The Correlation of Retinal Nerve Fiber Layer Thickness With Blood Pressure in a Chinese Hypertensive Population

To investigate the association between retinal nerve fiber layer (RNFL) thickness and blood pressure (BP) in subjects with systemic hypertension.Subjects with systemic hypertension on anti-hypertensive medications were screened by fundus photography and referred for glaucoma work-up if there was enlarged vertical cup-to-disc (VCDR) ratio ≥0.6, VCDR asymmetry ≥0.2, or optic disc hemorrhage. Workup included a complete ophthalmological examination, Humphrey visual field test, and RNFL thickness measurement by optical coherence tomography. The intraocular pressure (IOP) and RNFL thicknesses (global and quadrant) were averaged from both eyes and the means were correlated with: the systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) using Pearson correlation.Among 4000 screened hypertensive subjects, 133 were referred for glaucoma workup and 110 completed the workup. Of the 4000 screened subjects, 1.3% had glaucoma (0.9% had normal tension glaucoma [NTG], 0.2% had primary open angle glaucoma, and 0.2% had primary angle closure glaucoma), whereas 0.3% were NTG suspects. The SBP was negatively correlated with the mean superior RNFL thickness (P = 0.01). The DBP was negatively correlated with the mean global (P = 0.03), superior (P = 0.02), and nasal (P = 0.003) RNFL thickness. The MAP was negatively correlated with the mean global (P = 0.01), superior (P = 0.002), and nasal (P = 0.004) RNFL thickness while positively correlated with the mean IOP (P = 0.02).In medically treated hypertensive subjects, glaucoma was present in 1.3%, with NTG being most prevalent. MAP control may help with IOP lowering and RNFL preservation, although future prospective studies will be needed.Glaucoma is a chronic, progressive and irreversible optic neuropathy with characteristic anatomical and structural defects due to loss of the retinal ganglion cells. Loss of the retinal nerve fiber layer (RNFL) may precede visual field changes.^1,2 Various studies have demonstrated that up to 40–50% of the retinal ganglion cells need to be lost before visual field defects are observed in standard automated perimetry, which is still considered to be one of the gold standard investigations for glaucoma.^3,4 Assessment of RNFL thickness, on the other hand, is an objective test that has a high degree of correlation with visual field defects but at the same time able to detect earlier, pre-perimetric disease.^5,6Intraocular pressure (IOP) is still the most important modifiable risk factor of glaucoma progression. Vascular risk factors such as systemic hypertension, ocular perfusion pressure, hypercoagulability, carotid artery disease, and vasospasm have been extensively studied and it has been demonstrated that ocular hypoperfusion and systemic blood pressure play a vital role in the pathogenesis of glaucoma.^7–13 Some studies have demonstrated a positive association between systemic hypertension (HT) and glaucoma,^14–18 whereas others have demonstrated no significant association between the 2 entities.^19,20To our knowledge, very few studies have examined the association between RNFL thickness and BP.^21,22 The purpose of our study was to determine association between RNFL thickness with systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in subjects with medically treated systemic HT.     

Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review

Adult-onset Still''s disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients.Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent.Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2–6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3–47.5] mg/day at ANK onset to 5 [0–10] at 12 months. After a median [IQR] follow-up of 16 [5–50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5).ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations.Adult-Onset Still''s Disease (AOSD) is a systemic inflammatory disease of unknown origin characterized by daily high-spiking fevers, evanescent maculopapular rash, sore throat, arthritis and/or arthralgia, myalgia, serositis, lymphadenopathy, and hepatosplenomegaly. Laboratory evaluation typically demonstrates elevated acute-phase reactants, leukocytosis with neutrophil predominance, elevated levels of liver enzymes, and high levels of serum ferritin.^1,2AOSD is considered a complex autoinflammatory syndrome in which various environmental factors trigger an autoinflammatory systemic response in genetically predisposed individuals. Interleukin-1 (IL-1) appears to be implicated in AOSD pathogenesis as increased levels of this cytokine have been found in these patients compared to healthy controls.^3,4 Cytokine profile in AOSD sera is also characterized by the presence of interleukin-6 (IL-6), IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ).^5,6 Moreover, one of the major events in the pathogenesis of this syndrome seems to be a dysregulation of inflammasome complex and a related overproduction of active IL-1β promoted by IL-18.⁷The central role of the inflammasome complex may explain the intermittent course of the disease and the clinical and laboratory features that are found in genetically predisposed autoinflammatory syndromes.First-line treatment in AOSD has been classically based on nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. In an attempt to use the lowest possible dose of corticosteroids, other therapies, such as methotrexate, azathioprine, leflunomide, intravenous immunoglobulin, anti-TNF-α drugs, rituximab, or abatacept, are often given to achieve adequate control of the disease. However, the efficacy of these drugs is variable and they are not exempt from potential severe side effects.Anakinra (ANK) is a recombinant, nonglycosylated form of human IL-1 receptor that acts as a pure receptor antagonist binding tightly to the IL-1 receptor and preventing activation of this receptor by either IL-1β or IL-1α. Approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis in 2001, its use in AOSD is supported by the pivotal role of IL-1β in this disease. In fact, ANK has been used for the treatment of AOSD with satisfactory results. However, in most cases information related to this issue was based on isolated cases reports or AOSD small series.^3,4,8–11Nevertheless, in an open, randomized, multicenter study that included 22 patients with AOSD taking prednisolone ≥10 mg/day, ANK induced more beneficial responses than disease-modifying antirheumatic drugs (DMARD).¹²Taking into account these considerations, our aim was to evaluate the efficacy of ANK in a large series of Spanish patients with AOSD refractory to other therapies.     

