Real-world disparities and ethical considerations with access to CFTR modulator drugs: Mind the gap!

The third Sustainable Development Goal (SDG), to ensure healthy lives and promote well-being for all at all ages, has particular relevance and implementation challenges amongst people living with rare diseases such as cystic fibrosis (CF). Although the treatment and projected outcome of CF has significantly improved with the advent of CF transmembrane conductance regulator protein modulator (CFTRm) therapy, there remains significant global inequality with regards to access to these life-saving and life-altering drugs. Elexacaftor, tezacaftor, and ivacaftor (ETI) triple combination therapy, first licensed in the United States in 2019, has rapidly become the standard of care for children aged 6 years and older in most high-income countries for individuals with CFTR variants responsive to ETI. Negotiated agreements for access to ETI are currently in place in North America,Europe, Israel ,Australia and New Zealand. However, less priority has been given to negotiate agreements for access to CFTRm in low-middle income countries(LMIC) with significant CF populations such as Central and South America, India, the Middle East, and Southern Africa. These countries and individuals living with CF are therefore effectively being left behind, in direct conflict with the stated principle of the 2030 SDGs. In this review, we highlight the current global inequity in access to CFTRm drugs and its impact on widening disparities between high-income countries and LMIC in CF outcomes and survival. We further discuss the reasons for this inequity and explore the ethical- and human rights-based principles and dilemmas that clinicians, families, governments, and healthcare funders must consider when prioritizing fair and affordable access to expensive CFTRm drugs. Lastly, we propose possible solutions to overcoming the barriers to accessing affordable CFTRm drugs in LMIC and illustrate with examples how access to drug therapies for other conditions have been successfully negotiated in LMIC through innovative partnerships between governments and pharmaceutical industries.

Risk factors and outcomes of extubation failure in a South African tertiary paediatric intensive care unit.

Background: Extubation failure contributes to poor outcome of mechanically ventilated children, yet the prevalence and risk factors have been poorly studied in South African (SA) children. Objectives: To determine the prevalence, risk factors and outcomes of extubation failure in an SA paediatric intensive care unit (PICU). Methods: This was a prospective, observational study of all mechanically ventilated children admitted to a tertiary PICU in Cape Town, SA. Extubation failure was defined as requiring re-intubation within 48 hours of planned extubation. Results: There were 219 episodes of mechanical ventilation in 204 children (median (interquartile range (IQR)) age 8 (1.6 - 44.4) months). Twenty-one of 184 (11.4%) planned extubations (95% confidence interval (CI) 7.2% - 16.9%) failed. Emergency cardiac admissions (adjusted odds ratio (aOR) 7.58 (95% CI 1.90 - 30.29), dysmorphology (aOR 4.90; 95% CI 1.49 - 16.14), prematurity (aOR 4.39; 95% CI 1.24 - 15.57), and ventilation ≥48 hours (aOR 6.42 (95% CI 1.57 - 26.22) were associated with extubation failure. Children who failed extubation had longer durations of ventilation (231 hours (146.0 - 341.0) v. 53 hours (21.7 - 123.0); p<0.0001); longer duration of PICU (15 (9 - 20) days v. 5 (2 - 9) days; p<0.0001) and hospital length of stay (32 (21 - 53) days v. 15 (8 - 27) days; p=0.009); and higher 30-day mortality (28.6% v. 6.7%; p=0.001) than successfully extubated children. Conclusion: Extubation failure was associated with significant morbidity and mortality in our setting. Risk factors for extubation failure identified in our context were similar to those reported in other settings. Contributions of the study: This study provides novel data on the prevalence, risk factors and outcomes associated with extubation failure in a single-centre South African PICU. The results of this study may help identify high-risk groups for extubation failure within our local context, and forms a basis for practice improvement initiatives aimed at decreasing extubation failure rates and improving outcomes.

O-serotype distribution of Escherichia coli bloodstream infection isolates in critically ill patients in The Netherlands.

