Development of an Image-Based HCS-Compatible Method for Endothelial Barrier Function Assessment.

The recent renascence of phenotypic drug discovery (PDD) is catalyzed by its ability to identify first-in-class drugs and deliver results when the exact molecular mechanism is partially obscure. Acute respiratory distress syndrome (ARDS) is a severe, life-threatening condition with a high mortality rate that has increased in frequency due to the COVID-19 pandemic. Despite decades of laboratory and clinical study, no efficient pharmacological therapy for ARDS has been found. An increase in endothelial permeability is the primary event in ARDS onset, causing the development of pulmonary edema that leads to respiratory failure. Currently, the detailed molecular mechanisms regulating endothelial permeability are poorly understood. Therefore, the use of the PDD approach in the search for efficient ARDS treatment can be more productive than classic target-based drug discovery (TDD), but its use requires a new cell-based assay compatible with high-throughput (HTS) and high-content (HCS) screening. Here we report the development of a new plate-based image cytometry method to measure endothelial barrier function. The incorporation of image cytometry in combination with digital image analysis substantially decreases assay variability and increases the signal window. This new method simultaneously allows for rapid measurement of cell monolayer permeability and cytological analysis. The time-course of permeability increase in human pulmonary artery endothelial cells (HPAECs) in response to the thrombin and tumor necrosis factor α treatment correlates with previously published data obtained by transendothelial resistance (TER) measurements. Furthermore, the proposed image cytometry method can be easily adapted for HTS/HCS applications.

A two-pronged approach to reduce noise levels in the neonatal intensive care unit.

OBJECTIVES: The aim of this study was to assess the efficacy of a visual noise feedback system and "quiet time" in reducing noise levels in the neonatal intensive care unit (NICU). DESIGN: A prospective cross-sectional study was performed in a combined level II/III NICU at a Canadian tertiary care hospital. Noise levels were recorded continuously for three weeks without and then three weeks with visual noise feedback system. Noise levels were compared after one year of using visual feedback, and subsequently with the addition of two "quiet times." RESULTS: Visual feedback reduced noise levels from 54.2 dB (95% CI 53.8-54.7 dB) to 49.4 dB (95% CI 48.9-49.8 dB; P < 0.0001) and increased the amount of time spent under 45 dB from 0 to 25% (P < 0.0001) after three weeks of use. However, this effect was not sustained at one year of visual feedback, with noise levels at 54.7 dB (95% CI 54.5-55.0 dB, P = 0.55). Quiet Time did not further reduce daily noise in the NICU (average noise levels 54.7, 95% CI 54.4-55.0 dB, P = 0.836). CONCLUSIONS: While visual noise feedback system reduced noise levels in the short term, these effects were not sustainable at one year and could not be remediated with the addition of a Quiet Time initiative. Continuing education regarding the detrimental effects of noise is paramount to ensure persistent noise reduction in the NICU.

Exploratory study of "real world" implementation of a clinical poverty tool in diverse family medicine and pediatric care settings.

BACKGROUND: Poverty is associated with increased morbidity related to multiple child and adult health conditions and increased risk of premature death. Despite robust evidence linking income and health, and some recommendations for universal screening, poverty screening is not routinely conducted in clinical care. METHODS: We conducted an exploratory study of implementing universal poverty screening and intervention in family medicine and a range of pediatric care settings (primary through tertiary). After attending a training session, health care providers (HCPs) were instructed to perform universal screening using a clinical poverty tool with the question "Do you ever have difficulty making ends meet at the end of the month?" for the three-month implementation period. HCPs tracked the number of patients screened and a convenience sample of their patients were surveyed regarding the acceptability of being screened for poverty in a healthcare setting. HCPs participated in semi-structured focus groups to explore barriers to and facilitators of universal implementation of the tool. RESULTS: Twenty-two HCPs (10 pediatricians, 9 family physicians, 3 nurse practitioners) participated and 150 patients completed surveys. Eighteen HCPs participated in focus groups. Despite the self-described motivation of the HCPs, screening rates were low (9% according to self-reported numbers). The majority of patients either supported (72%) or were neutral (22%) about the appropriateness of HCPs screening for and intervening on poverty. HCPs viewed poverty as relevant to clinical care but identified time constraints, physician discomfort, lack of expertise and habitual factors as barriers to implementation of universal screening. CONCLUSIONS: Poverty screening is important and acceptable to clinicians and patients. However, multiple barriers need to be addressed to allow for successful implementation of poverty screening and intervention in health care settings.