Jamestown Canyon Virus Disease in the United States—2000–2013

Jamestown Canyon virus (JCV) is a mosquito-borne orthobunyavirus in the California serogroup that can cause an acute febrile illness, meningitis, or meningoencephalitis. We describe epidemiologic and clinical features for JCV disease cases occurring in the United States during 2000–2013. A case of JCV disease was defined as an acute illness in a person with laboratory evidence of a recent JCV infection. During 2000–2013, we identified 31 cases of JCV disease in residents of 13 states. The median age was 48 years (range, 10–69) and 21 (68%) were male. Eleven (35%) case patients had meningoencephalitis, 6 (19%) meningitis, 7 (23%) fever without neurologic involvement, and 7 (23%) had an unknown clinical syndrome. Fifteen (48%) were hospitalized and there were no deaths. Health-care providers and public health officials should consider JCV disease in the differential diagnoses of viral meningitis and encephalitis, obtain appropriate specimens for testing, and report cases to public health authorities.Jamestown Canyon virus (JCV) is a mosquito-borne orthobunyavirus that causes an acute febrile illness, meningitis, or meningoencephalitis.^1–5 Although JCV is widely distributed throughout temperate North America, reports of human JCV infection in the United States are rare.¹ JCV was first isolated in 1961 from a pool of Culiseta inornata mosquitoes in Jamestown Canyon, CO.⁶ Since then, the virus has been isolated from various mosquito species (e.g., Aedes, Coquillettidia, Culex, and Culiseta species) in the northeastern, midwestern, and western United States.^6–19 JCV neutralizing antibodies have been found in various mammals throughout mainland North America,^13,20–36 and identified in humans throughout the United States.^{1–5,34,37–41}JCV is a member of the California serogroup viruses, which include La Crosse virus (LACV), California encephalitis virus, and snowshoe hare virus.⁴² Although the presence of anti-JCV immunoglobulin (Ig) M detected by enzyme-linked immunosorbent assay (ELISA) is usually evidence of a recent JCV infection, it also may indicate infection with another closely related California serogroup virus.^35,42,43 Plaque reduction neutralization tests (PRNTs) can be performed to measure virus-specific neutralizing antibodies and to potentially discriminate among cross-reacting antibodies from closely related California serogroup viruses.^44,45Prior to 2014, testing for JCV infection in the United States was performed at the Arboviral Diseases Branch of the Centers for Disease Control and Prevention (CDC) and at the Wadsworth Laboratory of the New York State Department of Health (NYSDOH). Since 2000, NYSDOH has been able to perform JCV PRNTs on acute and convalescent samples testing positive for California serogroup IgG antibodies by immunofluorescence assay. At the CDC, PRNTs have been used to detect JCV neutralizing antibodies since 1995. All samples testing positive or equivocal for LACV IgM antibodies by ELISA at the CDC have JCV PRNTs performed. A JCV IgM ELISA was developed at the CDC in 2010. Beginning in 2013, all samples submitted to the CDC for domestic arbovirus testing were routinely tested for JCV IgM antibodies by ELISA, and if positive, were confirmed by JCV PRNTs. We describe the demographic and clinical characteristics of laboratory-confirmed cases of JCV disease occurring in the United States during 2000–2013.     

Impact of prehypertension on left ventricular mass and QT dispersion in adult black Nigerians

The heterogeneity of individuals with blood pressure (BP) < 140/90 mmHg in terms of cardiovascular (CV) risk was reported as early as 1939 by Robinson and Brucer.1 BP in the range of 120–139/80–89 mmHg (labelled then as prehypertension) was observed to be associated with high risk of progression to hypertension (HT) and cardiovascular disease (CVD) later in life when compared with BP < 120/80 mm Hg.1The term prehypertension was adopted in May 2003 by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High blood Pressure (JNC-7) to describe BP range of 120–139/80–89 mmHg.2 The resuscitation of this terminology/concept in JNC-7 was a sequel to the documentation of a higher morbidity in individuals with prehypertension in landmark publications.3-5 Prehypertension (PHT) was defined in JNC-7 not only to emphasise the excess risk associated with BP in this range, but also to focus increased clinical and public health attention on prevention.2,6,7Prevalence rates of PHT among adults in the United States, Ghana and northern Nigeria have been reported to be 31, 40 and 58.7%, respectively.7-9 In most studies, including the ones above, PHT was more prevalent than hypertension.7-9 Though PHT is associated with increased risk of major CV events independently of other CV risk factors,10 most individuals (90%) with PHT have at least one cardiovascular risk factor such as dyslipidaemia, abdominal obesity, hyperinsulinaemia, impaired fasting glucose levels, insulin resistance, a prothrombotic state, tobacco use, endothelial dysfunction, and impaired vascular distensibility.6,7,9,10QT interval dispersion (QTd) (the difference between the longest and the shortest QT intervals on a surface ECG), when excessive, is associated with increased risk of cardiovascular morbidity and mortality in population studies, and many clinical conditions, including hypertension.11,12 This has been related to ventricular electrical instability, providing the necessary substrate for lethal ventricular arrhythmias.12,13 Greater QTd and left ventricular mass have been demonstrated in hypertensive individuals compared with normal individuals.11,13,14Considering the well-established, linear relationship between BP and the risk of cardiovascular events, the CV risk associated with PHT is intermediate between normotension and hypertension.2,03 Hence, electrocardiographic and echocardiographic indices of target-organ damage in PHT may also be intermediate between normotension and hypertension. The aims of this study were: (1) to compare the QTd and indices of left ventricular hypertrophy in adult black normal and prehypertensive subjects, and (2) to evaluate the relationship of QTd with electrocardiographic and echocardiographic indices in these subjects.     

Sickle cell trait is not associated with chronic kidney disease in adult Congolese patients: a clinic-based,cross-sectional study

Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with significant cardiovascular (CV) and renal morbidity and mortality rates, with substantial economic burden.1,2 Therefore, early identification of CKD patients at high risk of progression is urgently needed for early and targeted treatment to improve patient care.1-3 Diabetes and hypertension are the primary risk factors for CKD and ESRD but do not fully account for CKD and ESRD risk.1-3 Marked variability in the incidence of CKD suggests that factors other than diabetes and hypertension contribute to its aetiology.4Family studies have suggested a genetic component to the aetiology of CKD and ESRD.5 In African Americans, high-risk common variants in the Apol1/MYH9 locus may explain up to 70% of the differences in ESRD rates between European and African Americans.5 While this finding has great implications for ESRD, the identification of additional risk factors for CKD, including genetic loci in association with estimated glomerular filtration rate (eGFR), may help to advance our understanding of the underpinnings of CKD in African Americans.5 In this era of identifying genetic risk factors for kidney disease, it may be appropriate to revisit one of the most common genetic disorders: sickle cell haemoglobinopathies.5In this regard, sickle cell trait (SCT), present in approximately 7–9% of African Americans, has been reported to be a potential candidate gene.6 However, conflicting reports exist as to whether SCT is a risk factor for the progression of nephropathy.6,7 Haemoglobin S (HbS) was selected for in Africa because of the protection it affords from malarial infection, a scenario similar to the protection from trypanosomal infection provided by heterozygosity for APOL1 nephropathy risk variants.6Whereas APOL1 contributes to risk for nephropathy in an autosomal recessive inheritance pattern, HbS reportedly had a dominant effect on risk, with SCT being associated with ESRD.6 In line with this finding, a few small studies on African Americans reported HbS as an independent risk factor for CKD and ESRD.8 However, other studies using a large sample of African Americans stated that SCT was not independently associated with susceptibility to ESRD in African Americans,6 highlighting the need for further studies in other populations such as those of sub-Saharan Africa where SCT is prevalent.Although SCT is very prevalent in black Africans,9 few studies have been conducted to assess the association between SCT and CKD.10 In Democratic Republic of Congo (DRC), the prevalence of CKD and SCT has been reported to be 12% and 17–24%, respectively.11-13 No study has evaluated the frequency of SCT among CKD patients to assess its association with reduced kidney function. Therefore, the aim of this clinic-based, cross-sectional study was to assess the potential association between SCT and CKD among adult Congolese patients.     

