Human Papillomavirus throughout Pregnancy: A Prospective Study

Objective

Much controversy still exists about maternal-to-infant transmission of human papillomavirus (HPV) infection, specifically about the magnitude of the risk and the route and timing of such vertical transmission. This prospective cohort study examines the risk of vertical transmission of maternal HPV in each trimester of pregnancy.

Study design

One hundred fifty three healthy pregnant women were followed longitudinally throughout pregnancy and cervical swabs obtained in each trimester and postpartum for HPV detection. Cord blood, neonatal nasopharyngeal aspirates, and placental biopsies were collected at delivery. DNA isolation, polymerase chain reaction, and hybridization were performed using the GG HPV Genotyping Chip Kit (Goodgene Inc., Seoul, Korea). Detection of HPV in neonates was defined as the presence of HPV DNA in either cord blood or neonatal nasopharyngeal aspirate.

Results

HPV DNA was detected in 14%(22/153) of healthy women in the first trimester, 18%(22/124) in the second trimester, and 10%(15/153) in the third trimester; 24%(37/153) were positive for HPV DNA on at least one occasion in pregnancy. At birth, 5.2%(8/153) of neonates were HPV DNA positive. Seven of these eight infants were born to HPV-positive mothers. Placental HPV DNA was positive in 3.3%(5/152) of cases, and all five cases were from mothers with at least one HPV-positive test. Detection of HPV DNA in neonates was associated with detection of HPV in mothers during any of the three trimesters of pregnancy.

Conclusion

HPV DNA was detected at birth in 5.2%(8/153) of neonates born to healthy women, and was associated with the detection of HPV in mothers during any of the three trimesters of pregnancy.     

Risky Drinking Patterns Are Being Continued into Pregnancy: A Prospective Cohort Study

Background

Risky patterns of alcohol use prior to pregnancy increase the risk of alcohol-exposed pregnancies and subsequent adverse outcomes. It is important to understand how consumption changes once women become pregnant.

Objective

The aim of this study was to describe the characteristics of women that partake in risky drinking patterns before pregnancy and to examine how these patterns change once they become pregnant.

Methods

A sample of 1577 women from the 1973–78 cohort of the Australian Longitudinal Study on Women’s Health were included if they first reported being pregnant in 2000, 2003, 2006, 2009 and reported risky drinking patterns prior to that pregnancy. Multinomial logistic regression was used to determine which risky drinking patterns were most likely to continue into pregnancy.

Results

When reporting risky drinking patterns prior to pregnancy only 6% of women reported weekly drinking only, whereas 46% reported binge drinking only and 48% reported both. Women in both binge categories were more likely to have experienced financial stress, not been partnered, smoked, used drugs, been nulliparous, experienced a violent relationship, and were less educated. Most women (46%) continued these risky drinking patterns into pregnancy, with 40% reducing these behaviors, and 14% completely ceasing alcohol consumption. Once pregnant, women who binged only prior to pregnancy were more likely to continue (55%) rather than reduce drinking (29%). Of the combined drinking group 61% continued to binge and 47% continued weekly drinking. Compared with the combined drinking group, binge only drinkers prior to pregnancy were less likely to reduce rather than continue their drinking once pregnant (OR = 0.37, 95% CI  =  0.29, 0.47).

Conclusions

Over a third of women continued risky drinking into pregnancy, especially binge drinking, suggesting a need to address alcohol consumption prior to pregnancy.     

Trypanosoma-Cruzi Cross-Reactive Antibodies Longitudinal Follow-Up: A Prospective Observational Study in Hematopoietic Stem Cell Transplantation

Antibodies named TcCRA “Trypanosoma cruzi Cross Reactive Antibodies” were detected in 47% of blood donors from French population unexposed to the parasite. In order to evaluate the passive or active transmissibility of TcCRA and further characterize its role and etiology, we have conducted a study in a cohort of 47 patients who underwent allogeneic Hematopoietic Stem Cell Transplantations (allo-HSCT). Donors and recipients were tested for TcCRA prior to transplantation. Recipients were further tested during follow-up after transplantation. Demographical, clinical and biological data were collected. Our primary end-point was to assess the risk of TcCRA acquisition after transplantation. During this initial analysis, we observed no seroconversion in patients receiving cells from TcCRA negative donors (n = 23) but detected seroconversion in 4 out of 24 patients who received hematopoietic stem cells from positive donors. Here, we are discussing possible scenarios to explain TcCRA-immune status in recipient after transplantation.     

Predictive Factors of Plasma HIV Suppression during Pregnancy: A Prospective Cohort Study in Benin

Objective

To investigate the factors associated with HIV₁ RNA plasma viral load (pVL) below 40 copies/mL at the third trimester of pregnancy, as part of prevention of mother-to-child transmission (PMTCT) in Benin.