OBJECTIVES: Invasive infections by extra-intestinal pathogenic Escherichia coli (ExPEC) strains are increasing. We determined O-serogroups of E. coli isolates from ICU patients having bloodstream infections (BSI) and the potential coverage of a 10-valent O-polysaccharide conjugate vaccine currently in development for the prevention of invasive ExPEC disease. METHODS: We studied E. coli BSI among patients admitted to a tertiary ICU in the Netherlands between April 2011 and November 2016. O-serogroups were determined in vitro by agglutination and whole genome sequencing. RESULTS: Among 714 ICU patients having BSI, 70 (10%) had an E. coli BSI. Among 68 (97%) isolates serogrouped, the most common serogroups were O25 (n = 11; 16%), O8 (n = 5; 7%), O2 (n = 4; 6%), O6 (n = 4; 6%), and O15 (n = 4; 6%). The theoretical coverage of a 10-valent ExPEC vaccine was 54% (n = 37). CONCLUSIONS: A multi-valent ExPEC O-polysaccharide conjugate vaccine in development could potentially aid in the prevention of E. coli BSI in Dutch ICU patients.

Effect of Cervical Lesions on Fracture Resistance and Failure Mode of Maxillary Central Incisors Restored with Fiber Posts and Complete Crowns.

PURPOSE: To investigate the effect of a cervical cavity extending 1 mm apical to the cemento-enamel junction (CEJ) on fracture resistance and failure mode of maxillary central incisors that have been treated endodontically, present with complete and incomplete ferrules, and are restored with and without a fiber post. METHODS AND MATERIALS: 50 intact human maxillary central incisors were divided into five groups (n=10): CG (control group) 6-mm fer-rule height, no cervical cavity, and without post; (CO) 6-mm ferrule height without post, with a cervical cavity (access to root canal and cervical cavity restored with composite resin), cervical cavity; and post with ferrule heights of 1 mm (CP1), 2 mm (CP2), and 6 mm (CP6) restored with fiberglass post and composite resin core. After complete metal crowns were cemented on all specimens, they were subjected to thermal cycling (6000 cycles, 5°C/55°C), followed by immediate testing of fracture resistance. After failure, the specimens were sectioned buccolingually to evaluate and identify the mode of failure. The data were analyzed with an analysis of variance (ANOVA) and the Student-Newman-Keuls multiple comparison tests (α =0.05). RESULTS: A 1-mm ferrule height (CP1) fracture resistance was significantly lower (531±125 N) compared to the 6-mm ferrule height (CP6) (769±175 N) (p<0.05). With respect to the groups with similar residual dentin, with and without a cervical cavity, CG (667±119 N) and CO (668±119 N), the presence of a post (CP6) increased the resistance to fracture, although no statistically significant difference was demonstrated. Partial decementation was observed in all specimens of CG and CP6, in nine of CP1 and CP2, and in three in CO. Root fractures occurred in 23 specimens. The root surface was exposed 2 mm below the CEJ to simulate bone level. Propagation of subosseous cracks occurred in four specimens in CG and CP2, in seven specimens in CP6, in two specimens in CP1, and in six specimens in CO. All were considered catastrophic failures. CONCLUSIONS: Within the limitations of this study it is suggested that, when restoring an endodontically treated maxillary central incisor that has a cervical lesion and needs to be restored with a complete crown, a fiber post is cemented to improve fracture resistance.

South African guidelines on the determination of death.

Death is a medical occurrence that has social, legal, religious and cultural consequences requiring common clinical standards for its diagnosis and legal regulation. This document compiled by the Critical Care Society of Southern Africa outlines the core standards for determination of death in the hospital context. It aligns with the latest evidence-based research and international guidelines and is applicable to the South African context and legal system. The aim is to provide clear medical standards for healthcare providers to follow in the determination of death, thereby promoting safe practices and high-quality care through the use of uniform standards. Adherence to such guidelines will provide assurance to medical staff, patients, their families and the South African public that the determination of death is always undertaken with diligence, integrity, respect and compassion, and is in accordance with accepted medical standards and latest scientific evidence. The consensus guidelines were compiled using the AGREE II checklist with an 18-member expert panel participating in a three-round modified Delphi process. Checklists and advice sheets were created to assist with application of these guidelines in the clinical environment (https://criticalcare.org.za/resource/death-determination-checklists/). Key points • Brain death and circulatory death are the accepted terms for defining death in the hospital context. • Death determination is a clinical diagnosis which can be made with complete certainty provided that all preconditions are met. • The determination of death in children is held to the same standard as in adults but cannot be diagnosed in children <36 weeks' corrected gestation. • Brain-death testing while on extra-corporeal membrane oxygenation is outlined. • Recommendations are given on handling family requests for accommodation and on consideration of the potential for organ donation. • The use of a checklist combined with a rigorous testing process, comprehensive documentation and adequate counselling of the family are core tenets of death determination. This is a standard of practice to which all clinicians should adhere in end-of-life care.