Improving the Management of Dysglycemia in Children in the Developing World

Improving the availability of point-of-care (POC) diagnostics for glucose is crucial in resource-constrained settings (RCS). Both hypo and hyperglycemia have an appreciable frequency in the tropics and have been associated with increased risk of deaths in pediatrics units. However, causes of dysglycemia, including hyperglycemia, are numerous and insufficiently documented in RCS. Effective glycemic control with glucose infusion and/or intensive insulin therapy can improve clinical outcomes in western settings. A non-invasive way for insulin administration is not yet available for hyperglycemia. We documented a few causes and developed simple POC treatment of hypoglycemia in RCS. We showed the efficacy of sublingual sugar in two clinical trials. Dextrose gel has been recently tested for neonate mortality. This represents an interesting alternative that should be compared with sublingual sugar in RCS. New studies had to be done to document dysglycemia mechanism, frequency and morbid-mortality, and safe POC treatment in the tropics.Recently, Michael Hawkes and colleagues¹ reported the performance of point-of-care (POC) tests to guide the management of 179 children with severe malaria in a resource-limited Ugandan hospital. They paired measurements of glucose using i-STAT and OneTouch Ultra glucometer and other measurements for lactate and hemoglobin. Despite the small sample size of children with hypoglycemia and the lack of gold standard methods, they concluded that diagnostic tools, although imperfect, may expedite clinical decision-making in the management of critically ill children in resource-constrained settings (RCS). We completely agree with the crucial need for improving the availability of point-of-care diagnostics for glucose, particularly in RCS where hypoglycemia is a common and underdiagnosed cause of death.^2–4 However, the sole diagnosis of dysglycemia is not sufficient if an access to effective therapy is not feasible, especially in the field for comatose children.For this purpose, we assessed the frequency of dysglycemia in sick children in non-malaria areas.² In the pediatric ward of a referral hospital in Madagascar, an appreciable frequency (10.9%) (95% confidence interval [CI], 8.1–14.3) of hyperglycemic children at admission carried an increased risk of death (risk ratio [RR]: 2.2, 95% CI: 1–4.7).² This association of hyperglycemia and increased mortality was described in rural Kenya and in a tertiary care hospital in India.^5,6 However, data on hyperglycemia frequency, causes, and mortality remains scarce in the tropics.^7,8 In the same study, we also found a 3.0% (95% CI, 1.6–5.2) prevalence of hypoglycemia among 420 consecutive children.² Hypoglycemia was associated with increased risk of deaths (RR: 19.4, 95% CI: 5.0–74.7) after multivariate analyses. The rate of hypoglycemia was consistent with reports from Tanzania⁹ but lower than rates reported in malaria areas.^5–7,10,11Hypoglycemia is a common and serious complication in children with severe malaria, and it also is indicative of mortality caused by this disease.^10,12 Depletion of glucose stores caused by starvation, parasite use of glucose, and cytokine-induced impairment of gluconeogenesis have been implicated.¹³ Hyperinsulinemia, secondary to parenteral quinine therapy, has been advanced as an iatrogenic cause and is well established in adults.^14,15 Hypoglycemia related to intoxication is probably another highly underestimated cause of death in the tropics. As an example, we investigated the seasonal epidemic of fatal encephalopathy in preschool children in Burkina Faso and related the deaths to the consumption of unripe ackee (Blighia sapida) fruit and hypoglycin, a potent lethal hypoglycemic agent present in unripe ackee.^16,17 There are numerous other causes that often remain undiagnosed. Moreover, hypoglycemia may be aggravated by several generally accepted risk factors such as the altered nutritional status, the severity of the infectious diseases, the young age, the delay in admittance to the hospital, the use of potentially toxic herbal preparations, and the lack of diagnostic facilities.^2,13Younger children and neonates are particularly susceptible to hypoglycemia, both in tropical and western countries.¹⁸ Undernourished children are prone to hypoglycemia any time their fragile nutritional balance is compromised. Delay in admittance to the hospital may impair glucose production and contribute to the worsening of hypoglycemia. We showed that the time of the last meal enhanced the depth of hypoglycemia.² In the tropics, prolonged delay of referral before both diagnosis and glucose administration increased the fasting period. Therefore, a period of prolonged fasting is considered as a risk factor because glycogen stores in the young child are limited, which can result in decreased hepatic glucose production.^3,19 Healthy adults are able to maintain normal plasma glucose levels up to 86 hours of fasting,⁹ although healthy children are not able to maintain a normal plasma glucose concentration during a fasting period of 24 hours and show a significant steeper decrease in plasma glucose concentration than adults. Therefore, the availability of POC tests must be extended to the primary health care settings for hypoglycemia detection at the consultation level. Moreover, repeated measurements should be advisable to detect late or recurrent hypoglycemia.Untreated hypoglycemia is a major cause of deaths in the tropics. Newborn hypoglycemia is probably underestimated completely as a result of the lack of safe and reliable POC diagnostic tests in maternity wards in resource-limited countries.¹ Despite considerable interest recently in neonate mortality in the new world, neonate hypoglycemia has been rarely documented in the tropics.^7,20–22 A rapid search in Medline using the terms “hypoglycemia,” “neonatal or neonates,” and “developing countries or low income” yields no more than 23 papers, although the same search found over 177,334 papers when dropping the terms “developing countries or low income.”Having an available POC test for hypoglycemia diagnostics resolves only one part of the problem, particularly in remote settings where dextrose infusion for young children is currently non-available or feasible. We proposed the use of the ordinary sugar powder administered by the sublingual route (SL), which benefits from an abundant absorption network for glucose.^23–25 This simple treatment is now recommended for the rapid on-site treatment of unripe Blighia sapida consumption.¹⁷ We also showed its efficacy in two clinical trials in resource-constrained settings in Mali and Burkina Faso. The SL absorption of glucose was faster than by the oral route (Figure 1).²⁴ An increase of 36 mg/dL (17.6–54.5) of blood glucose concentrations was obtained within 10 minutes and 64% of children reached blood glucose concentration higher than 3.3 mmol/L in 20 minutes. Indeed, the sublingual surface has a restricted absorption capacity that allows limited amounts of 0.2 g/kg to be absorbed in young infants. The saturation of the SL glucose carriers prevents the use of high doses and required repeated SL administration to by-pass this drawback.^23–25 Recently, evidence was given that 40% dextrose gel rubbed into the inside of the cheek is effective and well tolerated and could also be considered for first-line treatment to manage hypoglycemia in late preterm and term babies in the first 48 hours after birth.²⁶ The benefit of dextrose, the physiological D-isomer of glucose over the disaccharide sucrose, which required a split into glucose and fructose, is to be more rapidly and fully absorbed.²⁷ Dextrose gel reduces the admission rate to the intensive care unit (ICU), but its cost (US$2 per baby) and availability might be a limitation for resource-poor settings.²³ Sublingual administration of sugar should be proposed to health workers for the management of unconscious children hypoglycemic in out-of-hospital or when a dextrose infusion is not available. Further work is needed to increase the availability of this dextrose gel in the tropics and further trials to compare it with SL sugar.²³Open in a separate windowFigure 1.Mean delta of initial blood glucose concentration (g/L) after sublingual and oral sugar, and placebo (water) in young children in the tropics. Sixty-nine children (3–13 years of age) with blood glucose concentration < 3.9 mmol/L after overnight fasting randomly received 2.5 g of moistened sugar either orally or sublingually, oral water as placebo. Adapted from Barennes and others.²⁴In well-equipped intensive care, patients with or without diabetes have frequent dysglycemia, and hyperglycemia is associated with poor outcomes.²⁸ Several studies in western countries showed that a strict glycemic control is a safe and effective method for reducing the incidence of nosocomial infections in a predominantly non-diabetic, general surgical ICU patient population.^29,30 Effective glycemic control with glucose infusion and/or intensive insulin therapy showed improved clinical outcomes in critically ill term neonates.^31,32 Nevertheless, a recent multicenter trial has questioned the efficacy of a tight glucose control of hyperglycemia in critically ill children.³³ In RCS, the risk involved in hyperglycemia is probably underestimated and is rarely assessed outside of ICU.³⁰ Studies are needed for a better understanding of hyperglycemic outcomes and the necessity to initiate an early insulin therapy in severely ill hyperglycemic children admitted to pediatric emergency wards in the tropics. Therefore, recommendations of an intensive insulin therapy for hyperglycemia seem premature in primary health centers. Moreover, it requires a health system able to provide not only insulin and syringe but also ensure effective monitoring. A non-invasive way for insulin administration such as sublingual or nasal routes should be considered in the future.^34–36Finally, we conclude that increasing the availability of POC diagnostic tests is crucial but should be accompanied by increasing information on non-invasive treatment of dysglycemia. Sublingual sugar or ready to use dextrose gel being a good example of POC treatment of hypoglycemia, that will benefit all children.²⁶ New studies have to be done for hyperglycemia in children regarding diagnosis, understanding, and POC treatment in the tropics.     

