Influence of childhood trauma and traumatic stress on a woman's risk of having a child with a fetal alcohol spectrum disorder.

BACKGROUND: Maternal risk factors for having a child diagnosed on the fetal alcohol spectrum disorders (FASD) continuum are complex and include not only the quantity, frequency, and timing of alcohol use but also a woman's physical stature, socio-economic status, and pregnancy-related factors. Exposure to trauma may predispose women to a range of physiological and mental disorders. A woman's mental and physical health may in turn influence her probability of having a child with FASD. This study investigated the role of maternal childhood trauma and lifetime traumatic stress on prenatal alcohol consumption and on the risk of having a child with FASD. METHODS: A nested, case-control study was conducted for maternal risk assessment. Study participants were mothers of first-grade learners from five rural communities in the Western Cape Province of South Africa who were assessed for FASD. Face-to-face surveys were conducted, which included mental health and trauma assessment questionnaires. RESULTS: In logistic regression analyses, higher maternal childhood trauma scores were associated with an increased likelihood of having a child diagnosed with FASD, although the increase in risk was modest (OR = 1.014, p = 0.015). In addition, structural equation modeling investigated relationships between maternal drinking, childhood trauma, traumatic stress, and a child's FASD diagnosis. Traumatic stress and drinking during pregnancy, but not lifetime alcohol use, were associated with maternal childhood trauma. Lifetime alcohol use influenced drinking during pregnancy, which in turn was significantly associated with having a child diagnosed on the continuum of FASD. CONCLUSION: No direct influence of maternal childhood trauma on FASD diagnosis could be demonstrated. However, maternal trauma may indirectly contribute to the risk of having a child diagnosed with FASD.

New solutions to old problems: A practical approach to identify samples with intravenous fluid contamination in clinical laboratories.

OBJECTIVES: Contamination with intravenous (IV) fluids is a common cause of specimen rejection or erroneous results in hospitalized patients. Identification of contaminated samples can be difficult. Common measures such as failed delta checks may not be adequately sensitive nor specific. This study aimed to determine detection criteria using commonly ordered tests to identify IV fluid contamination and validate the use of these criteria. METHODS: Confirmed contaminated and non-contaminated samples were used to identify patterns in laboratory results to develop criteria to detect IV fluid contamination. The proposed criteria were implemented at a tertiary care hospital laboratory to assess performance prospectively for 6 months, and applied to retrospective chemistry results from 3 hospitals and 1 community lab to determine feasibility and flagging rates. The algorithm was also tested at an external institution for transferability. RESULTS: The proposed algorithm had a positive predictive value of 92 %, negative predictive value of 91 % and overall agreement of 92 % when two or more criteria are met (n = 214). The flagging rates were 0.03 % to 0.07 % for hospital and 0.003 % for community laboratories. CONCLUSIONS: The proposed algorithm identified true contamination with low false flagging rates in tertiary care urban hospital laboratories. Retrospective and prospective analysis suggest the algorithm is suitable for implementation in clinical laboratories to identify samples with possible IV fluid contamination for further investigation.

Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.

Invasion of human erythrocytes by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins: apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2). While antibodies to AMA1 provide limited protection against Pf in non-human primate malaria models, clinical trials using recombinant AMA1 alone (apoAMA1) yielded no protection due to insufficient functional antibodies. Immunization with AMA1 bound to RON2L, a 49-amino acid peptide from its ligand RON2, has shown superior protection by increasing the proportion of neutralizing antibodies. However, this approach relies on the formation of a complex in solution between the two vaccine components. To advance vaccine development, here we engineered chimeric antigens by replacing the AMA1 DII loop, displaced upon ligand binding, with RON2L. Structural analysis confirmed that the fusion chimera (Fusion-FD12) closely mimics the binary AMA1-RON2L complex. Immunization studies in female rats demonstrated that Fusion-FD12 immune sera, but not purified IgG, neutralized vaccine-type parasites more efficiently compared to apoAMA1, despite lower overall anti-AMA1 titers. Interestingly, Fusion-FD12 immunization enhanced antibodies targeting conserved epitopes on AMA1, leading to increased neutralization of non-vaccine type parasites. Identifying these cross-neutralizing antibody epitopes holds promise for developing an effective, strain-transcending malaria vaccine.

Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.