South African guidelines on the determination of death.

Summary: Death is a medical occurrence that has social, legal, religious and cultural consequences requiring common clinical standards for its diagnosis and legal regulation. This document compiled by the Critical Care Society of Southern Africa outlines the core standards for determination of death in the hospital context. It aligns with the latest evidence-based research and international guidelines and is applicable to the South African context and legal system. The aim is to provide clear medical standards for healthcare providers to follow in the determination of death, thereby promoting safe practices and high-quality care through the use of uniform standards. Adherence to such guidelines will provide assurance to medical staff, patients, their families and the South African public that the determination of death is always undertaken with diligence, integrity, respect and compassion, and is in accordance with accepted medical standards and latest scientific evidence. The consensus guidelines were compiled using the AGREE II checklist with an 18-member expert panel participating in a three-round modified Delphi process. Checklists and advice sheets were created to assist with application of these guidelines in the clinical environment (https://criticalcare.org.za/resource/death-determination-checklists/). Key points: Brain death and circulatory death are the accepted terms for defining death in the hospital context.Death determination is a clinical diagnosis which can be made with complete certainty provided that all preconditions are met.The determination of death in children is held to the same standard as in adults but cannot be diagnosed in children <36 weeks' corrected gestation.Brain-death testing while on extra-corporeal membrane oxygenation is outlined.Recommendations are given on handling family requests for accommodation and on consideration of the potential for organ donation.The use of a checklist combined with a rigorous testing process, comprehensive documentation and adequate counselling of the family are core tenets of death determination. This is a standard of practice to which all clinicians should adhere in end-of-life care.

The Critical Care Society of Southern Africa guidelines on the allocation of scarce critical care resources during the COVID-19 public health emergency in South Africa.

Letter by Gopalan et al. on article by Singh and Moodley (Singh JA, Moodley K. Critical care triaging in the shadow of COVID-19: Ethics considerations. S Afr Med J 2020;110(5):355-359. https://doi.org/10.7196/SAMJ.2020.v110i5.14778); and response by Singh and Moodley.

In vitro effects of macrophages on orthopaedic implant alloys and local release of metallic alloy components.

AIMS: This study aimed to determine if macrophages can attach and directly affect the oxide layers of 316L stainless steel, titanium alloy (Ti6Al4V), and cobalt-chromium-molybdenum alloy (CoCrMo) by releasing components of these alloys. METHODS: Murine peritoneal macrophages were cultured and placed on stainless steel, CoCrMo, and Ti6Al4V discs into a 96-well plate. Cells were activated with interferon gamma and lipopolysaccharide. Macrophages on stainless steel discs produced significantly more nitric oxide (NO) compared to their control counterparts after eight to ten days and remained elevated for the duration of the experiment. RESULTS: On stainless steel, both nonactivated and activated cell groups were shown to have a significant increase in metal ion release for Cr, Fe, and Ni (p < 0.001, p = 0.002, and p = 0.020 respectively) compared with medium only and showed macrophage-sized corrosive pits on the stainless steel surface. On titanium alloy discs there was a significant increase in aluminum (p < 0.001) among all groups compared with medium only. CONCLUSION: These results indicated that macrophages were able to attach to and affect the oxide surface of stainless steel and titanium alloy discs. Cite this article: Bone Joint J 2020;102-B(7 Supple B):116-121.

The effect of two composite placement techniques on fracture resistance of MOD restorations with various resin composites.

