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Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

Objective To explore attitudes and beliefs about the role of health coaching for vulnerable populations, including people experiencing substance use or homelessness. Methods From May-July 2016, we conducted semi-structured qualitative interviews with patients, primary care clinicians, pulmonary specialists, and health coaches participating in a study of health coaching for chronic obstructive pulmonary disease (COPD). We developed a codebook and applied it in Atlas.ti, generating themes for frequently occurring codes. Results All stakeholder groups (n=20 patients, 11 primary care clinicians, three specialists, and two health coaches), reported improved COPD management and behavior change, even for patients experiencing substance use or homelessness. Clinicians observed greater symptom awareness and prioritization of COPD during the medical visit. The strength of the health coaching relationship and flexibility of the role were key to its effectiveness. Conclusion Lay health coaching may provide a model to meet the needs of highly vulnerable populations with COPD.

Background Preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2_ infections in healthcare workers (HCWs) is critical for healthcare delivery. We aimed to estimate and characterize the prevalence and incidence of coronavirus disease 2019 (COVID-19) in a US HCW cohort and to identify risk factors associated with infection. Methods We conducted a longitudinal cohort study of HCWs at 3 Bay Area medical centers using serial surveys and SARS-CoV-2 viral and orthogonal serological testing, including measurement of neutralizing antibodies. We estimated baseline prevalence and cumulative incidence of COVID-19. We performed multivariable Cox proportional hazards models to estimate associations of baseline factors with incident infections and evaluated the impact of time-varying exposures on time to COVID-19 using marginal structural models. Results A total of 2435 HCWs contributed 768 person-years of follow-up time. We identified 21 of 2435 individuals with prevalent infection, resulting in a baseline prevalence of 0.86% (95% confidence interval [CI], .53%–1.32%). We identified 70 of 2414 incident infections (2.9%), yielding a cumulative incidence rate of 9.11 cases per 100 person-years (95% CI, 7.11–11.52). Community contact with a known COVID-19 case was most strongly correlated with increased hazard for infection (hazard ratio, 8.1 [95% CI, 3.8–17.5]). High-risk work-related exposures (ie, breach in protective measures) drove an association between work exposure and infection (hazard ratio, 2.5 [95% CI, 1.3–4.8). More cases were identified in HCWs when community case rates were high. Conclusions We observed modest COVID-19 incidence despite consistent exposure at work. Community contact was strongly associated with infections, but contact at work was not unless accompanied by high-risk exposure.

PURPOSE The quadruple aim of primary care transformation includes promoting well-being among the primary care workforce. We longitudinally assessed burnout among clinicians and staff in 2 health delivery organizations engaged in primary care redesign guided by a shared transformation model. METHODS We conducted a descriptive longitudinal study, using repeated cross-sectional measures from 6 waves of surveys of employed primary care clinicians (physicians, nurse practitioners, physician assistants) and staff conducted between 2012 to 2018 in the San Francisco Health Network and in UCSF Health. The 2018 wave had 613 respondents (response rate 88%). Outcome measures were scores on the Maslach Burnout Inventory emotional exhaustion and cynicism subscales. We used regression models to test for time trends in mean scores. RESULTS Trends in burnout differed by system and occupation. In one system, mean clinician scores steadily improved for emotional exhaustion (P = .04) and cynicism (P = .07). In the other system, clinician burnout scores initially worsened and then returned to baseline levels. In both systems, burnout trends among staff tended to move in the opposite direction from trends among clinicians. CONCLUSIONS The divergent trends of steady reduction in clinician burnout in one system and clinician burnout getting worse before getting better in the other system suggest that the effects of primary care transformation are influenced by the organizational context. Moreover, practice changes that reduce clinician burnout may not decrease—and may potentially even worsen—burnout among staff. Primary care transformation requires continuing efforts to promote meaningful work and sustainable workloads among all members of the primary care team.