Design

Sub study of the PACOME clinical trial of malaria prophylaxis in HIV-infected pregnant women, conducted before and after the implementation of the WHO 2009 revised guidelines for PMTCT.

Methods

HIV-infected women were enrolled in the second trimester of pregnancy. Socio-economic characteristics, HIV history, clinical and biological characteristics were recorded. Malaria prevention and PMTCT involving antiretroviral therapy (ART) for mothers and infants were provided. Logistic regression helped identifying factors associated with virologic suppression at the end of pregnancy.

Results

Overall 217 third trimester pVLs were available, and 71% showed undetectability. Virologic suppression was more frequent in women enrolled after the change in PMTCT recommendations, advising to start ART at 14 weeks instead of 28 weeks of pregnancy. In multivariate analysis, Fon ethnic group (the predominant ethnic group in the study area), regular job, first and second pregnancy, higher baseline pVL and impaired adherence to ART were negative factors whereas higher weight, higher antenatal care attendance and longer ART duration were favorable factors to achieve virologic suppression.

Conclusions

This study provides more evidence that ART has to be initiated before the last trimester of pregnancy to achieve an undetectable pVL before delivery. In Benin, new recommendations supporting early initiation were well implemented and, together with a high antenatal care attendance, led to high rate of virologic control.     

Micronutrient Levels and Supplement Intake in Pregnancy after Bariatric Surgery: A Prospective Cohort Study

Background

Studies report frequent micronutrient deficiencies after bariatric surgery, but less is known about micronutrient levels of pregnant women after bariatric surgery.

Objective

To prospectively evaluate micronutrient levels and supplement intake in pregnancy following bariatric surgery.

Design

A multicenter prospective cohort study including women with restrictive or malabsorptive types of bariatric surgery. Nutritional deficiencies, together with supplement intake, were screened during pregnancy.

Results

The total population included 18 women in the restrictive and 31 in the malabsorptive group. Most micronutrients were depleted and declined significantly during pregnancy. The proportion of women with low vitamin A and B-1 levels increased to respectively 58 and 17% at delivery (P = 0.005 and 0.002). The proportion of women with vitamin D deficiency decreased from 14% at trimester 1 to 6% at delivery (P = 0.030). Mild anemia was found in respectively 22 and 40% of the women at trimester 1 and delivery. In the first trimester, most women took a multivitamin (57.1%). In the second and third trimester, the majority took additional supplements (69.4 and 73.5%). No associations were found between supplement intake and micronutrient deficiencies.

Conclusion

Pregnant women with bariatric surgery show frequent low micronutrient levels. Supplementation partially normalizes low levels of micronutrients.     

Sequential Analysis of Longitudinal Data in a Prospective Nested Case–Control Study

Summary The nested case–control design is a relatively new type of observational study whereby a case–control approach is employed within an established cohort. In this design, we observe cases and controls longitudinally by sampling all cases whenever they occur but controls at certain time points. Controls can be obtained at time points randomly scheduled or prefixed for operational convenience. This design with longitudinal observations is efficient in terms of cost and duration, especially when the disease is rare and the assessment of exposure levels is difficult. In our design, we propose sequential sampling methods and study both (group) sequential testing and estimation methods so that the study can be stopped as soon as the stopping rule is satisfied. To make such a longitudinal sampling more efficient in terms of both numbers of subjects and replications, we propose applying sequential sampling methods to subjects and replications, simultaneously, until the information criterion is fulfilled. This simultaneous sequential sampling on subjects and replicates is more flexible for practitioners designing their sampling schemes, and is different from the classical approaches used in longitudinal studies. We newly define the σ‐field to accommodate our proposed sampling scheme, which contains mixtures of independent and correlated observations, and prove the asymptotic optimality of sequential estimation based on the martingale theories. We also prove that the independent increment structure is retained so that the group sequential method is applicable. Finally, we present results by employing sequential estimation and group sequential testing on both simulated data and real data on children's diarrhea.     

Comparisons of Prediction Models of Quality of Life after Laparoscopic Cholecystectomy: A Longitudinal Prospective Study

Background

Few studies of laparoscopic cholecystectomy (LC) outcome have used longitudinal data for more than two years. Moreover, no studies have considered group differences in factors other than outcome such as age and nonsurgical treatment. Additionally, almost all published articles agree that the essential issue of the internal validity (reproducibility) of the artificial neural network (ANN), support vector machine (SVM), Gaussian process regression (GPR) and multiple linear regression (MLR) models has not been adequately addressed. This study proposed to validate the use of these models for predicting quality of life (QOL) after LC and to compare the predictive capability of ANNs with that of SVM, GPR and MLR.