Betatrophin: The long awaited circulating factor from the liver promoting β-cell replication?

Regenerative therapy in diabetes with the capacity to reconstitute a functional β-cell mass sufficient for glycemic control holds the promise to effectively prevent the development of devastating late complications due to the unique ability of the β-cell to sense and regulate blood-glucose levels. An ability that cannot be mimicked by insulin replacement therapy or any other means of current treatment regiments for very large patient populations. Recently, Douglas A. Melton’s group from Harvard University reported the identification of a circulating protein secreted from the liver under insulin resistant states which is sufficient to dramatically and specifically increase the replication rate of β-cells in the mouse resulting in an increased functional β-cell mass over time. They re-named the factor betatrophin and described a number of exciting features of this molecule which suggested that it could be a potential candidate for development as a regenerative medicine in diabetes.¹ The official name of the gene encoding mouse betatrophin is Gm6484, but it has been annotated a number of times under different names: {"type":"entrez-nucleotide","attrs":{"text":"EG624219","term_id":"116865639","term_text":"EG624219"}}EG624219^2,3, RIFL⁴, Lipasin⁵ and ANGPTL8.⁶ The official human gene name is C19orf80, but it has also been annotated as TD26⁷, LOC55908⁸, as well as RIFL, Lipasin, ANGPTL8 and betatrophin.     

Prevalence of hypertension in the Gambia and Sierra Leone,western Africa: a cross-sectional study

Hypertension (HTN) is a chronic, slowly progressive disease affecting about one billion people globally and leading to about 7.1 million deaths annually. People of African origin may be particularly susceptible to hypertension.1-3 Defined as a sustained systolic blood pressure (SBP) above 140 mmHg, a diastolic blood pressure (DBP) above 90 mmHg or both, the aetiology of HTN can be classified as primary or secondary. While there is no known cause for primary (essential) HTN, which accounts for 90–95% of cases, the remaining 5–10% of cases is defined as secondary HTN and is caused by other disease conditions, which may affect the renal, circulatory, endocrine or other organ systems.Many factors are associated with, and may contribute to the development and persistence of primary HTN, including obesity, stress, smoking,4 low potassium intake, high sodium (salt) and alcohol intake,5,6 familial and genetic influences,7,8 and low birth weight.9 On the other hand, hyperthyroidism, hypothyroidism and other conditions causing hormonal changes may be associated with primary pulmonary HTN.10,11 Regardless of the cause, the consequences of HTN include renal failure, heart failure, myocardial infarction, pulmonary oedema and stroke.12Given these undesirable outcomes, treatment and prevention have assumed increasing emphasis in the management of HTN. Modification of risk factors can be achieved by reducing body weight and decreasing sugar intake, along with lowering alcohol consumption,13,14 as well as reducing salt intake and increasing potassium intake.15,16 Secondary HTN is managed by treating the underlying cause. Drugs available for the treatment of HTN, whether primary or secondary, include calcium-channel blockers (CCB), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, α-blockers and β-blockers.Race and ethnicity may influence pathogenesis, prevalence and treatment of HTN,17 perhaps through genetic influences. As a consequence, HTN remains one of the most common CVDs in Africa and one of the most frequent causes of death in the sub-Saharan African region.18,19 In 2000, the rate of HTN in sub-Saharan Africa was reported to be 26.9% in males and 28.3% in females.20 Low socio-economic status (SES) may additionally play an important role in the high prevalence of HTN in western and sub-Saharan Africa.A cross-sectional survey in Tanzania revealed that treatment rates for HTN were very low, especially among people with low SES.21 Low SES led to inadequate education levels as a factor correlating with a higher blood pressure (BP) in adults and resulted in a low treatment rate for HTN due to monetary issues.22Stress, in addition, was another factor related to HTN prevalence, especially in Africa.23 It has been shown that psychosocial stress affects the L-arginine/nitric oxide (NO) system, with a higher susceptibility in black Africans, which in turn contributes to a higher risk of CVD in those individuals.24Therefore, a multiplicity of factors may be associated with and contributing to a high prevalence of HTN among Africans. The current study was undertaken to determine and quantitate the prevalence of HTN in two countries in western sub-Saharan Africa, namely, the Gambia and Sierra Leone.     

Pinta: Latin America's Forgotten Disease?

