Metabolic Dysfunction in New-Onset Idiopathic Intracranial Hypertension: Identification of Novel Biomarkers.

OBJECTIVE: Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity. METHODS: This is a prospective case-control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry. RESULTS: Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate-severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = -0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH. INTERPRETATION: We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595-607.

Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva and operative tissue, when available, were collected. Among the 102 children, 13 were having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection, and RNA-Seq analysis of NF1, MAPK pathway genes and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation and increased MCP1 expression. In summary, NF-1-related RVH in children is rare but often severe and progressive and, as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.

Cancer diagnosis after emergency presentations in people with mental health and substance use conditions: a national cohort study.

BACKGROUND: Cancer survival and mortality outcomes for people with mental health and substance use conditions (MHSUC) are worse than for people without MHSUC, which may be partly explained by poorer access to timely and appropriate healthcare, from screening and diagnosis through to treatment and follow-up. Access and quality of healthcare can be evaluated by comparing the proportion of people who receive a cancer diagnosis following an acute or emergency hospital admission (emergency presentation) across different population groups: those diagnosed with cancer following an emergency presentation have lower survival. METHODS: National mental health service use datasets (2002-2018) were linked to national cancer registry and hospitalisation data (2006-2018), to create a study population of people aged 15 years and older with one of four cancer diagnoses: lung, prostate, breast and colorectal. The exposure group included people with a history of mental health/addiction service contact within the five years before cancer diagnosis, with a subgroup of people with a diagnosis of bipolar disorder, schizophrenia or psychotic disorders. Marginal standardised rates were used to compare emergency presentations (hospital admission within 30 days of cancer diagnosis) in the exposure and comparison groups, adjusted for age, gender (for lung and colorectal cancers), ethnicity, area deprivation and stage at diagnosis. RESULTS: For all four cancers, the rates of emergency presentation in the fully adjusted models were significantly higher in people with a history of mental health/addiction service use than people without (lung cancer, RR 1.19, 95% CI 1.13, 1.24; prostate cancer RR 1.69, 95% CI 1.44, 1.93; breast cancer RR 1.42, 95% CI 1.14, 1.69; colorectal cancer 1.31, 95% CI 1.22, 1.39). Rates were substantially higher in those with a diagnosis of schizophrenia, bipolar disorder or psychotic disorders. CONCLUSIONS: Implementing pathways for earlier detection and diagnosis of cancers in people with MHSUC could reduce the rates of emergency presentation, with improved cancer survival outcomes. All health services, including cancer screening programmes, primary and secondary care, have a responsibility to ensure equitable access to healthcare for people with MHSUC.

Addressing Intergenerational Inequity in Tobacco-Harm: What Helps Children of Smokers to Remain Nonsmokers?

INTRODUCTION: Children of people who smoke are more likely to take up smoking themselves. In Aotearoa New Zealand (NZ), adolescent smoking declined dramatically between 2000 and 2016 despite limited change in parental smoking, demonstrating that the cycle can be broken. AIMS AND METHODS: This study aimed to identify modifiable factors associated with never smoking in Year 10 students (14-15 years) who had at least one caregiver who smoked. We used data from the Youth Insights Survey (2016 and 2018, pooled, N = 5,422) and identified students with at least one caregiver (mother, father, grandparent, other caregiver) who smoked (N = 2,205). To investigate modifiable factors potentially associated with nonsmoking we used logistic regression with marginally adjusted prevalence estimates. RESULTS: Overall, 41% of students had at least one caregiver who smoked. In this group, the majority (65%) had never smoked themselves. After adjustment, never-smoking was more prevalent among students attending low-deprivation (more affluent) schools (73% had never smoked) compared to high-deprivation schools (44%); students not exposed to others' smoking inside the home (72%) or in cars (70%) in the past week compared to those exposed (59% and 51%, respectively); and students whose parents would be upset if they were caught smoking (68% vs 49% for those whose parents would not be upset), or who had high self-esteem (69% vs 55% for those with low self-esteem). CONCLUSIONS: Modifiable factors independently associated with non-smoking in adolescents with caregiver(s) who smoked were: nonexposure to smoking inside the home and in cars, parental expectations of nonsmoking, and high self-esteem. IMPLICATIONS: Even in countries like NZ with relatively low adult smoking rates, children's exposure to caregiver smoking may be prevalent, particularly in structurally disadvantaged populations. This study suggests that action to promote smokefree homes and cars, build high self-esteem in young people, and communicate expectations of non-smoking are likely to help children of people who smoke to remain nonsmokers. A comprehensive approach that also addresses "upstream" factors (eg, socioeconomic deprivation) and underlying causes of structural inequity (eg, institutional racism) is needed. Such policy and community action may help to break intergenerational cycles of tobacco use and health inequity.