Invasion of human red blood cells (RBCs) by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins, apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) 1,2 . Antibodies to AMA1 confer limited protection against P. falciparum in non-human primate malaria models 3,4 . However, clinical trials with recombinant AMA1 alone (apoAMA1) saw no protection, likely due to inadequate levels of functional antibodies 5-8 . Notably, immunization with AMA1 in its ligand bound conformation using RON2L, a 49 amino acid peptide from RON2, confers superior protection against P. falciparum malaria by enhancing the proportion of neutralizing antibodies 9,10 . A limitation of this approach, however, is that it requires the two vaccine components to form a complex in solution. To facilitate vaccine development, we engineered chimeric antigens by strategically replacing the AMA1 DII loop that is displaced upon ligand binding with RON2L. Structural characterization of the fusion chimera, Fusion-F D12 to 1.55 Å resolution showed that it closely mimics the binary receptor-ligand complex. Immunization studies showed that Fusion-F D12 immune sera neutralized parasites more efficiently than apoAMA1 immune sera despite having an overall lower anti-AMA1 titer, suggesting improvement in antibody quality. Furthermore, immunization with Fusion-F D12 enhanced antibodies targeting conserved epitopes on AMA1 resulting in greater neutralization of non-vaccine type parasites. Identifying epitopes of such cross-neutralizing antibodies will help in the development of an effective, strain-transcending malaria vaccine. Our fusion protein design is a robust vaccine platform that can be enhanced by incorporating polymorphisms in AMA1 to effectively neutralize all P. falciparum parasites.

Defining ferritin clinical decision limits to improve diagnosis and treatment of iron deficiency: A modified Delphi study.

BACKGROUND: Iron deficiency is highly prevalent worldwide and is an issue of health inequity. Despite its high prevalence, uncertainty on the clinical applicability and evidence-base of iron-related lab test cut-offs remains. In particular, current ferritin decision limits for the diagnosis of iron deficiency may not be clinically appropriate nor scientifically grounded. METHODS: A modified Delphi study was conducted with various clinical experts who manage iron deficiency across Canada. Statements about ferritin decision limits were generated by a steering committee, then distributed to the expert panel to vote on agreement with the aim of achieving consensus and acquiring feedback on the presented statements. Consensus was reached after two rounds, which was defined as 70% of experts rating their agreement for a statement as 5 or higher on a Likert scale from 1 to 7. RESULTS: Twenty-six clinical experts across 10 different specialties took part in the study. Consensus was achieved on 28 ferritin decision limit statements in various populations (including patients with multiple comorbid conditions, pediatric patients, and pregnant patients). For example, there was consensus that a ferritin <30 µg/L rules in iron deficiency in all adult patients (age ≥ 18 years) and warrants iron replacement therapy. CONCLUSION: Consensus statements generated through this study corresponded with current evidence-based literature and guidelines. These statements provide clarity to facilitate clinical decisions around the appropriate detection and management of iron deficiency.

64Cu Treatment Planning and 67Cu Therapy with Radiolabeled [64Cu/67Cu]MeCOSar-Octreotate in Subjects with Unresectable Multifocal Meningioma: Initial Results for Human Imaging, Safety, Biodistribution, and Radiation Dosimetry.

Our aim was to report the use of 64Cu and 67Cu as a theranostic pair of radionuclides in human subjects. An additional aim was to measure whole-organ dosimetry of 64Cu and 67Cu attached to the somatostatin analog octreotate using the sarcophagine MeCOSar chelator (SARTATE) in subjects with somatostatin receptor-expressing lesions confined to the cranium, thereby permitting normal-organ dosimetry for the remainder of the body. Methods: Pretreatment PET imaging studies were performed up to 24 h after injection of [64Cu]Cu-SARTATE, and normal-organ dosimetry was estimated using OLINDA/EXM. Subsequently, the trial subjects with multifocal meningiomas were given therapeutic doses of [67Cu]Cu-SARTATE and imaged over several days using SPECT/CT. Results: Five subjects were initially recruited and imaged using PET/CT before treatment. Three of the subjects were subsequently administered 4 cycles each of [67Cu]Cu-SARTATE followed by multiple SPECT/CT imaging time points. No serious adverse events were observed, and no adverse events led to withdrawal from the study or discontinuation from treatment. The estimated mean effective dose was 3.95 × 10-2 mSv/MBq for [64Cu]Cu-SARTATE and 7.62 × 10-2 mSv/MBq for [67Cu]Cu-SARTATE. The highest estimated organ dose was in spleen, followed by kidneys, liver, adrenals, and small intestine. The matched pairing was shown by PET and SPECT intrasubject imaging to have nearly identical targeting to tumors for guiding therapy, demonstrating a potentially accurate and precise theranostic product. Conclusion: 64Cu and 67Cu show great promise as a theranostic pair of radionuclides. Further clinical studies will be required to examine the therapeutic dose required for [67Cu]Cu-SARTATE for various indications. In addition, the ability to use predictive 64Cu-based dosimetry for treatment planning with 67Cu should be further explored.