Pinta is a neglected, chronic skin disease that was first described in the sixteenth century in Mexico. The World Health Organization lists 15 countries in Latin America where pinta was previously endemic. However, the current prevalence of pinta is unknown due to the lack of surveillance data. The etiological agent of pinta, Treponema carateum, cannot be distinguished morphologically or serologically from the not-yet-cultivable Treponema pallidum subspecies that cause venereal syphilis, yaws, and bejel. Although genomic sequencing has enabled the development of molecular techniques to differentiate the T. pallidum subspecies, comparable information is not available for T. carateum. Because of the influx of migrants and refugees from Latin America, U.S. physicians should consider pinta in the differential diagnosis of skin diseases in children and adolescents who come from areas where pinta was previously endemic and have a positive reaction in serological tests for syphilis. All stages of pinta are treatable with a single intramuscular injection of penicillin.The endemic treponematoses, pinta, yaws, and bejel, are caused by spiral-shaped, not-yet-cultivable bacteria of the genus Treponema.^1–3 These neglected infectious diseases (NIDs), for which there are no vaccines, present a diagnostic dilemma to physicians because their clinical manifestations must be differentiated from those of other diseases that affect the skin. Moreover, serological tests cannot differentiate the endemic treponematoses from each other or from venereal syphilis, which is caused by the closely related spirochete, Treponema pallidum subspecies pallidum. Unlike venereal syphilis, the endemic treponematoses are usually acquired by children or adolescents living in poor rural communities in tropical climates (see references ¹ and ² for maps showing the geographical distribution of endemic treponematoses). Whereas venereal syphilis has a global distribution and is transmitted primarily by sexual activity, the endemic treponematoses are transmitted by nonsexual, direct skin-to-skin contact with infectious lesions.Pinta, also known as mal del pinto or carate, is the most benign of the endemic treponematoses since it affects only the skin.^1–3 Pinta was first described in the sixteenth century in the Aztec and Carib Amerindians by Spanish conquistadors and missionaries.⁴ In the 1950s, there were an estimated 1 million cases of pinta in Mexico, Central America, and northern South America. Although pinta was most highly endemic in Mexico and Columbia, cases declined in these countries due to treatment campaigns and possibly due to improvements in living standards, access to health services, and hygiene.^4,5 The World Health Organization (WHO) lists 15 countries in Latin America where pinta was previously endemic. Because of the lack of surveillance data, the current prevalence of pinta is unknown. However, some findings suggest that pinta has not disappeared. For example, in 1982 and 1983, clinical evidence of pinta was discovered in 20% of the examined inhabitants of a remote village in Panama.⁶ In 1987 and 1993, pinta cases were reported in native Indians (Ticuna) living in the Amazon border region of Brazil, Columbia, and Peru.^7,8 Although the last reported case of pinta in Cuba was in 1975, an active, early pinta lesion was identified in a Cuban female who was visiting Austria in 1999.⁹ On the basis of these data, it is plausible that pinta has remained endemic in some remote areas of Latin America where access to health services is limited and living standards have not yet risen.^1,2Like syphilis, pinta is classified into stages (see references ^1–3 for pictures of the clinical stages of pinta). The primary stage is characterized by the presence of one or several papules or erythematous scaly plaques that develop about 3 weeks after infection. The body area most commonly affected is the exposed skin of the extremities. The papule or plaque, which is teeming with infectious treponemes, does not ulcerate, but expands to a diameter of 10 cm or greater. Regional lymphadenopathy is common. During early infection, serological tests for syphilis (STS) may be negative for antibodies to nontreponemal (cardiolipin) and treponemal antigens. Plaques may last for months to years and pigmentary changes may be observed in the plaques. The lesions may heal spontaneously or they may persist and become indistinguishable from the lesions of secondary pinta.The secondary stage usually appears several months after the initial manifestations of the primary stage.^1–3 Small disseminated lesions known as “pintids” may coalesce into plaques. The pintids change from an initial red color to brown, slate-blue, black, or gray colors. Different pigmentation may occur within a pintid. The secondary lesions can remain active and infectious for a long time, leading to extensive depigmentation. STS are positive in the majority of untreated cases.The late (tertiary) stage usually develops 2–5 years after initial infection and is characterized by pigmentary abnormalities (i.e., from dyschromic treponeme-containing lesions to achromic treponeme-free lesions), skin atrophy, and hyperkeratosis.^1–3 The degree of lesion pigmentation can be different in the same patient, resulting in a mottled appearance of the skin, which can persist lifelong. Lesions may turn into various colors (e.g., brown, gray-blue, or black). STS are positive in virtually all untreated cases.The etiological agent of pinta, Treponema carateum, was not identified until over 30 years after the 1905 discovery of the related agents of venereal syphilis and yaws.^4,10–12 Initially, it was thought that a pathogenic fungus caused pinta. However, two observations suggested otherwise. First, laboratory studies of pinta patients'' sera showed that the Wassermann test, an early STS, was positive in the majority of cases. Second, treatments that were effective against syphilis (i.e., mercury and arsenicals) were also effective against pinta. In August 1938, Sáenz and others¹⁰ using dark-field microscopy, demonstrated the presence of spirochetes that were morphologically indistinguishable from the T. pallidum subspecies in exudate from a Cuban pinta patient''s lesions. Subsequently, other investigators reported the presence of spirochetes in pinta lesions. Because the presence of these bacteria was insufficient to prove causality, León-Blanco performed skin inoculation experiments on himself and human volunteers with lesion exudate that contained the spirochetes and succeeded in reproducing the early manifestations of pinta.^4,12 León-Blanco also showed that some immunity to reinfection develops during pinta. Patients with late-stage pinta could not be reinfected, whereas patients whose early-stage pinta had been cured could be reinfected. Furthermore, León-Blanco and Briceno Ross and Iriarte demonstrated that syphilis and yaws patients, respectively, were not immune to infection with pinta, despite the antigenic similarity of the etiological agents.^4,11,12Because animal models are necessary to propagate the T. pallidum subspecies for experimental studies, several investigators attempted to determine if laboratory animals could be infected with T. carateum.¹¹ León-Blanco and Oteiza¹³ reported infection of one of the four rabbits that they inoculated intradermally with exudate from a pinta patient''s lesions. However, they were unable to successfully passage T. carateum from the rabbit''s lesion to other rabbits. Later, Kuhn and others¹⁴ demonstrated that chimpanzees could be infected intradermally and that these animals developed lesions similar to those of pinta patients. Unfortunately, T. carateum isolates are not available for study. Although phylogenetic data obtained via genomic sequencing have enabled the development of techniques to differentiate the T. pallidum subspecies, comparable information is not available for T. carateum.^1,2 Thus, despite the morphological and antigenic relatedness of the agents of pinta and syphilis, molecular knowledge of T. carateum is currently insufficient to warrant classification of this spirochete as a T. pallidum subspecies.Pinta can be treated with a single intramuscular injection of long-acting benzathine penicillin (1.2 MU for adults; 0.6 MU for children), which renders the lesions noninfectious in less than 24 hours.^1,3,11 Information is scant concerning the efficacy of other antibiotics. Although early pinta lesions heal within several months after penicillin administration, this treatment cannot reverse the skin changes of late pinta that can stigmatize those who were infected.⁴ Penicillin treatment was the mainstay for the “National Campaign to Eradicate Mal del Pinto” conducted in Mexico (1960s) and for the WHO campaign against the endemic treponematoses (1952–1964).^1,2,4 A national campaign against yaws that was conducted in Columbia in the 1950s resulted in an almost parallel decline in the incidence of both yaws and pinta, even though pinta was not specifically targeted.⁵ Despite the initial success of these campaigns, the endemic treponematoses, particularly yaws, have resurged due to the lack of sustained resources and political will. The WHO has initiated a campaign to eradicate yaws by 2020 that is based on mass treatment of endemic communities with an oral dose of azithromycin, a macrolide antibiotic with demonstrated efficacy against yaws.^1,2,15 If T. carateum is sensitive to azithromycin as is likely, this treatment strategy could have a concomitant effect on pinta in areas of Latin America where yaws and pinta may be co-endemic. Moreover, if the endemic treponematoses were rolled into the program area of the Pan American Health Organization''s (PAHO''s) Strategic Plan (2014–2019) that targets selected NIDs and focuses on strengthening national capacity for screening, treatment, and surveillance of NIDs, this could facilitate elimination of pinta and yaws in PAHO member countries and would aid WHO''s yaws eradication campaign (www.paho.org/hq/).The possibility of importation of NIDs such as the endemic treponematoses increases as record numbers of migrants and refugees from Latin America continue to enter the United States for economic or political reasons.^2,3,16 Accordingly, physicians should consider pinta in the differential diagnosis of skin diseases for Latin American children and adolescents who come from areas where pinta was previously endemic and have a positive reaction in STS.^3,16 This is critical to guide treatment as well as to avoid the inadvertent psychological harm and legal ramifications that can result from making an incorrect diagnosis of syphilis. Although pinta may be a forgotten disease, it is unlikely to be extinct.^9,17     