Equity of travel to access surgery and radiation therapy for lung cancer in New Zealand.

PURPOSE: Centralisation of lung cancer treatment can improve outcomes, but may result in differential access to care for those who do not reside within treatment centres. METHODS: We used national-level cancer registration and health care access data and used Geographic Information Systems (GIS) methods to determine the distance and time to access first relevant surgery and first radiation therapy among all New Zealanders diagnosed with lung cancer (2007-2019; N = 27,869), and compared these outcomes between ethnic groups. We also explored the likelihood of being treated at a high-, medium-, or low-volume hospital. Analysis involved both descriptive and adjusted logistic regression modelling. RESULTS: We found that Maori tend to need to travel further (with longer travel times) to access both surgery (median travel distance: Maori 57 km, European 34 km) and radiation therapy (Maori 75 km, European 35 km) than Europeans. Maori have greater odds of living more than 200 km away from both surgery (adjusted odds ratio [aOR] 1.83, 95% CI 1.49-2.25) and radiation therapy (aOR 1.41, 95% CI 1.25-1.60). CONCLUSIONS: Centralisation of care may often improve treatment outcomes, but it also makes accessing treatment even more difficult for populations who are more likely to live rurally and in deprivation, such as Maori.

The impact of racism on subsequent healthcare use and experiences for adult New Zealanders: a prospective cohort study.

BACKGROUND: Racism is an important determinant of health and driver of racial/ethnic health inequities. Experience of racism has been linked to negative healthcare use and experiences although most studies have been cross-sectional. This study examines the relationship between reported experience of racism and subsequent use and experience of health services. METHODS: This is a prospective cohort study design. The 2016/2017 adult New Zealand Health Survey (NZHS) provided the sampling frame and baseline data on exposures, health status and confounders. This stand-alone study invited all exposed individuals to participate when sampled based on their reported experience of racism (ever), stratified by broad ethnic groupings (Maori, Pacific, Asian, European/Other). Equal numbers of unexposed participants were selected for invitation using propensity score matching (propensity to experience racism, based on key available predictive factors). Follow-up was one to two years after NZHS interview. Outcome variables (last 12 months) were: unmet healthcare need (overall, for mental health, for a general practitioner); satisfaction with usual medical centre; and experiences with general practitioners (explaining care, involvement in decision-making, treated with respect/dignity, confidence and trust). Logistic regression models examining the association between experience of racism (at baseline) and health service use and experience (at follow-up) used doubly-robust estimation to weight for propensity scores used in the sampling with additional adjustment for confounders. RESULTS: The study had 2010 participants. Experience of racism (ever) at baseline was associated with higher overall unmet need at follow-up (adjusted OR (aOR) = 1.71, 95% CI 1.31, 2.23), with similar patterns for other unmet need measures. Experience of racism was associated with higher dissatisfaction with a usual medical centre (aOR = 1.41, 95% CI 1.10, 1.81) and with higher reporting of negative patient experiences. CONCLUSION: In line with how racism structures oppression, exposure to racism is largely felt by non-European groups in Aotearoa New Zealand. Experiences of racism potentially lead to poorer healthcare and healthcare inequities through higher unmet need, lower satisfaction and more negative experiences of healthcare. The health system has a critical role to play in addressing racism within healthcare and supporting societal efforts to eliminate racism and ethnic inequities.