Importance Surveys in the US have found that Black and Latinx individuals have more reservations than their white counterparts about COVID-19 vaccination. However, little is known about the degree to which racial-ethnic differences in COVID-19 vaccination intentions are explained by differences in beliefs or perceptions about COVID-19 vaccines. Objective To compare intention to receive COVID-19 vaccination by race-ethnicity, to identify perceptional factors that may mediate the association between race-ethnicity and intention to receive the vaccine, and to identify the demographic and perceptional factors most strongly predictive of intention to receive a vaccine. Design Cross-sectional survey conducted from November, 2020 to January, 2021, nested within two longitudinal cohort studies of prevalence and incidence of SARS CoV-2 among the general population and healthcare workers. Setting Six San Francisco Bay Area counties. Study Cohort 3,161 participants in the Track COVID cohort (a population-based sample of adults) and 1,803 participants in the CHART Study cohort (a cohort of employees at three large medical centers). Results Rates of high vaccine willingness were significantly lower among Black (45.3%), Latinx (62.5%), Asian (65%), multi-racial (67.2%), and other race (61.0%) respondents than among white respondents (77.6%). Black, Latinx, and Asian respondents were significantly more likely than white respondents to endorse reasons to not get vaccinated, especially lack of trust. Participants’ motivations and concerns about COVID-19 vaccination only partially explained racial-ethnic differences in vaccination willingness. Being a health worker in the CHART cohort and concern about a rushed government vaccine approval process were the two most important factors predicting vaccination intention. Conclusions and Relevance Special efforts are required to reach historically marginalized racial-ethnic communities to support informed decision-making about COVID-19 vaccination. These campaigns must acknowledge the history of racism in biomedical research and health care delivery that has degraded the trustworthiness of health and medical science institutions among non-white population and may continue to undermine confidence in COVID-19 vaccines. Highlights Black, Latinx, Asian, Multi-racial, and Other race respondents were significantly less likely than white respondents to have high willingness to receive COVID-19 vaccination when surveyed around the time that the first COVID-19 vaccines received Emergency Use Authorization in the US. Racial-ethnic differences in vaccination intention were present for both health workers and the general population. Motivations and concerns about COVID-19 vaccination only partially explained racial-ethnic differences in COVID-19 vaccine willingness. The most important factors explaining COVID-19 vaccination intention were being a health worker, concern about government rushing the vaccine process, concern about having a bad reaction to the vaccine, motivation to protecting one’s self and family from COVID-19, and concern about getting COVID from the vaccine

Health coaching has emerged as an important tool for improving patient-centered care in primary care practice but has not specifically been evaluated for patients whose care is shared by a primary care provider (PCP) and specialist.As part of a nine-month randomized controlled trial comparing health coaching to usual care for patients with chronic obstructive pulmonary disease (COPD), the authors developed the Pulmonary Specialist Health Coach Consultation (PuSHCon). In this novel model, health coaches facilitated pulmonary specialist consultations for patients with COPD without the need for an in-person visit. Observational data from the randomized controlled trial were analyzed to study the implementation, adoption, and impact of the PuSHCon model for 70 of 92 patients randomized to the health coaching arm and for 17 of 100 patients in the control arm (who received PuSHCon after the end of the study). Quality of care was measured using the Patient Assessment of Chronic Illness Care (PACIC).Of 87 patients who participated in PuSHCon, 74 (85.1%) received one or more specialist recommendations, of which 86.8% were implemented. Only 12 patients (13.8%) subsequently required an in-person visit with the PuSHCon specialist. The proportion of PuSHCon participants receiving guideline-concordant care increased from 64.7% to 94.1% (p0.001). The mean PACIC item score increased from 3.48 to 3.74 (p = 0.03).The PuSHCon model facilitated consultations that resulted in changes in care, which were implemented for a majority of patients. Guideline-concordant care and patient-reported quality of care increased over nine months. This model could potentially be expanded to help patients with other chronic conditions when PCPs and specialists share patient care.

BackgroundHealthcare personnel (HCP) are prioritized for earliest SARS-CoV-2 vaccine administration, yet relatively few data exist on HCP’s knowledge, motivations, concerns, and intentions regarding COVID-19 vaccines.MethodsWe conducted a cross-sectional survey Nov.16-Dec.8, 2020 among HCP enrolled in a cohort study at three Northern California medical centers serving diverse roles including COVID-19 patient care. Eligible HCP were adult (age≥18) on-site employees of the University of California, San Francisco, San Francisco General Hospital, and Stanford Healthcare. A one-time electronically-administered survey was sent to cohort HCP on November 16, 2020 and responses analyzed.ResultsOverall, among 2,448 HCP invited, 2,135 completed the COVID-19 vaccine survey (87.2% response rate). HCPs had mean age 41 years, were 73% female, and had diverse jobs including COVID-19 patient contact. Enthusiasm for vaccination was overall strong, and more HCP (1,453, 69%) said they would definitely/likely receive vaccine if formally FDA-approved versus if approved via emergency use authorization only (785, 35%). While 541 (25%) respondents wanted to be among the earliest to receive vaccine, more desired vaccination after the first round (777, 36%) or >2 months after vaccinations began (389, 18%). Top factors increasing motivation for vaccination included perceiving risk from COVID-19 to self (1,382, 65%) or to family/friends (1355, 63%). Top concerns were vaccine side effects, cited by 596 (28%), and concerns about political involvement in FDA’s approval process (249, 12%).ConclusionsHCP were enthusiastic about COVID-19 vaccination for individual protection and protecting others, but harbored concerns about vaccine side effects. Our data may inform emerging vaccine education campaigns.Key PointsAmong 2,135 healthcare personnel surveyed, we found enthusiasm for COVID-19 vaccination both for individual benefit and protecting others. However, healthcare personnel rated their knowledge of COVID-19 vaccines as only moderate and harbored concerns about vaccine side effects. Education raising awareness of vaccine efficacy and side effects may help maximize vaccine uptake.