Methodology/Principal Findings

A total of 400 LC patients completed the SF-36 and the Gastrointestinal Quality of Life Index at baseline and at 2 years postoperatively. The criteria for evaluating the accuracy of the system models were mean square error (MSE) and mean absolute percentage error (MAPE). A global sensitivity analysis was also performed to assess the relative significance of input parameters in the system model and to rank the variables in order of importance. Compared to SVM, GPR and MLR models, the ANN model generally had smaller MSE and MAPE values in the training data set and test data set. Most ANN models had MAPE values ranging from 4.20% to 8.60%, and most had high prediction accuracy. The global sensitivity analysis also showed that preoperative functional status was the best parameter for predicting QOL after LC.

Conclusions/Significance

Compared with SVM, GPR and MLR models, the ANN model in this study was more accurate in predicting patient-reported QOL and had higher overall performance indices. Further studies of this model may consider the effect of a more detailed database that includes complications and clinical examination findings as well as more detailed outcome data.     

Passive Smoking Is Associated with Poor Asthma Control during Pregnancy: A Prospective Study of 500 Pregnancies

Background and Aim

Asthma and tobacco exposure is common among pregnant women. We investigated the effect of passive and active smoking on asthma control during pregnancy.

Methods

Prospective observational design. Patients had their asthma control, based on symptoms, use of medication, spirometry, and exhaled nitric oxide [F_ENO], assessed every four weeks during 2^nd and 3^rd trimester of pregnancy; data on tobacco exposure were also collected prospectively. The primary outcome was episodes of uncontrolled and partly controlled asthma during pregnancy (defined according to GINA-guidelines).

Results

A total of 500 pregnant women with asthma (mean age 30.8 years, range 17 to 44) were consecutively included, of whom 32 (6.4%), 115 (23.0%) and 353 (70.6%), respectively, were current smokers, ex-smokers and never smokers [NS]. Sixty-five NS (18.4%) reported passive tobacco exposure. NS with passive tobacco exposure had significantly lower FEV₁% predicted (p<0.02) and F_ENO (p = 0.01) compared to NS without passive tobacco exposure. The relative risk [RR] of an episode of uncontrolled asthma during pregnancy was 4.5 (95% CI 2.7–7.5: p<0.001) in current and ex-smokers compared with never smokers, and 2.9 (95% CI 1.4–5.9; p = 0.004) in NS-women with passive tobacco exposure compared with NS-women not reporting passive tobacco exposure. Treatment with inhaled corticosteroids, most likely as a marker of more severe asthma, was also associated with a higher risk (RR 8.1, 95% CI 5.1–13.0; p<0.001) of an episode of uncontrolled asthma.

Conclusion

Passive tobacco exposure in never smokers is associated with an increased risk of episodes of uncontrolled asthma during pregnancy, which is likely to have adverse effects on pregnancy outcome.     

Risk of Adverse Pregnancy Outcomes among Women Practicing Poor Sanitation in Rural India: A Population-Based Prospective Cohort Study

BackgroundThe importance of maternal sanitation behaviour during pregnancy for birth outcomes remains unclear. Poor sanitation practices can promote infection and induce stress during pregnancy and may contribute to adverse pregnancy outcomes (APOs). We aimed to assess whether poor sanitation practices were associated with increased risk of APOs such as preterm birth and low birth weight in a population-based study in rural India.ConclusionsThis study provides the first evidence, to our knowledge, that poor sanitation is associated with a higher risk of APOs. Additional studies are required to elucidate the socio-behavioural and/or biological basis of this association so that appropriate targeted interventions might be designed to support improved birth outcomes in vulnerable populations. While it is intuitive to expect that caste and poverty are associated with poor sanitation practice driving APOs, and we cannot rule out additional confounders, our results demonstrate that the association of poor sanitation practices (open defecation) with these outcomes is independent of poverty. Our results support the need to assess the mechanisms, both biological and behavioural, by which limited access to improved sanitation leads to APOs.     

Sleep Apnea: A Prospective Study

Sleep apnea is remarkably prevalent among general medical patients. Of 26 men randomly selected on a Veterans Administratin hospital medical ward, with a mean age of 66.2 (SD=11.5) years, 7 (27%) had sleep apnea. Of concern is that two of the seven patients were receiving hypnotic drugs. Portable sleep recordings may need to be done when routinely assessing elderly medical patients.     

Candiduria in Hospital Patients: A Study Prospective

Tinea capitis is rare in adults. We report a case of adult tinea capitis due to Trichophyton violaceum in China. The female patient was immunosuppressed with prednisone due to the underlying disease of vulgaris pemphigus and was treated successfully with terbinafine. We also reviewed published cases of adult tinea capitis in China and compared these data with the characteristics of published cases in other regions in the world.