The physical health and premature mortality of Indigenous Maori following first-episode psychosis diagnosis: A 15-year follow-up study.

BACKGROUND: People experiencing psychosis are at greater risk of physical health conditions and premature mortality. It is likely that Indigenous Maori youth, who experience additional systemic inequities caused by settler-colonisation, face even greater physical health and mortality risks following a diagnosis of first-episode psychosis. OBJECTIVE: Compare Maori and non-Maori for risk of hospitalisation and mortality for up to 15 years following first-episode psychosis diagnosis. METHODS: A cohort (N = 14,122) of young people (16-24 years) with first-episode psychosis diagnosis between 2001 and 2019 were identified. Using crude Kaplan-Meier and adjusted Cox proportional hazards models, Maori (n = 5211) and non-Maori (n = 8911) were compared on hospitalisation and mortality outcomes for up to 15 years. RESULTS: In the 15 years following first-episode psychosis diagnosis, Maori had higher adjusted risk of all-cause mortality (hazard ratio = 1.21, 95% confidence interval = [1.01, 1.45]), hospitalisation with diabetes (hazard ratio = 1.44, 95% confidence interval = [1.15, 1.79]), injury/poisoning (hazard ratio = 1.11, 95% confidence interval = [1.05, 1.16]), general physical health conditions (hazard ratio = 1.07, 95% confidence interval = [1.02, 1.13]) and also appeared to be at greater risk of cardiovascular hospitalisations (hazard ratio = 1.34, 95% confidence interval = [0.97, 1.86]). Kaplan-Meier plots show hospitalisation and mortality inequities emerging approximately 4-7 years following first-episode psychosis diagnosis. CONCLUSIONS: Maori are at greater risk for hospitalisation and premature mortality outcomes following first-episode psychosis. Early screening and intervention, facilitated by culturally safe health service delivery, is needed to target these inequities early.

Impact of diabetes on surgery and radiotherapy for breast cancer.

PURPOSES: This study aims to examine whether diabetes has an impact on the use of surgery and adjuvant radiotherapy in treating women with localised breast cancer. METHODS: Women diagnosed with stage I-III breast cancer between 2005 and 2020 were identified from Te Rehita Mate Utaetae-Breast Cancer Foundation New Zealand National Register, with diabetes status determined using New Zealand's Virtual Diabetes Register. The cancer treatments examined included breast conserving surgery (BCS), mastectomy, breast reconstruction after mastectomy, and adjuvant radiotherapy after BCS. Logistic regression modelling was used to estimate the adjusted odds ratio (OR) and 95% confidence interval (95% CI) of having cancer treatment and treatment delay (> 31 days) for patients with diabetes at the time of cancer diagnosis compared to patients without diabetes. RESULTS: We identified 25,557 women diagnosed with stage I-III breast cancer in 2005-2020, including 2906 (11.4%) with diabetes. After adjustment for other factors, there was no significant difference overall in risk of women with diabetes having no surgery (OR 1.12, 95% CI 0.94-1.33), although for patients with stage I disease not having surgery was more likely (OR 1.45, 95% CI 1.05-2.00) in the diabetes group. Patients with diabetes were more likely to have their surgery delayed (adjusted OR of 1.16, 95% CI 1.05-1.27) and less likely to have reconstruction after mastectomy compared to the non-diabetes group-adjusted OR 0.54 (95% CI 0.35-0.84) for stage I cancer, 0.50 (95% CI 0.34-0.75) for stage II and 0.48 (95% CI 0.24-1.00) for stage III cancer. CONCLUSIONS: Diabetes is associated with a lower likelihood of receiving surgery and a greater delay to surgery. Women with diabetes are also less likely to have breast reconstruction after mastectomy. These differences need to be taken in to account when considering factors that may impact on the outcomes of women with diabetes especially for Maori, Pacific and Asian women.