Rationale and design of the Pan-African Sudden Cardiac Death survey: the Pan-African SCD study

For many years there has been a debate about the definition and nature of ‘sudden death’ or out-of-hospital cardiac arrest.1-8 Issues pertaining to this debate have been the temporal definition of ‘sudden’, whether death was unexpected, whether death was witnessed, and the aetiology of the event. The time frame used to describe the duration of the terminal event initially was 24 hours. The current definition of sudden cardiac death (SCD) describes death within one hour of the onset of symptoms,2 since this period seems to describe most accurately patients with arrhythmic sudden cardiac death.9A very difficult issue is the classification of unwitnessed deaths. Most authors have erred in favour of classifying such events as SCDs, even though it is often impossible to determine when the patient was last seen alive or the duration of symptoms prior to death. Hence, SCD can be defined as follows: ‘Natural death due to cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms’. Pre-existing heart disease may have been known to be present, but the time and mode of death are unexpected.1The incidence of SCD occurring out of hospital varies with age, gender and presence or absence of cardiovascular disease. Incidence rates of SCD between 0.36 and 1.28 per 1 000 inhabitants per year have been reported in Europe and the United states.10-13 In these studies, only witnessed victims seen or resuscitated by the emergency medical services are included; these data therefore underestimate the incidence of SCD in the general population. Sudden cardiac death is responsible for about 300 000 to 400 000 deaths per year in Europe and the United States, respectively.14Several diseases linked with sudden cardiac arrest (SCA) have been reported.15,16 Autopsy studies in unselected subjects suggest that about two-thirds of such deaths are cardiac in origin, with coronary artery disease and its complications accounting for the overwhelming majority of deaths in the industrialised world.17,18 Indeed, coronary artery disease (CAD) is the leading cause of sudden death worldwide.3In Europe, cardiovascular diseases (CVD) account for around 40% of all deaths under the age of 75 years. SCA is responsible for more than 60% of adult deaths from ischaemic heart disease (IHD).2 Conversely, in young populations under 40 years, inherited ‘arrhythmogenic’ cardiac disorders are the main cause.8 The initial recorded rhythm in patients presenting with a sudden cardiovascular collapse is ventricular fibrillation (VF) in 75 to 80%, whereas bradyarrhythmias and asystole are thought to contribute to a minority of SCDs.4,16     

Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects: A Strobe Compliant Article

Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF < 0.5%) and low-frequency (MAF, 0.5%–5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF = 0.06%; p.Gly71Arg], rs144398951 [MAF = 0.06%; p.Ile215Val], rs35003977 [MAF = 0.78%; p.Val225Gly], and rs57307513 [MAF = 0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P = 2.34 × 10⁻³⁴, P = 7.02 × 10⁻³⁴, and P = 8.27 × 10⁻³⁴), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P = 1.98 × 10⁻²⁶; rs2070959, p.Thr181Ala, P = 2.87 × 10⁻²⁷; and rs1105879, p.Arg184Ser, P = 3.27 × 10⁻²⁹), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone–related cholecystectomy (OR, 4.58; 95% CI, 1.58–13.28; P = 3.21 × 10⁻³). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.Bilirubin is the major metabolite of heme, the iron-binding tetrapyrrole ring found in hemoglobin, myoglobin, and cytochromes.¹ The straight-chain compound biliverdin is produced through the oxidation of heme porphyrin ring by microsomal heme oxygenase. Biliverdine reductase, a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme, reduces biliverdin to produce bilirubin.¹ After being captured by the hepatocyte through its membrane surface in contact with the sinusoids, bilirubin is transported to the smooth endoplasmic reticulum and becomes the substrate of the UDP-glucuronosyltransferase 1 family, polypeptide A1 enzyme (UGT1A1), which catalyzes the esterification of the propionic acid side chains of bilirubin with glucuronic acid (present as uridine diphosphoglucuronic acid) to form mainly the diglucuronide conjugate, a water-soluble conjugated molecule.¹ Conjugated bilirubin is then actively secreted into the bile canaliculi by a membrane ATP-dependent transporter, designated as multidrug resistance-associated protein 2 (MRP2).²It is now well established that unconjugated hyperbilirubinemia is a risk factor for gallstones.^3,4 In patients with sickle cell disease, it has been shown that genetic variation in the promoter of UGT1A1 may be a risk factor for symptomatic gallstones in older people.⁵ However, no studies are available in the healthy population, especially among older subjects.Genome-wide association studies (GWASs) systematically evaluate common genetic variants, typically with a minor allele frequency (MAF) >5% and have been extensively used to dissect the genetic architecture of complex diseases and quantitative traits.⁶ The high number of genetic variations identified in GWASs contrasts with their low effect on disease risk or quantitative trait variation. Thus, GWASs generally fail to translate into functional understanding or clinical practice. The “missing heritability” observed in GWASs could be explained by the fact that they do not assess low-frequency (MAF, 0.5%–5%) and rare (MAF < 0.5%) genetic variants that play a major role in human pathology.⁶ Recent evidence suggest that low-frequency and rare variants are associated with complex diseases.^6–8It is estimated that the protein-coding regions of the human genome constitute about 85% of the disease-causing mutations.⁹ The Illumina Human Exome BeadChip provides coverage of functional exonic variants. Around 250,00 markers on this BeadChip represent SNPs in RefSeq genes, non-synonymous SNPs, and SNPs in coding regions (including untranslated regions, UTRs). It has been demonstrated that exome-wide genotyping identified additional medically actionable variant calls and helped resolve ambiguous single-nucleotide variants in comparison with genome-wide approaches.¹⁰To date, there are no available data regarding the exome-wide association study approach that evaluated potential-associated variants with unconjugated, conjugated, and total serum bilirubin levels in physiological conditions. To determine the role of rare and low-frequency coding variants in traits reflecting unconjugated, conjugated, and total serum bilirubin level, we evaluated putative functional coding variants using the Illumina HumanExome BeadChip on a well-characterized cohort of ambulatory elderly subjects from Italy.^11–13 Furthermore, we assessed the potential influence of bilirubin-related variants on hyperbilirubinemia risk and the risk of gallstone-related cholecystectomy.     