Are observed associations between a high maternal prepregnancy body mass index and offspring IQ likely to be causal?

BACKGROUND: A high maternal prepregnancy body mass index has been associated with lower offspring IQ, but it is unclear if the relationship is causal. To explore this, our objectives were to compare maternal and paternal estimates and to assess whether certain factors mediate the association. METHODS: We analysed data from the Avon Longitudinal Study of Parents and Children, which initially recruited 14 541 women residing in Avon, UK, with an expected date of delivery in 1991-1992. Data were collected during and after pregnancy by questionnaire, medical record abstraction and clinical assessment. At approximately 8 years of age, psychologists administered an abbreviated form of the Wechsler Intelligence Scale for Children-III. We fit multivariable logistic regression models to estimate parental prepregnancy obesity and overweight-offspring IQ associations. Counterfactually defined indirect (mediated) effects of maternal prepregnancy obesity on offspring IQ were estimated through path analysis. RESULTS: Among 4324 mother-father-child triads and using normal weight as the referent, we observed consistently stronger associations for maternal prepregnancy obesity and offspring performance IQ (eg, adjusted ß (95% CI)=-3.4 (-5.7 to -1.2) vs -0.97 (-2.9 to 0.96) for paternal obesity). The indirect effects of maternal obesity on offspring IQ through pathways involving gestational weight gain and duration of breastfeeding were small but significant. CONCLUSION: Our findings are consistent with a weak biologic effect of maternal adiposity in pregnancy on offspring performance IQ. Given the growing prevalence of obesity worldwide, more evidence is needed to resolve the correlation versus causation debate in this area.

Bridging the gap in genetics: a progressive model for primary to specialist care.

BACKGROUND: The rapid expansion of genetic knowledge, and the implications for healthcare has resulted in an increased role for Primary Care Providers (PCPs) to incorporate genetics into their daily practice. The objective of this study was to explore the self-identified needs, including educational needs, of both urban and rural Primary Care Providers (PCPs) in order to provide genetic care to their patients. METHODS: Using a qualitative grounded theory approach, ten key informant interviews, and one urban and two rural PCP focus groups (FGs) (n = 19) were conducted. All PCPs practiced in Southeastern Ontario. Data was analyzed using a constant comparative method and thematic design. The data reported here represent a subset of a larger study. RESULTS: Participants reported that PCPs have a responsibility to ensure patients receive genetic care. However, specific roles and responsibilities for that care were poorly defined. PCPs identified a need for further education and resources to enable them to provide care for individuals with genetic conditions. Based on the findings, a progressive stepped model that bridges primary and specialty genetic care was developed; the model ranged from PCPs identifying patients with genetic conditions that they could manage alone, to patients who they could manage with informal or electronic consultation to those who clearly required specialist referral. CONCLUSIONS: PCPs identified a need to integrate genetics into primary care practice but they perceived barriers including a lack of knowledge and confidence, access to timely formal and informal consultation and clearly defined roles for themselves and specialists. To address gaps in PCP confidence in providing genetic care, interventions that are directed at accessible just-in-time support and consultation have the potential to empower PCPs to manage patients' genetic conditions. Specific attention to content, timing, and accessibility of educational interventions is critical to address the needs of both urban and rural PCPs. A progressive framework for bridging primary to specialty care through a 'stepped' model for providing continuing medical education, and genetic care can was developed and can be used to guide future design and delivery of educational interventions and resources.

High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site.

BACKGROUND: Focal Adhesion Kinase (FAK) is a major cancer drug target that is involved in numerous aspects of tumor progression and survival. While multiple research groups have developed ATP-competitive small molecule inhibitors that target the kinase enzyme, recent attention has been focused on the FAK FERM (Band 4.1, Ezrin, Radixin, Moesin) domain that contains key residue Y397 and contributes to many protein-protein interactions. Previous x-ray crystal structures of the FAK FERM domain gave conflicting results on the structure of the Y397 region and therefore the overall druggability. RESULTS: Here, we report the identification of a higher resolution crystal structure of the avian FAK FERM domain that shows conformational differences in Y397 and surrounding residues in the F1 lobe. In addition, we resolve the residues of the Src SH3 binding site, an area of the FERM domain that has previously shown limited electron density. CONCLUSIONS: These crystallographic data suggest that the Y397 region is highly dynamic and question the druggability of a putative pocket on the F1 lobe. In addition, new electron density data around the Src SH3 binding site provide structural insight on the FAK-Src activation cascade through a putative auto-inhibitory conformation.