Association of diabetes and breast cancer characteristics at diagnosis.

PURPOSE: This study aims to examine the association of diabetes and breast cancer characteristics at diagnosis in Aotearoa/New Zealand. METHODS: Patients diagnosed with invasive breast cancer between 2005 and 2020 were identified from the National Breast Cancer Register. Logistic regression modeling was used to estimate the adjusted odds ratio (OR) of having stage III-IV cancer and the OR of having stage IV cancer for women with diabetes compared to those without diabetes. The adjusted OR of having screen-detected breast cancers for patients aged 45-69 years with diabetes compared to patients without diabetes was estimated. RESULTS: 26,968 women were diagnosed with breast cancer, with 3,137 (11.6%) patients having diabetes at the time of cancer diagnosis. The probability of co-occurrence of diabetes and breast cancer increased with time. Maori, Pacific and Asian women were more likely to have diabetes than European/Others. The probability of having diabetes also increased with age. For patients with diabetes, the probability of being diagnosed with stage III-IV cancer and stage IV cancer was higher than for patients without diabetes (OR 1.14, 95% CI 1.03-1.27; and 1.17, 95% CI 1.00-1.38). Women aged 45-69 years with diabetes were more likely to have screen-detected cancer than those without diabetes (OR 1.13, 95% CI 1.02-1.26). CONCLUSIONS: The co-occurrence of diabetes and breast cancer is becoming more common. Overall there is a small but significant adverse impact of having advanced disease for women with diabetes that is found at the time of breast cancer diagnosis, and this may contribute to other inequities that occur in the treatment pathway that may impact on patient outcomes.

Cycle-dependent sex differences in expression of membrane proteins involved in cerebrospinal fluid secretion at rat choroid plexus.

BACKGROUND: Female sex is a known risk factor of brain disorders with raised intracranial pressure (ICP) and sex hormones have been suggested to alter cerebrospinal fluid (CSF) dynamics, thus impairing ICP regulation in CSF disorders such as idiopathic intracranial hypertension (IIH). The choroid plexus (CP) is the tissue producing CSF and it has been hypothesized that altered hormonal composition could affect the activity of transporters involved in CSF secretion, thus affecting ICP. Therefore, we aimed to investigate if expression of various transporters involved in CSF secretion at CP were different between males and females and between females in different estrous cycle states. Steroid levels in serum was also investigated. METHODS: Female and male rats were used to determine sex-differences in the genes encoding for the transporters Aqp1 and 4, NKCC1, NBCe2, NCBE; carbonic anhydrase enzymes II and III (CA), subunits of the Na+/K+-ATPase including Atp1a1, Atp1b1 and Fxyd1 at CP. The estrous cycle stage metestrus (MET) and estrous (ES) were determined before euthanasia. Serum and CP were collected and subjected to RT-qPCR analysis and western blots. Serum was used to measure steroid levels using liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: Significant differences in gene expression and steroid levels between males and ES females were found, while no differences were found between male and MET females. During ES, expression of Aqp1 was lower (p < 0.01) and NKCC1 was higher in females compared to males. CAII was lower while CAIII was higher in ES females (p < 0.0001). Gene expression of Atp1a1 was lower in ES compared to male (p = 0.0008). Several of these choroidal genes were also significantly different in MET compared to females in ES. Differences in gene expression during the estrus cycle were correlated to serum level of steroid hormones. Protein expression of AQP1 (p = 0.008) and CAII (p = 0.035) was reduced in ES females compared to males. CONCLUSIONS: This study demonstrates for the first time that expression at CP is sex-dependent and markedly affected by the estrous cycle in female rats. Further, expression was related to hormone levels in serum. This opens a completely new avenue for steroid regulation of the expression of CSF transporters and the close link to the understanding of CSF disorders such as IIH.