OBJECTIVE: The aim of this in vitro study was to compare the effect of two restorative placement techniques, centripetal incremental technique (CIT) and bulk-fill technique (BT) on the fracture resistance of Class II MOD restorations with various resin composites in molar teeth. MATERIALS AND METHODS: Fifty-six extracted, caries free third molars were prepared with MOD preparations and restored with resin composites. The specimens were divided into two groups by placement technique, centripetal incremental technique (CIT) and bulk-fill technique (BT). Each group was subdivided into four groups according to resin composite: hybrid (Aelite LS), nano-hybrid (Virtuoso Universal), bulk fill (Filtek One Bulk Fill) and the micro-hybrid (Herculite XRV) as the control. RESULTS: Two-way analysis of variance test (ANOVA) followed by the multiple comparison procedure, Student-Newman-Keuls Method showed no a statistically significant difference between placement techniques and fracture resistance of Class II resin composite restorations (P > 0.05). Herculite XRV resisted a significantly higher load before fracture than the other three materials at a 0.05 level of significance, while Virtuoso Universal scored the lowest load. CONCLUSIONS: There was no significant effect of the two placement techniques on the fracture resistance of Class II resin composite restorations CLINICAL SIGNIFICANCE: Resin composite restorations in Class II MODs using a simplified bulk fill placement technique showed no significant difference in fracture resistance with the centripetal technique in molar teeth.

Critical care triage during the COVID-19 pandemic in South Africa: A constitutional imperative!

Triage and rationing of scarce intensive care unit (ICU) resources are an unavoidable necessity. In routine circumstances, ICU triage is premised on the best interests of an individual patient; however, when increased demand exceeds capacity, as during an infectious disease outbreak, healthcare providers need to make difficult decisions to benefit the broader community while still respecting individual interests. We are currently living through an unprecedented period, with South Africa (SA) facing the challenges of the global COVID-19 pandemic. The Critical Care Society of Southern Africa (CCSSA) expedited the development of a triage guidance document to inform the appropriate and fair use of scarce ICU resources during this pandemic. Triage decision-making is based on the clinical odds of a positive ICU outcome, balanced against the risk of mortality and longer-term morbidity affecting quality of life. Factors such as age and comorbid conditions are considered for their potential impact on clinical outcome, but are never the sole criteria for denying ICU-level care. Arbitrary, unfair discrimination is never condoned. The CCSSA COVID-19 triage guideline is aligned with SA law and international ethical standards, and upholds respect for all persons. The Bill of Rights, however, does not mandate the level of care enshrined in the constitutional right to healthcare. ICU admission is not always appropriate, available or feasible for every person suffering critical illness or injury; however, everyone has the right to receive appropriate healthcare at another level. If ICU resources are used for people who do not stand to benefit, this effectively denies others access to potentially life-saving healthcare. Appropriate triaging can therefore be considered a constitutional imperative.

Non-invasive continuous positive airway pressure ventilation and high-flow nasal cannula oxygen therapy use in children without primary lung pathology: A prospective observational study