Primary care providers' lived experiences of genetics in practice.

To effectively translate genetic advances into practice, engagement of primary care providers (PCPs) is essential. Using a qualitative, phenomenological methodology, we analyzed key informant interviews and focus groups designed to explore perspectives of urban and rural PCPs. PCPs endorsed a responsibility to integrate genetics into their practices and expected advances in genetic medicine to expand. However, PCPs reported limited knowledge and difficulties accessing resources, experts, and continuing education. Rural practitioners' additional concerns included cost, distance, and poor patient engagement. PCPs' perspectives are crucial to develop relevant educational and systems-based interventions to further expand genetic medicine in primary care.

Interpregnancy Intervals in a Contemporary Manitoba Cohort: Prevalence of So-Called Suboptimal Intervals and Associated Maternal Characteristics.

OBJECTIVE: Short and long interpregnancy intervals (IPIs) have been associated with various adverse outcomes, and a 2016 American College of Obstetricians and Gynecologists' Committee Opinion recommends an optimal IPI of 18 months to 5 years. Descriptive data on the IPI in Canada are lacking. The objective of this study was to examine IPIs in a Manitoba cohort. METHODS: The study analyzed a subset of records from a larger dataset used to examine the IPI and adverse perinatal outcomes. For that study, Manitoba's Hospital Abstracts data were searched to identify births from 1985 to 2014. Each two consecutive live births to the same mother formed a sibling pair. The IPI was calculated as the interval between the two siblings' births, minus the younger sibling's GA. Information on maternal characteristics was extracted from various datasets housed in the Manitoba Population Research Data Repository. The current analysis examined second and higher-order births between 2010 and 2014. The proportion of suboptimal IPIs was determined and IPIs were cross-tabulated with birth year and maternal subgroups. RESULTS: More than half of pregnancies were conceived following a suboptimal interval. IPIs of less than 6 months - which have been associated with the highest risk of adverse outcomes - were more prevalent among certain subgroups. These included younger women as well as women who received inadequate prenatal care, smoked or drank alcohol during pregnancy, were low income, or did not graduate from high school. CONCLUSION: Suboptimal IPIs were common in this Manitoba cohort. Stakeholders should consider whether greater efforts to promote appropriate birth spacing are warranted.

Selective left mainstem bronchial intubation in the neonatal intensive care unit / Intubação seletiva do brônquio principal esquerdo em unidade de terapia intensiva neonatal

Abstract Background: Selective neonatal left mainstem bronchial intubation to treat right lung disease is typically achieved with elaborate maneuvers, instrumentation and devices. This is often attributed to bronchial geometry which favors right mainstem entry of an endotracheal tube deliberately advanced beyond the carina. Case summary: A neonate with severe bullous emphysema affecting the right lung required urgent non-ventilation of that lung. We achieved left mainstem bronchial intubation by turning the endotracheal tube 180° such that the Murphy's eye faced the left instead of the right, and simulated a left-handed intubation by slightly orientating the endotracheal tube such that its concavity faced the left instead of the right as in a conventional right-handed intubation. Conclusion: Urgent intubation of the left mainstem bronchus with an endotracheal tube can be easily achieved by recognizing that it is the position of the endotracheal tube tip and the direction of its concavity that are the chief determinants of which bronchus an endotracheal tube goes when advanced. This is important in critically ill neonates as the margin of safety and time window are small, and the absence of double-lumen tubes. Use of fiberoptic bronchoscope and blockers should be reserved as backup plans.

Resumo Justificativa: A intubação seletiva neonatal do brônquio principal esquerdo para tratar a doença pulmonar direita é tipicamente feita com elaboradas manobras, instrumentação e dispositivos. Isso é frequentemente atribuído à geometria brônquica que favorece a entrada principal direita de um tubo endotraqueal (TET) deliberadamente avançado para além da carina. Resumo do caso: Recém-nascido com enfisema bolhoso grave que afetava o pulmão direito e precisou com urgência da não ventilação desse pulmão. Para conseguir a intubação brônquica esquerda fizemos uma rotação de 180° do TET, de forma que o olho de Murphy ficasse voltado para a esquerda, e não para a direita, e para simular uma intubação à esquerda orientamos ligeiramente o TET, de modo que sua concavidade virasse para a esquerda em vez de para a direita, como em uma intubação convencional à direita. Conclusão: A intubação urgente do brônquio principal esquerdo com um TET pode ser facilmente obtida se reconhecermos que é a posição da ponta do TET e a direção de sua concavidade que determinam para qual brônquio o TET irá quando avançado. Isso é importante em neonatos criticamente doentes diante da margem de segurança e janela de tempo pequenas e na ausência de tubos de duplo lúmen. O uso de broncofibroscópio e bloqueadores deve ser considerado como planos de segurança.