Effects of caffeine on intracranial pressure and pain perception in freely moving rats.

OBJECTIVE: Caffeine, a non-selective adenosine receptor (AR) antagonist, is the most consumed psychostimulant in the world. Caffeine has been suggested to regulate cerebrospinal fluid secretion and is known both to alleviate and to trigger headache; however, its effect on the regulation of intracranial pressure (ICP) is not known. Therefore, we aimed to investigate the effects of caffeine on ICP and nociceptive responses. METHODS: Female Sprague-Dawley rats were implanted with a novel telemetric device for continuous ICP recordings, which allowed for continuous recordings in freely moving rats. A single dose of caffeine (30 or 120 mg/kg intraperitoneally) was given. In a second group (non-implanted), the acute effects of 30 mg/kg caffeine on periorbital threshold using Von Frey testing and spontaneous behavior were utilized using an automated behavioral registration platform (Laboratory, Animal, Behavior, Observation, Registration and Analysis System) in a randomized cross-over study. Quantitative polymerase chain reaction and immunofluorescence were used to localize ARs in the choroid plexus. RESULTS: A single dose of 30 mg/kg caffeine lowered the ICP by 35% at 165 min after administration (saline: 0.16 ± 0.9 vs caffeine: -1.18 ± 0.9 ΔmmHg, p = 0.0098) and lasted up to 12 h. Administration of 120 mg/kg caffeine showed a faster onset of decrease in ICP within 15 min by 50% (p = 0.0018) and lasted up to 12 h. The periorbital pain thresholds were higher after 1 h (saline: 224.6 ± 15.1 vs caffeine: 289.5 ± 8.7 g, p = 0.005) and lasted up to 5 h. Caffeine-treated rats had increased locomotor activity, speed, and changed grooming behavior. Expression of AR1 was found in the choroid plexus. CONCLUSIONS: This study demonstrates that caffeine has a lowering effect on ICP as an acute treatment. Interestingly, caffeine acutely caused an increased response in cephalic thresholds supporting hypoalgesic effects. Future studies investigating the beneficial effects of caffeine for elevated ICP are warranted.

Indications and prescribing patterns of antiseizure medications in children in New Zealand.

AIM: To determine indications and prescribing patterns for antiseizure medications (ASMs) in children by age, sex, and socioeconomic status. METHOD: This retrospective study searched the New Zealand database of ASM prescriptions dispensed to individuals aged 18 years or under during 2015 in three regions of New Zealand (48% paediatric population). Medical records were reviewed by a paediatric neurologist for indication. ASMs were grouped into old or new (1993 onwards). RESULTS: In total, 2594 children (0 to 18 years, mean age 11 years 2 months, median 12 years; 51% male) were dispensed 3557 ASMs for seizures (76%), pain (6%), headache (5%), mental health (3%), and movement disorders (2%). After 10 years of age, lamotrigine was more likely and valproate less likely to be prescribed in females than males. No sex difference was observed for valproate prescriptions for non-seizure indications. Topiramate prescriptions increased in adolescent females. Prescriptions for non-seizure indications increased from 7% in children aged 6 years or under to 31% in 16- to 18-year-olds. The proportion of children receiving a new ASM compared to an old ASM was greater in children from higher than lower socioeconomic areas. INTERPRETATION: Our results highlight a need for focused ASM teratogenicity messaging to clinicians prescribing ASMs for non-seizure indications. In addition, to improve equity of epilepsy care, it is critical for health policies to consider socioeconomic factors that impact on ASM prescribing.

Retrospective Cohort Study of the Incidence of Acute Kidney Injury with Vancomycin Area under the Curve-Based Dosing with Concomitant Piperacillin-Tazobactam Compared to Meropenem or Cefepime.