Background. Non-invasive nasal continuous positive airway pressure (nCPAP) and high-flow nasal cannula oxygen therapy (HFNC) are non-invasive ventilation (NIV) modalities appropriate for children in developing countries. There is minimal literature describing nCPAP and HFNC use in children with respiratory compromise secondary to non-pulmonary disease. Objectives. Th present study aimed to describe the characteristics and outcomes of children without primary lung pathology, who received nCPAP and HFNC during their admission to Red Cross War Memorial Children's Hospital, Cape Town, South Africa. Methods. This was a prospective observational study of routinely collected data, between August 2015 and January 2016. Primary and secondary outcome measures were NIV failure (progression to intubation and invasive ventilation) and paediatric intensive care unit (PICU) admission, respectively. Comparative statistics were conducted using Mann-Whitney U or t-tests. Data significantly associated with the primary and secondary outcomes on univariate analysis were entered into backward stepwise logistic regression models to determine independent predictive factors. Results. There were 31 cases of nCPAP and 1 case of HFNC use in 31 patients (median age 3.5 (interquartile range (IQR) 1.8 - 7.6) months). The majority (n=23; 71.9%) presented with primary diarrhoeal disease. There were 2 deaths (6.5%), 17 (53.1%) PICU admissions, and 5 (15.6%) cases received invasive ventilation (NIV failure). The median duration of hospital stay was 11.5 (IQR 6.0 - 17.5) days. Patients who failed NIV had lower admission SaO2 levels than those without treatment failure (95% (IQR 95 - 99) v. 100% (IQR 100 - 100); p=0.03). On multiple logistic regression, lower temperature (adjusted OR (aOR) 0.19; 95% confidence interval (CI) 0.05 - 0.78; p=0.02) and receiving inotropes in the emergency setting (aOR 23.05; 95% CI 1.64 - 325.06; p=0.02) were independently associated with PICU admission. Conclusion. nCPAP was used clinically for the management of children with respiratory compromise secondary to non-pulmonary illnesses, particularly diarrhoeal disease. Larger controlled clinical studies are needed to determine the effectiveness and utility of nCPAP in this population. HFNC was not commonly used, and this modality requires further investigation in this population

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

No evidence for the presence of genetic variants predisposing to psychotic disorders on the non-deleted 22q11.2 allele of VCFS patients.

The velo-cardio-facial syndrome (VCFS) is caused by hemizygous deletions on chromosome 22q11.2. The VCFS phenotype is complex and characterized by frequent occurrence of neuropsychiatric symptoms with up to 25-30% of cases suffering from psychotic disorders compared with only ~1% in the general population (odds ratio≈20-25). This makes the 22q11.2 deletion one of the most prominent risk factors for schizophrenia. However, its penetrance for neuropsychiatric phenotypes is incomplete suggesting that additional risk factors are required for disease development. These additional risk factors could lie anywhere on the genome, but by reducing the normal diploid to a haploid state, the 22q11.2 deletion could result in the unmasking of otherwise recessive alleles or functional variants on the non-deleted 22q11.2 allele. To test this hypothesis, we captured and sequenced the whole 22q11.2 non-deleted region in 88 VCFS patients with (n=40) and without (n=48) psychotic disorders to identify genetic variation that could increase the risk for schizophrenia. Single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants were called and their distributions were compared between the two diagnostic groups using variant-, gene- and region-based association tests. None of these tests resulted in statistical evidence for the existence of a genetic variation in the non-deleted allele that would increase schizophrenia risk in VCFS patients. Power analysis showed that our study was able to achieve >80% statistical power to detect association of a risk variant with an odd ratio of ⩾22. However, it is certainly under-powered to detect risk variant of smaller effect sizes. Our study did not provide evidence that genetic variants of very large effect size located on the non-deleted 22q1.2 allele in VCFS patients increase the risk for developing psychotic disorders. Variants with smaller effects may be located in the remaining 22q11.2 allele and elsewhere in the genome. Therefore, whole exome or even genome sequencing for larger sample size would appear to be the next logical steps in the search for the genetic modifiers of the 22q11.2-deletion neuropsychiatric phenotype.

Acute viral bronchiolitis in South Africa: Diagnostic flow.

Bronchiolitis may be diagnosed on the basis of clinical signs and symptoms. In a young child, the diagnosis can be made on the clinical pattern of wheezing and hyperinflation. Clinical symptoms and signs typically start with an upper respiratory prodrome, including rhinorrhoea, low-grade fever, cough and poor feeding, followed 1 - 2 days later by tachypnoea, hyperinflation and wheeze as a consequence of airway inflammation and air trapping.The illness is generally self limiting, but may become more severe and include signs such as grunting, nasal flaring, subcostal chest wall retractions and hypoxaemia. The most reliable clinical feature of bronchiolitis is hyperinflation of the chest, evident by loss of cardiacdullness on percussion, an upper border of the liver pushed down to below the 6th intercostal space, and the presence of a Hoover sign(subcostal recession, which occurs when a flattened diaphragm pulls laterally against the lower chest wall).Measurement of peripheral arterial oxygen saturation is useful to indicate the need for supplemental oxygen. A saturation of <92% at sea level and 90% inland indicates that the child has to be admitted to hospital for supplemental oxygen. Chest radiographs are generally unhelpful and not required in children with a clear clinical diagnosis of bronchiolitis.Blood tests are not needed routinely. Complete blood count tests have not been shown to be useful in diagnosing bronchiolitis or guiding its therapy. Routine measurement of C-reactive protein does not aid in management and nasopharyngeal aspirates are not usually done.Viral testing adds little to routine management. Risk factors in patients with severe bronchiolitis that require hospitalisation and may even cause death, include prematurity, congenital heart disease and congenital lung malformations.