[Selective left mainstem bronchial intubation in the neonatal intensive care unit]. / Intubação seletiva do brônquio principal esquerdo em unidade de terapia intensiva neonatal.

BACKGROUND: Selective neonatal left mainstem bronchial intubation to treat right lung disease is typically achieved with elaborate maneuvers, instrumentation and devices. This is often attributed to bronchial geometry which favors right mainstem entry of an endotracheal tube deliberately advanced beyond the carina. CASE SUMMARY: A neonate with severe bullous emphysema affecting the right lung required urgent non-ventilation of that lung. We achieved left mainstem bronchial intubation by turning the endotracheal tube 180° such that the Murphy's eye faced the left instead of the right, and simulated a left-handed intubation by slightly orientating the endotracheal tube such that its concavity faced the left instead of the right as in a conventional right-handed intubation. CONCLUSION: Urgent intubation of the left mainstem bronchus with an endotracheal tube can be easily achieved by recognizing that it is the position of the endotracheal tube tip and the direction of its concavity that are the chief determinants of which bronchus an endotracheal tube goes when advanced. This is important in critically ill neonates as the margin of safety and time window are small, and the absence of double-lumen tubes. Use of fiberoptic bronchoscope and blockers should be reserved as backup plans.

Structures of human plasma ß-factor XIIa cocrystallized with potent inhibitors.

Activated factor XIIa (FXIIa) is a serine protease that has received a great deal of interest in recent years as a potential target for the development of new antithrombotics. Despite the strong interest in obtaining structural information, only the structure of the FXIIa catalytic domain in its zymogen conformation is available. In this work, reproducible experimental conditions found for the crystallization of human plasma ß-FXIIa and crystal growth optimization have led to determination of the first structure of the active form of the enzyme. Two crystal structures of human plasma ß-FXIIa complexed with small molecule inhibitors are presented herein. The first is the noncovalent inhibitor benzamidine. The second is an aminoisoquinoline containing a boronic acid-reactive group that targets the catalytic serine. Both benzamidine and the aminoisoquinoline bind in a canonical fashion typical of synthetic serine protease inhibitors, and the protease domain adopts a typical chymotrypsin-like serine protease active conformation. This novel structural data explains the basis of the FXII activation, provides insights into the enzymatic properties of ß-FXIIa, and is a great aid toward the further design of protease inhibitors for human FXIIa.

Hypoglycemia in unmonitored full-term newborns-a surveillance study.

BACKGROUND AND OBJECTIVES: Hypoglycemia monitoring is not recommended for most full-term newborns. We wished to determine the incidence, presentation and case characteristics of hypoglycemia in low-risk newborns. METHODS: With the assistance of the Canadian Paediatric Surveillance Program, we conducted a national study of severe hypoglycemia in apparently low-risk full-term newborns. Paediatricians who reported a case were sent a detailed questionnaire and the data were analyzed. RESULTS: All 93 confirmed cases were singletons, 56% were first-borns and 65% were male. An 8% rate of First Nations cases was twofold the population rate. Maternal hypertension rate was 23%, fourfold the general pregnancy rate. Maternal obesity was double the general pregnancy rate at 23%. Concerning signs or feeding issues were noted in 98% at the time of diagnosis. Median time to diagnosis was 4.1 hours. Mean blood glucose at intravenous (IV) start was 1.4 ± 0.5 hours (SD). Seventy-eight per cent had at least one of four potential stress indicators and were more likely to have early diagnosis (P=0.03). Major signs were present in 20%. Those cases presented later and had lower glucose levels (median=0.8 mmol/L versus 1.6 mmol/L, [P<0.001). Twenty-five per cent of cases had birth weight less than the 10th centile. Neurodevelopmental concern was reported in 20%. Of the 13 cases which had brain magnetic resonance imaging, 11 were abnormal. CONCLUSION: Hypoglycemia in unmonitored newborns is uncommon but is associated with significant morbidity. We provide a range of clues to help identify these newborns soon after birth. Widespread adoption of norm-based standards to identify small-for-gestational age infants is supported.