Acute kidney injury (AKI) is a complication associated with vancomycin. Previous studies demonstrated that the combination of vancomycin and piperacillin-tazobactam increases the risk of AKI compared to vancomycin with meropenem or cefepime. These studies did not utilize area under the curve (AUC)-based dosing, which reduces vancomycin exposure and may decrease nephrotoxicity compared with trough-based dosing. This study evaluated the incidence of AKI in patients receiving AUC-dosed vancomycin with either concomitant piperacillin-tazobactam (VPT) or meropenem or cefepime (VMC). This retrospective cohort study included patients admitted to Sentara Norfolk General Hospital between October 2019 and September 2020 who received AUC-dosed vancomycin and concomitant piperacillin-tazobactam, meropenem, or cefepime for at least 48 h. The primary outcome was the incidence of AKI during treatment or within 24 h of discontinuation. A total of 435 patients (VPT, n = 331; VMC, n = 104) who received a median duration of 4 days of treatment were included. The incidence of AKI was significantly higher with VPT than with VMC (13.6% versus 4.8% [P = 0.014]). Multivariable analysis showed VPT to be an independent risk factor for the development of AKI (odds ratio [OR], 3.00 [95% confidence interval {CI}, 1.15 to 7.76]). VPT was associated with more frequent AKI than VMC, even with the relatively short courses of antimicrobial therapy administered in this population. In comparison with the precedent in the literature for trough-based vancomycin dosing, our results suggest that the use of AUC-based vancomycin dosing in combination with piperacillin-tazobactam, meropenem, or cefepime may result in a lower overall incidence of AKI.

Histologic and morphologic character of pediatric abdominal aortic developmental coarctation and hypoplasia.

OBJECTIVES: Abdominal aortic coarctation and hypoplasia are uncommon diseases, recognized most often in pediatric-aged individuals. Comprehensive studies regarding the pathologic spectrum of these aortopathies are nonexistent. This investigation was undertaken to better define the histologic and morphologic character of abdominal aortic narrowings affecting children and assess its potential relevance to contemporary clinical practice. METHODS: Aortic specimens obtained during open operations in children being treated for symptomatic, noninflammatory abdominal aortic narrowings at the University of Michigan were subjected to histologic study after hematoxylin and eosin, Movat, Verhoeff Van Gieson, and Masson's trichrome preparations. Microscopic findings were correlated with the anatomic aortic images. In addition, a detailed review was completed of all prior reports in the English literature that included images depicting the histologic character of noninflammatory abdominal aortic narrowings in children. RESULTS: Among a series of 67 pediatric-aged individuals undergoing open surgical interventions for abdominal aortic narrowings, eight children ranging in age from 9 months to 18 years, had adequate aortic tissue available for study. The loci of the specimens paralleled the anatomic sites of segmental coarctations observed in the entire series, with involvement of the suprarenal abdominal aorta (n = 3), intrarenal aorta (n = 2), and infrarenal aorta (n = 1). Diffusely hypoplastic abdominal aortas (n = 2) included one case of a de facto aortic duplication, represented by a channel that paralleled the narrow native aorta and gave origin to celiac artery branches, as well as the superior mesenteric and renal arteries. Concentric or eccentric intimal fibroplasia was observed in every aorta, often with internal elastic fragmentation and duplication (n = 4). Media abnormalities included elastic tissue disorganization (n = 3) and focal medial fibrosis (n = 1). Organizing luminal thrombus occurred in two infants. Coexistent ostial stenoses of the celiac, superior mesenteric, or renal arteries were observed in all but the only child who had an infrarenal aortic coarctation. Neurofibromatosis type 1 affected one child whose histologic findings were indistinguishable from those of the other children. A review of prior published histologic images of abdominal aortic coarctation and hypoplasia affecting children from other centers revealed a total of 14 separate reports, each limited to single case photomicrographs, of which 11 exhibited intimal fibroplasia. CONCLUSIONS: Intimal fibroplasia is a common accompaniment of developmental abdominal aortic coarctation and hypoplasia. It is posited that intimal fibroplasia, which is likely progressive in instances of abnormal shear stresses in these diminutive vessels, may contribute to less salutary outcomes after endovascular and certain open reconstructions of pediatric abdominal aortic narrowings.