Ambulatory blood pressure profiles in a subset of HIV-positive patients pre and post antiretroviral therapy

South Africa has 5.6 million people living with HIV/AIDS and has the largest antiretroviral therapy (ART) programme globally, with more than two million people accessing ART.1 Although ART has significantly decreased the mortality rate from HIV infection, these individuals are now living longer and are at risk of developing metabolic (dyslipidaemia, lipodystrophy, dysglycaemia), cardiovascular and renal complications from ART and chronic exposure to HIV infection.2-7Chronic HIV and ART are associated with increased risk of developing hypertension.8 In studies of HIV-positive patients in high-income countries, hypertension prevalence ranges from 13 to 34%.9,10 However, data from low- and middle-income countries remain sparse.Nocturnal blood pressure (BP) is superior to daytime or office BP as a predictor of cardiovascular disease.11 Non-dipping is defined as an abnormal diurnal rhythm manifested by a blunted nocturnal decline in systolic BP (SBP).11 It is associated with more severe hypertensive target-organ damage (left ventricular hypertrophy, microalbuminuria and cerebrovascular disease) and is also a predictor of increased cardiovascular risk, both in hypertensive and normotensive populations.11Studies from high-income countries have shown an increased prevalence of non-dipping with HIV infection.9,12 However, the participants in these studies were largely white, middle-aged males. Since the majority of subjects with HIV infection in sub-Saharan Africa are young black females, it is not known whether the same relationship between dipping status and HIV infection would be found. In addition, there are data showing that black HIV-negative individuals have less nocturnal dipping compared to their white counterparts.5,13,14Therefore, the aims of this study were to document the prevalence of chronic kidney disease (CKD) and hypertension at baseline (ART naïve) in a healthy HIV-positive cohort, and to assess changes in these parameters after six months on ART. The characteristics of ambulatory blood pressure (ABP) in a subset of patients were to be recorded and compared to a control group of HIV-negative patients.     

Response to the Critique by Hahn and Others Entitled “Conservation and Malaria in the Brazilian Amazon”

Hahn and others have recently criticized our study, “Conservation efforts may increase malaria burden in the Brazilian Amazon,” suggesting that results were flawed because of methodological limitations. Here, we briefly comment on some of their claims, showing that (1) several of their criticisms are misleading and others are incorrect, (2) they heavily criticize methods that they themselves have previously used, and (3) they selectively highlight some findings while ignoring others. We end this rebuttal by suggesting a way forward in this debate.Hahn and others¹ have recently written a perspective piece, which was published in The American Journal of Tropical Medicine and Hygiene, criticizing our study published in 2013.² Here, we respond to their critique, commenting and clarifying some of the points raised. Our response is organized in the same order as the issues were raised.Hahn and others¹ provide literature that supports their view that intact forests can help eliminate local malaria transmission. They¹ place special emphasis on a study that was based on a theoretical model parameterized to a different vector and applied to a completely different ecosystem (∼1,000 km away from our study region) on a region that has not had any reported malaria cases for the past 30 years.³ Unfortunately, Hahn and others¹ fail to acknowledge the large literature that support the opposite view regarding the role of forests, and most of those studies were conducted in the Brazilian Amazon.^4–10Hahn and others¹ claim that it is problematic to assume a constant population given that the Brazilian Amazon population increased from 2000 to 2010 by 23%. First, this statement is misleading, because the length of our study corresponds to less than one-half of this time interval. Second, population data arise from the Brazilian Census, which was conducted in 2000, 2007, and 2010. To account for fluctuation in population size, one would have to interpolate between three data points for each county, and it is not clear if this method is a better solution than adopting the 2007 population count for the 2004–2008 study period. Nevertheless, we performed our analysis again (this time using only 2007 malaria data) and found that our original conclusions hold (results available on request).Hahn and others¹ then criticize the fact that we excluded rural health facilities and the two easternmost states in the Brazilian Amazon (Maranhao and Tocantins). First, we did not have data from Maranhao and Tocantins, and therefore, these data were not excluded. Second, as explicitly mentioned in ref. 2, we excluded the rural health facilities because we did not have their spatial coordinates, thus precluding the assessment of the effect of proximity to forests. Third, the remark that we only accounted for 4.8% of the Brazilian Amazon region is misleading, because it ignores the fact that the human population in this region is highly clustered in the vicinities of established cities.^11,12 Even if we had the geographical location of all health facilities, it is likely that the sum of their catchment area would still only account for a small proportion of the overall area. To dispel any questions regarding selection bias, we use all (urban and rural) available data from 2007, this time assuming that all health facilities are located in the vicinity of the established cities. We find that the same results still hold, regardless of adoption of a 20- (as in the original analysis) or 50-km buffer size (which encompasses the great majority of the population in each county; results available on request).Hahn and others¹ suggest that our analysis suffers from the classic ecological fallacy. Any analysis that aggregates data potentially suffers from this problem. However, aggregate data is often the only available data, particularly at the spatial scale of our analysis. Examples of studies that rely on aggregate data abound (including studies by the critique authors themselves^13–15), providing important insights regarding large-scale drivers and spatial patterns of disease risk. Furthermore, our findings do corroborate the results of several entomological and epidemiological site-specific studies in the Brazilian Amazon. Hahn and others¹ then criticize the land use/land cover classification product that we used in our analysis. Interestingly, Hahn and others¹ have also used the same remote sensing product to implicate deforestation in malaria risk.¹⁴ Finally, Hahn and others¹ emphasize results from the works by Vittor and others^16,17 on Plasmodium vivax, while ignoring P. falciparum results from the same study, despite P. falciparum comprising approximately 40% of all detected infections. The PhD thesis of Vittor,¹⁸ which is the basis of the claims by Hahn and others,¹ indicates that P. falciparum prevalence was negatively associated with deforested land, and these results directly conflict with their mosquito and P. vivax data.^16,17 These Plasmodium results were never published in a peer-reviewed journal because of the low numbers of detected infections (110 infections of a total of 2,938 individuals examined). However, Hahn and others¹ do not hesitate to selectively report the results from P. vivax to support their claim.Hahn and others¹ say that we ignore the fate of the cleared forest in our analysis. However, they do so in their earlier analysis, which pointed to deforestation as an important malaria incidence driver.¹⁴ Furthermore, they assert that (1) deforestation results mainly from timber production and mining in Para rather than pasture/cattle ranching and soybean and (2) protected areas (PAs) tend to be located in areas of high deforestation pressure. These assertions are incorrect and shocking for anybody that knows this region.^19,20 Finally, Hahn and others¹ criticize us for not distinguishing among two very distinct types of PAs. Any type of aggregation can be criticized. For instance, one could take one step further and argue that the proposed classes are not enough because they exhibit considerable heterogeneity within themselves.²¹ We combined all PAs because we were not interested in comparing the effect of different classes of PAs on malaria risk.The role of biodiversity in decreasing disease risk has been and will probably continue to be the theme of a heated debate.^22–26 However, to criticize the methods we employed while also making use of them in their most recent study published in 2014²⁷ is, at a minimum, awkward. To effectively move this debate forward, we have to focus on more constructive ideas and suggestions. To this end, one of the critique authors (i.e., Amy Vittor) and I have partnered to reanalyze the mosquito data in refs. 16 and 17 and review the evidence regarding the role of forests in malaria risk, hoping to gain a more coherent picture of what is known about this important relationship. I invite the other authors of the critique to be part of this new exciting work.     