Hierarchy of Evidence Within the Medical Literature.

The quality of evidence from medical research is partially deemed by the hierarchy of study designs. On the lowest level, the hierarchy of study designs begins with animal and translational studies and expert opinion, and then ascends to descriptive case reports or case series, followed by analytic observational designs such as cohort studies, then randomized controlled trials, and finally systematic reviews and meta-analyses as the highest quality evidence. This hierarchy of evidence in the medical literature is a foundational concept for pediatric hospitalists, given its relevance to key steps of evidence-based practice, including efficient literature searches and prioritization of the highest-quality designs for critical appraisal, to address clinical questions. Consideration of the hierarchy of evidence can also aid researchers in designing new studies by helping them determine the next level of evidence needed to improve upon the quality of currently available evidence. Although the concept of the hierarchy of evidence should be taken into consideration for clinical and research purposes, it is important to put this into context of individual study limitations through meticulous critical appraisal of individual articles.

The Bubble of Normalisation: A Qualitative Study of Carers of People With Dementia Who Do Not Seek Help for a Diagnosis.

OBJECTIVE: Improving dementia diagnosis rates are a key feature of dementia strategy and policy worldwide. This study aimed to explore the experience of carers of people diagnosed with dementia during or following a hospital admission in order to identify factors that had prevented them from seeking help beforehand. Semi-structured interviews were conducted with 12 informal carers including adults caring for a parent, a friend or a spouse diagnosed with dementia between 2010-2019, following an acute hospital admission for a physical health problem, having not sought help previously. MAIN FINDINGS: Carers created a 'bubble of normalisation' around themselves and the person living with dementia (PLWD) to reject the label of dementia and protect the PLWD from a loss of independence, discrimination and prejudice they felt would be the result of a diagnosis. Carers struggled to talk to the PLWD about dementia reinforcing denial and stigma. Post-diagnosis carers felt unsupported and questioned the value of diagnosis. PRINCIPAL CONCLUSIONS: Stigma related to images of dementia as a disease that takes away independence and identity prevented discussion about dementia between carers and the PLWD. A lack of open discussion about memory concerns between health care professionals and carers also served to delay diagnosis.

Is the diagnostic rate for the common subtypes of A1AT deficiency consistent across two Canadian Provinces?

BACKGROUND: The diagnosis of alpha-1-antitrypsin (A1AT) deficiency has been hindered by obscurity concerning the testing process and treatment implications. In this study, we aimed to identify regional differences in the diagnostic rates for A1AT deficiency in the western Canadian provinces of British Columbia (BC) and Alberta (AB). METHODS: The number of A1AT deficiency variant genotype (ZZ, SZ, MZ, SS, and MS) diagnoses were reviewed for BC and AB. The regional diagnostic rates for A1AT deficiency variants in these two provinces, normalized for the predicted population prevalence of each variant genotype, was defined as the annual provincial diagnostic rate (APDR) for a given variant genotype. Sex specific variations in the mean age at diagnosis for the five variant genotypes were compared both within and between provinces. RESULTS: The SZ and MZ genotype APDRs were significantly increased in the AB population compared to the BC population. The SS and MS APDRs were similar between AB and BC. There was a significantly decreased mean age of diagnosis for AB males, as compared to BC males (for the SZ, MS, and MZ genotypes) and as compared to AB females (for the MS, MZ, and SS genotypes). There were no significant differences in the mean age of diagnosis between the females and males in BC, or between females in AB and BC, for any genotype. CONCLUSION: The notably higher APDR for more severe A1AT deficiency genotypes, and lower mean age of diagnosis for most variant genotypes in AB males, deserves further investigation to determine the explanation(s) for these differences.

Revising Ferritin Lower Limits: It's Time to Raise the Bar on Iron Deficiency.