Interpregnancy Interval and Congenital Anomalies: A Record-Linkage Study Using the Manitoba Population Research Data Repository.

OBJECTIVE: Congenital anomalies are a serious public health issue, and relatively few modifiable risk factors have been identified. Our objective was to investigate one such potential risk factor, the interpregnancy interval (IPI). METHODS: We conducted a secondary analysis of data housed at the Manitoba Centre for Health Policy. In-hospital live births and stillbirths of at least 20 weeks' gestation were identified, and consecutive births to the same mother were grouped into sibling pairs to calculate the IPI for the younger siblings of each pair. Logistic regression models were fit to examine the association between the IPI and any congenital anomaly, as well as CNS and chromosomal anomalies, while controlling for potentially confounding sociodemographic and clinical factors. RESULTS: Among 172 909 live births and stillbirths, the IPI was not significantly associated with congenital anomalies overall or with chromosomal anomalies. Short IPIs were associated with significantly increased odds of CNS anomalies relative to IPIs of 18-23 months (adjusted OR [aOR] for IPIs <6 months 2.15; 95% CI 1.48-3.12), whereas the aOR for IPIs ≥60 months was elevated but not statistically significant (aOR 1.50; 95% CI 0.96-2.34). In a sensitivity analysis in which the cohort was restricted to births from 2003 onwards (which yielded more complete data on health-related behaviours), the observed effect for IPIs shorter than 6 months and CNS anomalies was attenuated and no longer significant, but it remained elevated (aOR 1.65; 95% CI 0.85-3.24). CONCLUSION: The findings for CNS anomalies warrant further investigation.

Esophageal Atresia/Tracheoesophageal Fistula Repair Complicated by Tracheomalacia: A Case Report of Successful Management of Respiratory Distress Using Caudal Morphine.

We report a case of severe respiratory distress in a neonate who was not endotracheally intubated soon after esophageal atresia/tracheoesophageal fistula (EA/TEF) repair. In this serious situation, any form of emergency respiratory support or definitive airway management may compromise the esophageal anastomosis and fistula repair. The cause of respiratory distress in the early postoperative period after EA/TEF is multifactorial, and in this case, included symptomatic tracheomalacia, which is commonly associated with EA/TEF.

Interpregnancy Interval and Adverse Perinatal Outcomes: A Record-Linkage Study Using the Manitoba Population Research Data Repository.

OBJECTIVE: To examine the association between the interpregnancy interval (IPI) and preterm birth, low birth weight, and SGA birth in a developed country with universal health coverage. METHODS: We conducted a secondary analysis of data housed at the Manitoba Centre for Health Policy. All live births in Manitoba hospitals over a 29-year period were identified and consecutive births to the same mother were grouped into sibling pairs to calculate the IPI for the younger siblings. Logistic regression models were fit to examine the association between the IPI and adverse perinatal outcomes, adjusted for potentially confounding sociodemographic and clinical factors. RESULTS: In a cohort of more than 171 000 births and relative to IPIs of 18 to 23 months, IPIs shorter than 12 and longer than 23 months were associated with significantly increased odds of preterm birth overall and both medically indicated and spontaneous preterm births, low birth weight, and SGA birth. The strongest association observed was for intervals shorter than 6 months and spontaneous preterm birth (adjusted OR 1.83, 95% CI 1.65-2.03). When the outcome was modelled as GA categories, the strongest association observed was for intervals shorter than 6 months and early preterm birth (<34 weeks' GA; adjusted OR 2.47, 95% CI 2.07-2.94). CONCLUSION: If the associations observed between the IPI and adverse perinatal outcomes in this large, population-based cohort are causal, birth spacing could form an important target of public health messaging in Canada.

Effect of Picture Archiving and Communication System Image Manipulation on the Agreement of Chest Radiograph Interpretation in the Neonatal Intensive Care Unit.