Short-term outcomes after hospital discharge in patients admitted with heart failure in Abeokuta,Nigeria: Data from the Abeokuta Heart Failure Registry

Heart failure (HF) has emerged as a global epidemic in at-risk populations, including those living in high-income countries and, as recently described, in low- to middle-income regions of the world, such as sub-Saharan Africa.11-4 While there are well-established HF registries to capture both the characteristics and health outcomes among those hospitalised with AHF in Europe,5,6 North America,7,8 and the Asia–Pacific region,3,9,10 there are few reports from sub-Saharan Africa.11 This includes Nigeria (the most populous country in the region), where HF has emerged as a potentially large public health problem.1Although there have been many therapeutic gains in the management of chronic HF,12 leading to improved overall survival rates,13 there has been very little parallel success (pending further evaluation of the recently reported RELAX trial14 with regard to AHF). This is particularly important when one considers the high proportion of patients who still require hospitalisation for acute HF, and associated high levels of in-patient case fatality and poor short- to medium-term health outcomes.Given the paucity of data describing health outcomes in unselected patients hospitalised with AHF in Nigeria (and indeed the wider sub-Saharan Africa), we examined short- (30 days) to medium-term outcomes (180 days) in consecutive subjects with AHF recruited into the Abeokuta HF registry over a period of six months. Standardised data collected via the registry were used to both describe the baseline characteristics of the cohort and identify correlates of mortality during the six-month follow up.     

Simultaneous coronary artery bypass grafting and carotid endarterectomy can be performed with low mortality rates

There is controversy over the best approach for patients with concomitant carotid and coronary artery disease.1 Therapeutic strategies include isolated coronary artery bypass grafting (CABG), staged carotid endarterectomy (CEA) and CABG, reversed staged CEA and CABG, and simultaneous procedures under single anaesthesia.2Although reported experiences over three decades are available, combining CEA with CABG remains to be elucidated.3 Furthermore, risk of cerebrovascular accident (CVA), which is one of the major predictors of prognosis of CABG, has been reported to increase up to 14% in patients with severe carotid artery stenosis (> 80%).4-9Peri-operative neurological events such as stroke after CABG are the major neurological complications, which increase with age.10 The incidence of peri-operative stroke has been well documented at approximately 2% of all cardiac surgeries.11 Despite reduced overall complication rates over the years after CABG, the incidence of stroke remains relatively unchanged.10The aetiology of peri-operative stroke is multi-factorial including hypotension or hypoperfusion-induced reduced brain flow, atherosclerosis due to micro- or macro-embolisation, and intra- or extra-cranial vascular diseases.5 In addition, carotid artery disease is a critical factor; however, it is considered unlikely to be the only culprit for peri-operative strokes.12Although no consensus on the optimal management of patients with concomitant carotid and coronary artery disease has been reached,13 simultaneous CEA and CABG surgery is often associated with low rates of mortality and morbidity.14-17 In this study, we report our experience with simultaneous CEA and CABG surgery in our clinic in the light of data in the literature.     

Ischemic Stroke in Young Adults and Preexisting Psychiatric Disorders: A Nationwide Case–Control Study

Previous studies showed that psychiatric disorders such as major depression, bipolar disorders, and alcohol misuse are associated with an increased risk of ischemic stroke. However, the link between psychiatric disorders and stroke in the young population is rarely investigated.Using the Taiwan National Health Insurance Research Database, 2063 young adults aged between 18 and 45 years with ischemic stroke and 8252 age- and sex-matched controls were enrolled in our study between 1998 and 2011. Participants who had preexisting psychiatric disorders were identified.After adjusting for preexisting physical disorders and demographic data, patients with ischemic stroke had an increased risk of having preexisting psychiatric disorders, including bipolar disorder (odds ratio [OR]: 2.23, 95% confidence interval [CI]: 1.06∼4.67), unipolar depression (OR: 2.15, 95% CI: 1.62∼2.86), anxiety disorders (OR: 2.63, 95% CI: 1.87∼3.69), and alcohol use disorders (OR: 2.86, 95% CI: 1.79∼4.57). Young ischemic stroke (age ≥30 years) was related to the risk of preexisting unipolar depression (OR: 1.49, 95% CI: 1.05∼2.11), anxiety disorders (OR: 1.99, 95% CI: 1.33∼2.97), and alcohol use disorders (OR: 2.54, 95% CI: 1.55∼4.14); very young stroke (age <30 years) was only associated with the risk of preexisting unipolar depression (OR: 4.15, 95% CI: 1.47∼11.72).Patients who had experienced ischemic stroke at age younger than 45 years had a higher risk of having pre-existing bipolar disorder, unipolar depression, anxiety disorders, and alcohol use disorders than those who did not after adjusting for demographic data and stroke-related medical comorbidities.Ischemic strokes in adults younger than 45 years of age were regarded as a relatively uncommon event in the proportion of <5% of all ischemic strokes.¹ However, other epidemiological studies have shown a higher proportion of approximately 10% of all ischemic strokes occurring in young adults.^2,3 Compared with stroke in the elderly, stroke in the young adult resulted in a disproportionately great personal, familial, and socioeconomic impacts and consequences by leaving patients disabled before their most productive years.^4,5 The most significantly established risk factors for young ischemic stroke included hypertension, dyslipidemia, diabetes mellitus, and smoking.^5–7The association between psychiatric disorders and stroke has gained the clinical and scientific attention in the past decade.^8–10 For example, Tsai et al¹¹ followed 80,569 patients with schizophrenia for 5 years, and revealed that those with schizophrenia were 1.13 times more likely to have a stroke (95% confidence interval [CI]: 1.05∼1.22). Li et al¹² followed 1003 patients with major depression and 4012 controls for 9 years and found that patients with major depression had a higher risk of stroke (odds ratio [OR]: 1.55, 95% CI: 1.08∼2.211) than the control group during the follow-up. Dong et al⁸ reported a significant positive association between depression and subsequent risk of stroke (relative risk [RR]: 1.34, 95% CI: 1.17∼1.54). Prieto et al''s¹⁰ meta-analysis study composed of 27,092 bipolar patients showed that the risk of stroke in bipolar disorder was significantly increased (RR: 1.74, 95% CI 1.29∼2.35). The First National Health and Nutrition Examination Survey in United States demonstrated that more anxiety symptoms at baseline were associated with increased risk of incident stroke (hazard ratio [HR]: 1.14, 95% CI: 1.03∼1.25).⁹ Following 19,544 men aged 40 to 59 years for 11 years, Iso et al¹³ determined that alcohol consumption was positively associated with the risk of stroke with a 68% excess risk among drinkers of ≥450 g ethanol per week compared with occasional drinkers. However, stroke in the above studies occurred in the late mid-life or in old age but not in the younger age groups. The association between young stroke and psychiatric disorders was less investigated and still unclear.In our study, using the Taiwan National Health Insurance Research Database (NHIRD) with a large sample size and a retrospective study design, we investigated the association between the young ischemic stroke and the risk of preexisting psychiatric disorders, including schizophrenia, bipolar disorder, major depression, anxiety disorders, and alcohol use disorder.