Ferritin is a key diagnostic marker of iron deficiency (ID), but the interpretative guidance provided to physicians varies significantly. Clear discrepancies exist between clinical guidelines that recommend evidence-based ferritin cutoffs and clinical laboratories that report highly variable ferritin reference intervals (RIs) derived from apparently healthy populations. In this study, clinical laboratories across North America were surveyed to assess the RIs provided with ferritin results. Although clinical guidelines often recommend ferritin cutoffs of 15 or 30 µg/L to identify uncomplicated ID, the survey showed that 18 of 23 responding laboratories reported female RI lower limits well below 15 µg/L. To understand the clinical impact, we analyzed 52 027 unique patient ferritin values over a 5-year period (2013-2017) from a tertiary care hospital. In this population, the 90th percentile ferritin cutoff to identify ID anemia in adults was 24 µg/L in female patients and 25 µg/L in male patients. Distribution of ferritin results in female patients showed that menopausal status had a significant effect on median values, which increased 2- to 3-fold in the postmenopausal state. Furthermore, sorting the data for female patients by physician specialty showed the highest prevalence of low ferritin values in patients seen in obstetrics and gynecology. This study highlights the discrepancy between clinical guidelines and clinical laboratory practice for ferritin reporting and indicates that ferritin RIs, particularly for female patients, are set to an inappropriately low threshold in most clinical laboratories in North America; this level provides good specificity but poor sensitivity when screening for ID.

Alpha-1-antitrypsin molecular testing in Canada: A seven year, multi-centre comparison.

BACKGROUND: Laboratory confirmation of alpha-1-antitrypsin (A1AT) deficiency may be achieved by multiple methods. Here, we compare the relative comprehensiveness and efficiency of pathogenic variant (PV) detection of four different protocols utilized at different diagnostic centres in Canada. METHODS: Diagnostic results from 2011 to 2018 at clinical laboratories in British Columbia (BC), Alberta (AB), Ontario (ON), and Québec (QC) were reviewed. The four labs utilize the following protocols: BC-CGID (serum A1AT Concentration/Genotyping/Isoelectric focussing (IEF)/SERPINA1 DNA sequencing), AB-CID (serum A1AT Concentration/IEF/DNA sequencing), ON-CD (serum A1AT Concentration/DNA sequencing), and QC-G (Genotyping). As the respective catchment areas varied in size and ethnic composition, the comprehensiveness of PV detection was assessed by comparing the frequency of individual genotypes to the ZZ genotype, which is clearly identified by all protocols. RESULTS: Collectively 5399 index patients were tested identifying 396 ZZ genotypes. Serum A1AT concentration as a determinant of further testing efficiently identified PV. ON-CD had the highest detection rate for PV; genotypes with at least one PV, other than S, Z or F, were identified at 0.67/ZZ as compared to <0.2/ZZ (all others). However, ON-CD had the highest rates of undefined molecular variants (UMV) (0.16/ZZ) or likely benign variants (LBV) (0.08/ZZ), compared to all others (<0.12/ZZ and < 0.06/ZZ, respectively). The F variant was identified at 0.10/ZZ, only in the ON-CD and the AB-CID protocols. Collectively, MMalton was the next most common variant, identified as a compound heterozygous genotype at 0.04/ZZ, only in the ON-CD and BC-CGID protocols. CONCLUSION: Strategies which readily detect variants across the full coding sequence of SERPINA1 detect more PV as well as more UMV and LBV.

NullCanada: A novel α1-antitrypsin allele with in cis variants Glu366Lys and Ile100Asn.