Use of intermittently scanned continuous glucose monitoring in young people with high-risk type 1 diabetes-Extension phase outcomes following a 6-month randomized control trial.

AIMS: To describe the impact of a 12-month intervention using intermittently scanned continuous glucose monitoring (isCGM) on glycaemic control and glucose test frequency in adolescents and young adults with type 1 diabetes (T1D) and high-risk glycaemic control (HbA1c ≥75 mmol/mol [≥9.0%]). METHODS: In total, 64 young people (aged 13-20 years, 16.6 ± 2.1 years; 48% female; 41% Maori or Pacific ethnicity; mean diabetes duration 7.5 ± 3.8 years) with T1D were enrolled in a 6-month, randomized, parallel-group study comparing glycaemic outcomes from the isCGM intervention (n = 33) to self monitoring blood glucose (SMBG) controls (n = 31). In this 6-month extension phase, both groups received isCGM; HbA1c , glucose time-in-range (TIR), and combined glucose test frequency were assessed at 9 and 12 months. RESULTS: At 12 months, the mean difference in HbA1c from baseline was -4 mmol/mol [-0.4%] (95% confidence interval, CI: -8, 1 mmol/mol [-0.8, 0.1%]; p = 0.14) in the isCGM intervention group, and -7 mmol/mol [-0.7%] (95% CI: -16, 1 mmol/mol [-1.5, 0.1%]; p = 0.08) in the SMBG control group. No participants achieved ≥70% glucose TIR (3.9-10.0 mmol/L). The isCGM intervention group mean rate of daily glucose testing was highest at 9 months, 2.4 times baseline rates (p < 0.001), then returned to baseline by 12 months (incidence rate ratio = 1.4; 95% CI: 0.9, 2.1; p = 0.091). CONCLUSIONS: The use of isCGM in young people with high-risk T1D resulted in transient improvements in HbA1c and glucose monitoring over a 9-month time frame; however, benefits were not sustained to 12 months.

Psychological distress, loneliness, alcohol use and suicidality in New Zealanders with mental illness during a strict COVID-19 lockdown.

INTRODUCTION: People with pre-existing mental health conditions may have been disproportionally impacted by the COVID-19 pandemic and associated public health restrictions. In this study, we compared psychological outcomes, experiences and sources of stress over the pandemic lockdown in New Zealanders with and without a previous diagnosis of mental illness. METHODS: Two online surveys were conducted in New Zealand over the level 4 lockdown in April 2020 measuring psychological distress, anxiety, well-being, suicidality, alcohol use and subjective experiences. They included 3389 participants, of whom 18.4% reported having been previously diagnosed with a mental illness. RESULTS: During the lockdown, people previously diagnosed with a mental illness had about twice the risk of reporting moderate-high levels of psychological distress (K10 ⩾ 12), at least moderate levels of anxiety (GAD-7 ⩾ 10) and poor well-being (WHO-5 ⩽ 12). They reported increased alcohol use and were about four times as likely to have experienced suicidal thoughts with 3% reporting having made a suicide attempt over the lockdown period. They reported less satisfaction with, and poorer relationships with people in their 'bubble', reduced social contacts and greater loneliness. They also reported higher levels of health and financial concerns. CONCLUSION: During the COVID-19 lockdown in New Zealand, people with a previous diagnosis of a mental illness were at increased risk of detrimental psychological outcomes. This highlights the importance of recognising this and the challenges people face in pandemics.

Examining the potential preventability of adverse fetal/neonatal outcomes associated with severe maternal morbidity.