Acute viral bronchiolitis in South Africa: Strategies for management and prevention.

Management of acute viral bronchiolitis is largely supportive. There is currently no proven effective therapy other than oxygen for hypoxic children. The evidence indicates that there is no routine benefit from inhaled, rapid short-acting bronchodilators, adrenaline or ipratropium bromide for children with acute viral bronchiolitis. Likewise, there is no demonstrated benefit from routine use of inhaled or oral corticosteroids, inhaled hypertonic saline nebulisation, montelukast or antibiotics. The last should be reserved for children with severe disease, when bacterial co-infection is suspected. Prevention of respiratory syncytial virus (RSV) disease remains a challenge. A specific RSV monoclonal antibody, palivizumab, administered as an intramuscular injection, is available for children at risk of severe bronchiolitis, including premature infants, young children with chronic lung disease, immunodeficiency, or haemodynamically significant congenital heart disease. Prophylaxis should be commenced at the start of the RSV season and given monthly during the season. The development of an RSV vaccine may offer a more effective alternative to prevent disease, for which the results of clinical trials are awaited. Education of parents or caregivers and healthcare workers about diagnostic and management strategies should include the following: bronchiolitis is caused by a virus; it is seasonal; it may start as an upper respiratory tract infection with low-grade fever; symptoms are cough and wheeze, often with fast breathing; antibiotics are generally not needed; and the condition is usually self limiting, although symptoms may occur for up to four weeks in some children.

Characteristics and outcome of long-stay patients in a paediatric intensive care unit in Cape Town, South Africa.

BACKGROUND: Paediatric intensive care is a costly, specialised and limited resource in low- and middle-income countries. The implications of extended paediatric intensive care unit (PICU) stay in South Africa (SA) are not known. OBJECTIVES: To describe the characteristics, outcomes and resource consumption of long-stay patients (LSPs) and to identify predictive factors for long PICU stay. METHODS: A retrospective review of routinely collected data on all children admitted to an SA PICU over one calendar year. Long PICU stay was defined statistically as >19 days. Long- and short-stay patient (SSP) groups were compared, and variables significantly associated with long stay on univariate analysis were entered into a stepwise multiple regression model. RESULTS: Over the study period, 1 126 children (median age 8 months, 60.9% male) were admitted to the PICU, occupying 5 936 bed-days; 54  LSPs (4.8%) utilised 1 807 (30.4%) bed-days. Mortality and the standardised mortality ratio (actual/mean predicted mortality) in LSPs and SSPs were 29.6% v. 12% (p=0.002) and 2.4 v. 0.7 (p=0.002), respectively. Median duration of stay for LSPs and SSPs was 29.5 days and 2 days, respectively (p<0.0001). LSPs were younger than SSPs (median 4 months (interquartile range 2 - 17) v. 9 months (2 - 34); p=0.03), and fewer were male (48% v. 61.6%, p=0.049). On multivariate analysis, only female gender was independently associated with long PICU stay. CONCLUSIONS: LSPs represent a small proportion of PICU admissions, yet have a higher mortality rate than SSPs and consume disproportionate PICU resources. No predictive model could be established for early recognition of potential LSPs to plan PICU bed allocation effectively.

Is obesity still increasing among pregnant women? Prepregnancy obesity trends in 20 states, 2003-2009.