OBJECTIVE: Variability in image interpretation has been attributed to differences in the interpreters' knowledge base, experience level, and access to the clinical scenario. Picture archiving and communication system (PACS) has allowed the user to manipulate the images while developing their impression of the radiograph. The aim of this study was to determine the agreement of chest radiograph (CXR) impressions among radiologists and neonatologists and help determine the effect of image manipulation with PACS on report impression. MATERIALS AND METHODS: Prospective cohort study included 60 patients from the Neonatal Intensive Care Unit undergoing CXRs. Three radiologists and three neonatologists reviewed two consecutive frontal CXRs of each patient. Each physician was allowed manipulation of images as needed to provide a decision of "improved," "unchanged," or "disease progression" lung disease for each patient. Each physician repeated the process once more; this time, they were not allowed to individually manipulate the images, but an independent radiologist presets the image brightness and contrast to best optimize the CXR appearance. Percent agreement and opposing reporting views were calculated between all six physicians for each of the two methods (allowing and not allowing image manipulation). RESULTS: One hundred percent agreement in image impression between all six observers was only seen in 5% of cases when allowing image manipulation; 100% agreement was seen in 13% of the cases when there was no manipulation of the images. CONCLUSION: Agreement in CXR interpretation is poor; the ability to manipulate the images on PACS results in a decrease in agreement in the interpretation of these studies. New methods to standardize image appearance and allow improved comparison with previous studies should be sought to improve clinician agreement in interpretation consistency and advance patient care.

Novel Method to Improve Radiologist Agreement in Interpretation of Serial Chest Radiographs in the ICU.

OBJECTIVES: To determine whether a novel method and device, called a variable attenuation plate (VAP), which equalizes chest radiographic appearance and allows for synchronization of manual image windowing with comparison studies, would improve consistency in interpretation. MATERIALS AND METHODS: Research ethics board approved the prospective cohort pilot study, which included 50 patients in the intensive care unit (ICU) undergoing two serial chest radiographs with a VAP placed on each one of them. The VAP allowed for equalization of density and contrast between the patients' serial chest radiographs. Three radiologists interpreted all the studies with and without the use of VAP. Kappa and percent agreement was used to calculate agreement between radiologists' interpretations with and without the plate. RESULTS: Radiologist agreement was substantially higher with the VAP method, as compared to that with the non-VAP method. Kappa values between Radiologists A and B, A and C, and B and C were 46%, 55%, and 51%, respectively, which improved to 73%, 81%, and 66%, respectively, with the use of VAP. Discrepant report impressions (i.e., one radiologist's impression of unchanged versus one or both of the other radiologists stating improved or worsened in their impression) ranged from 24 to 28.6% without the use of VAP and from 10 to 16% with the use of VAP (χ (2) = 7.454, P < 0.01). Opposing views (i.e., one radiologist's impression of improved and one of the others stating disease progression or vice versa) were reported in 7 (12%) cases in the non-VAP group and 4 (7%) cases in the VAP group (χ (2) = 0.85, P = 0.54). CONCLUSION: Numerous factors play a role in image acquisition and image quality, which can contribute to poor consistency and reliability of portable chest radiographic interpretations. Radiologists' agreement of image interpretation can be improved by use of a novel method consisting of a VAP and associated software and has the potential to improve patient care.

The association between the interpregnancy interval and autism spectrum disorder in a Canadian cohort.

OBJECTIVES: Two studies reported an increased risk of autistic disorder in children conceived less than 12 months after a previous birth. Our objective was to examine the association between the interpregnancy interval (IPI) and autism spectrum disorder (ASD) in a Canadian cohort. METHODS: Using administrative datasets housed at the Manitoba Centre for Health Policy, we identified pairs of first- and second-born singleton siblings born between 1988 and 2005. Diagnoses of ASD were ascertained by searching physician billing claims, hospital discharge abstracts, education data, and a database containing information on individuals identified for a 2002-2007 ASD surveillance program in Manitoba. Logistic regression models were fit to examine the association between the IPI and ASD in 41,050 second-born siblings where the first-borns did not have ASD, using IPIs of ≥ 36 months as the reference category and specifying three case groups. Case Group 1 included individuals with at least one ASD code (n = 490); Case Group 2 included those with two or more ASD codes (n = 375); and Case Group 3 comprised individuals with a record in the ASD surveillance program database (n = 141). RESULTS: The adjusted odds ratios (ORs) for IPIs shorter than 12 months ranged from 1.22 (95% CI: 0.91-1.63) for Case Group 1 to 1.72 (95% CI: 0.96-3.06) for Case Group 3. When the case groups were restricted to individuals with more severe ASD, the ORs increased and were significant for Case Groups 1 and 2. CONCLUSION: Our findings also support an association between short IPIs and more severe ASD.