BACKGROUND: Severe maternal morbidity (SMM) occurs in 1-2% of pregnancies. Despite the knowledge that a SMM event can contribute to poor fetal/neonatal outcomes, little is known about the preventability of these adverse outcomes. AIMS: To examine adverse fetal/neonatal outcomes associated with SMM to determine if these outcomes were potentially preventable. MATERIALS AND METHODS: A New Zealand national retrospective cohort study examining cases of SMM with an adverse fetal/neonatal outcome. Maternity and initial neonatal care were explored by multidisciplinary panels utilising a preventability tool to assess whether the fetal/neonatal harm was potentially preventable. Adverse fetal/neonatal outcomes were defined as fetal or early neonatal death, Apgar score <7 at five minutes, admission to neonatal intensive care unit or special care baby unit and neonatal encephalopathy. RESULTS: Of 85 cases reviewed, adverse fetal/neonatal outcome was deemed potentially preventable in 55.3% of cases (n = 47/85). Preventability was related to maternal antenatal/peripartum care (in utero) in 39% (n = 33/85), to initial neonatal care (ex utero) in 36% (n = 29/80), and to both maternal and neonatal care in 20% (16/80) of cases. Main contributors to potential preventability were factors related to healthcare providers, particularly lack of recognition of high risk, delayed or failure to diagnose, and delayed or inappropriate treatment. CONCLUSIONS: Multidisciplinary panels found that over half of adverse fetal/neonatal harm associated with SMM was potentially preventable. The novel approach of examining both maternal and neonatal care identifies opportunities to improve fetal/neonatal outcomes associated with SMM at multiple points on the perinatal continuum of care.

Histologic and morphologic character of pediatric renal artery occlusive disease.

OBJECTIVE: The pathologic nature of pediatric renal artery occlusive lesions causing renovascular hypertension has been the subject of numerous anecdotal reports. This study was undertaken to define the character of childhood renal artery stenoses. A better understanding of this disease is particularly germane, given its unknown etiology and the limited success of certain contemporary treatment options. METHODS: Renal artery specimens obtained during open operations in children being treated for renovascular hypertension from 2004 to 2016 were studied. Excluded from study were arteries subjected to earlier open or endovascular operations. Histologic preparations employing hematoxylin-eosin, Movat, Masson trichrome, and Verhoeff-van Gieson stains allowed characterization of the intima, media, and adventitial tissues. External and luminal diameters were measured. Microscopic data were correlated with preoperative arteriographic images. The histologic and morphologic findings were assessed in regard to coexistent nonrenal arterial and aortic lesions as well as known syndromic diseases. RESULTS: Thirty-three stenotic renal arteries from 28 children were subjected to examination. Stenoses involved the proximal-ostial renal arteries (24), central renal arteries (7), and distal segmental renal arteries (2). Ostial stenoses commonly exhibited preocclusive concentric hyperplasia of intimal tissues, frequent internal elastic lamina disruptions, and diminutive and discontinuous media. Central and distal renal stenoses most often exhibited lesser intimal cellular hyperplasia and more noticeable fibrodysplasia of the media and adventitia. The mean external and luminal diameters of the renal arteries having ostial stenoses were smaller than the expected renal artery size for a given age. Abdominal aortic coarctation or hypoplastic aortas occurred in 14 children. Neurofibromatosis type 1 affected four children with ostial renal artery disease and one child with midrenal artery disease, but there were no distinguishing features unique to their stenoses. CONCLUSIONS: Pediatric renal artery stenotic disease affects exceedingly small arteries. Ostial lesions frequently exhibit extensive luminal encroachments characterized by cellular hyperplasia of intimal tissues and scant medial smooth muscle. Central and distal renal arterial stenoses were characterized most often by extensive fibrodysplasia of the media and adventitia. The early success and durability of catheter-based angioplasty may be compromised by the cellular abnormalities of pediatric renal artery occlusive disease observed in this investigation.

A Novel Recurrent COL5A1 Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia.

OBJECTIVE: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (P=0.005). CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.