OBJECTIVE: To estimate trends in prepregnancy obesity prevalence among women who delivered live births in the US during 2003-2009, by state, age, and race-ethnicity. METHODS: We used Pregnancy Risk Assessment Monitoring System (PRAMS) data from 2003, 2006, and 2009 to measure prepregnancy obesity (body mass index [BMI]≥30kg/m(2)) trends in 20 states. Trend analysis included 90,774 records from 20 US states with data for all 3 study years. We used a chi-square test for trend to determine the significance of actual and standardized trends, standardized to the age and race-ethnicity distribution of the 2003 sample. RESULTS: Prepregnancy obesity prevalence increased by an average of 0.5 percentage points per year, from 17.6% in 2003 to 20.5% in 2009 (P<0.001). Obesity increased among women aged 20-24 (P<0.001), 30-34 (P=0.001) and 35 years or older (P=0.003), and among non-Hispanic white (P<.001), non-Hispanic black (P=0.02), Hispanic (P=0.01), and other women (P=0.03). CONCLUSION: Overall, prepregnancy obesity prevalence continues to increase and varies by race-ethnicity and maternal age. These findings highlight the need to address obesity as a key component of preconception care, particularly among high-risk groups.

Susceptibility to a parkinsonian toxin varies during primate development.

Symptoms of Parkinson's disease typically emerge later in life when loss of nigrostriatal dopamine neuron function exceeds the threshold of compensatory mechanisms in the basal ganglia. Although nigrostriatal dopamine neurons are lost during aging, in Parkinson's disease other detrimental factors must play a role to produce greater than normal loss of these neurons. Early development has been hypothesized to be a potentially vulnerable period when environmental or genetic abnormalities may compromise central dopamine neurons. This study uses a specific parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to probe the relative vulnerability of nigrostriatal dopamine neurons at different stages of primate development. Measures of dopamine, homovanillic acid, 1-methyl-pyridinium concentrations and tyrosine hydroxylase immunoreactive neurons indicated that at mid-gestation dopamine neurons are relatively vulnerable to MPTP, whereas later in development or in the young primate these neurons are resistant to the neurotoxin. These studies highlight a potentially greater risk to the fetus of exposure during mid-gestation to environmental agents that cause oxidative stress. In addition, the data suggest that uncoupling protein-2 may be a target for retarding the progressive loss of nigrostriatal dopamine neurons that occurs in Parkinson's disease and aging.

Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease.

Methamphetamine is a CNS stimulant with limited therapeutic indications, but is widely abused. Short-term exposure to higher doses, or long-term exposure to lower doses, of methamphetamine induces lasting damage to nigrostriatal dopamine neurons in man and animals. Strong evidence indicates that the mechanism for this detrimental effect on dopamine neurons involves oxidative stress exerted by reactive oxygen species. This study investigates the relative susceptibility of dopamine neurons in mid-gestation, young, and adult (not aged) monkeys to four treatments with methamphetamine over 2 days. Primate dopamine neurons undergo natural cell death at mid-gestation, and we hypothesized that during this event they are particularly vulnerable to oxidative stress. The results indicated that at mid-gestation and in adults, dopamine neurons were susceptible to methamphetamine-induced damage, as indicated by loss of striatal tyrosine hydroxylase (TH) immunoreactivity and dopamine concentration. However, dopamine neurons in young animals appeared totally resistant to the treatment, despite this group having higher brain levels of methamphetamine 3 h after administration than the adults. As a possible explanation for the protection, striatal glial-derived neurotrophic factor (GDNF) levels were elevated in young animals 1 week after treatment, but not in adults following methamphetamine treatment. Implications of these primate studies are: (1) the susceptibility of dopamine neurons at mid-gestation to methamphetamine warns against the risk of exposing pregnant women to the drug or oxidative stressors, and supports the hypothesis of Parkinson's disease being associated with oxidative stress during development, (2) elucidation of the mechanism of resistance of dopamine neurons in the young animals to methamphetamine-induced oxidative stress may provide targets for slowing or preventing age- or disease-related loss of adult nigrostriatal dopamine (DA) neurons, and (3) the increased striatal production of GDNF in young animals, but not in adults, in response to methamphetamine, suggests the possibility of an age-related change in the neurotrophic capacity of the striatal dopamine system.