BACKGROUND: α1-Antitrypsin (A1AT) deficiency predisposes patients to pulmonary disease due to inadequate protection against human neutrophil elastase released during inflammatory responses. A1AT deficiency is caused by homozygosity or compound heterozygosity for A1AT variants; individuals with A1AT deficiency most commonly have at least one Z variant allele (c.1096G > A (Glu366Lys)). Null variants that result in complete absence of A1AT in the plasma are much rarer. With one recent exception, all reported A1AT variants are characterized by a single pathogenic variant. CASE: An 8 years old patient from Edmonton, Alberta, Canada, was investigated for A1AT deficiency. His A1AT phenotype was determined to be M (wild type)/Null by isoelectric focusing (IEF) but M/Z by targeted genotyping. Gene sequencing revealed two heterozygous variants: Z and Ile100Asn (c.299 T > A). The Ile100Asn substitution is predicted to disrupt the secondary structure of an α-helix in which it resides and the neighbouring tertiary structure, resulting in intracellular degradation of A1AT prior to hepatocyte secretion. METHODS: Family testing was conducted to verify potential inheritance of an A1AT allele carrying the two mutations in cis, as this arrangement of the mutations would explain "Z" detection by genotyping but not by IEF. Molecular modeling was used to assess the effect of the variants on A1AT structure and stability. DISCUSSION: Carrier status for a novel variant NullCanada with in cis mutations (c.[299 T > A;1096G > A], p.[(Ileu100Asn;Glu366Lys)]) was confirmed. A sibling was identified as having A1AT deficiency on the basis of compound heterozygosity for two alleles: NullCanada and the common Z allele. A separate pedigree from the Maritimes was subsequently recognized as carrying NullCanada. CONCLUSION: In cis mutations such as NullCanada may be more common than previously described due to failure to detect such mutations using historical testing methods. Combined approaches that include gene sequencing and segregation studies allow recognition of rare A1AT variants, including in cis mutations.

Persistent barriers and facilitators to seeking help for a dementia diagnosis: a systematic review of 30 years of the perspectives of carers and people with dementia.

OBJECTIVE: To identify barriers and facilitators to help seeking for a dementia diagnosis from the perspective of carers and people with dementia. DESIGN: A systematic review of the literature was conducted according to the PRISMA guidelines (PROSPERO protocol registration CRD42018092524). Nine electronic databases were searched for qualitative, quantitative, and mixed methods primary research studies. Two independent reviewers screened titles and abstracts, full texts of eligible studies, and conducted quality appraisal of included articles. A convergent qualitative synthesis approach was used. RESULTS: From 7496 articles, 35 papers representing 32 studies from 1986 to 2017 were included. Studies originated from 13 countries across 4 continents. Barriers and facilitators were reported predominantly by carers. A small number of studies included people with dementia. Barriers included denial, stigma and fear, lack of knowledge, normalization of symptoms, preserving autonomy, lack of perceived need, unaware of changes, lack of informal network support, carer difficulties, and problems accessing help. Facilitators included recognition of symptoms as a problem, prior knowledge and contacts, and support from informal network. CONCLUSIONS: Studies from a 30-year period demonstrated that barriers to help seeking persist globally, despite increasing numbers of national dementia policies. Barriers and facilitators rarely existed independently demonstrating the complexity of help seeking for a diagnosis of dementia. Multiple barriers compounded the decision-making process and more than one facilitator was often required to overcome them. Multi-faceted interventions to reduce barriers are needed, one approach would be a focus on the development of dementia friendly communities to reduce stigma and empower people with dementia and carers.

Improving Efficiency of Pediatric Hospital Medicine Team Daily Workflow.

BACKGROUND AND OBJECTIVES: Workflow inefficiencies by medical teams caring for hospitalized patients may affect patient care and team experience. At our institution, complexity and clinical volume of the pediatric hospital medicine (HM) service have increased over time; however, efficient workflow expectations were lacking. We aimed to increase the percentage of HM teams meeting 3 efficiency criteria (70% nurses present for rounds, rounds completed by 11:30 am, and HM attending notes completed by 5 pm) from 28% to 80% within 1 year. METHODS: Improvement efforts targeted 5 HM teams at a large academic hospital. Our multidisciplinary team, including HM attending physicians, pediatric residents, and nurses, focused on several key drivers: shared expectations, enhanced physician and nursing buy-in and communication, streamlined rounding process, and data transparency. Interventions included (1) daily rounding expectations with prerounds huddle, (2) visible reminders, (3) complex care team scheduled rounds, (4) real-time nurse notification of rounds via electronic platform, (5) workflow redesign, (6) attending feedback and data transparency, and (7) resource attending implementation. Attending physicians entered efficiency data each day through a Research Electronic Data Capture survey. Annotated control charts were used to assess the impact of interventions over time. RESULTS: Through sequential interventions, the percentage of HM teams meeting all 3 efficiency criteria increased from 28% to 61%. Nursing presence on rounds improved, and rounds end time compliance remained high, whereas attending note completion time remained variable. CONCLUSIONS: Inpatient workflow for pediatric providers was improved by setting clear expectations and enhancing team communication; competing demands while on service contributed to difficulty in improving timely attending note completion.