Background: Burnout and engagement are commonly conceptualized as opposite ends of a spectrum, and there is concern that high clinician burnout and lack of engagement may adversely impact patient care. Methods: We matched self-reported data on burnout and engagement for 182 primary care clinicians with data on clinical quality (cancer screenings, hypertension and diabetes control) and patient experience (Clinician and Group Survey-Consumer Assessment of Healthcare Providers and Systems [CG-CAHPS] communication scores, overall rating, and likelihood to recommend the clinic). Multivariable linear regression models examined burnout, engagement, or burnout-engagement phenotype (eg, high burnout-low engagement) as predictors of quality and patient experience. Results: One-third of clinicians in this sample did not fall along the spectrum of low burnout-high engagement to high burnout-low engagement. Neither burnout nor engagement on their own was associated with quality or patient experience measures. However, clinicians with high burnout who also were highly engaged had the highest average ratings for all 3 patient experience domains: clinician communication, overall rating of the clinician, and overall rating of the clinic. Discussion: The results of our study challenge the assumptions that burnout and engagement are opposite ends of a spectrum and that burnout or low engagement adversely impact quality of care and patient experience. Greater understanding is needed of how best to support dedicated clinicians who may provide quality care at the expense of their personal well-being.

Objective: The objective of this study was to identify changes in patients referred to CLP at a typical inner urban teaching hospital over two decades in the context of increased hospital admissions. Method: Multivariate analyses were conducted on data collected for all referrals to CLP at Royal Melbourne Hospital between 1998 and 2017. Analyses were conducted with reason for referral, current psychiatric contact, psychiatric diagnosis, discharge destination and follow up as dependent variables, and the year and annual hospital admissions as independent variables. Results: Annual hospital admissions grew at a rate (4.6%), greater than the annual increase in beds (2.0%). Psychosis, suicide attempt, past psychiatric history and behaviour became more common reasons for referral, whilst depression and somatisation became less common. Transfers to and from mental health inpatient units increased. Conclusions: An increasing proportion of patients seen by CLP have ‘acute’ problems. Patients with somatisation and depression are seen less frequently. These findings indicate that CLP services need to provide timely assessment and work closely with other elements of the local mental health service in order to optimise patient flow and ensure continuity of care. Local strategies may be required to ensure an adequate breadth of experience for trainees.

Background Adherence to positive airway pressure (PAP) therapies is poor, particularly among low-income populations and racial minorities. This study tested a low-resource, brief telephonic health coaching intervention to improve PAP adherence. Methods Post hoc analysis of a quality improvement initiative in which English- and Spanish-speaking patients from a county-based public health system were randomly assigned to receive health coaching or usual care. An unlicensed, trained health coach called patients three times to resolve barriers to adherence. A per-protocol analysis was conducted for adherence measures collected by device modem at baseline and 30 days. Results Of 131 people for whom device data were available, 56 were randomized to health coaching and 75 to usual care. At baseline, 47.3% of patients had used their device at any time in the past 30 days, with a mean of 2 hours of use per night. At 30 days, adjusting for baseline, patients in the coaching arm were more likely than usual care patients to use their device (55.4% vs. 41.3%, p = 0.03), and they increased their use for 0.4 hours over usual care (p = 0.04). Conclusion This pilot study suggests that a low-cost intervention could be effective at improving PAP adherence, even in a population known to have poor adherence and among long-term PAP users with poor adherence. Future research may examine whether a higher-touch intervention or one using videoconferencing yields greater improvements. This promising intervention warrants further study.

PURPOSE: Poor adherence to medications is more prevalent for chronic obstructive pulmonary disease (COPD) than for other chronic conditions and is associated with unfavorable health outcomes. Few interventions have successfully improved adherence for COPD medications; none of these use unlicensed health care personnel. We explored the efficacy of lay health coaches to improve inhaler adherence and technique. METHODS: Within a randomized controlled trial, we recruited English- and Spanish-speaking patients with moderate to severe COPD from urban, public primary care clinics serving a low-income, predominantly African American population. Participants were randomized to receive 9 months of health coaching or usual care. Outcome measures included self-reported adherence to inhaled controller medications in the past 7 days and observed technique for all inhalers. We used generalized linear models, controlling for baseline values and clustering by site. RESULTS: Baseline adherence and inhaler technique were uniformly poor and did not differ by study arm. At 9 months, health-coached patients reported a greater number of days of adherence compared with usual care patients (6.4 vs 5.5 days; adjusted P = .02) and were more likely to have used their controller inhalers as prescribed for 5 of the last 7 days (90% vs 69%; adjusted P = .008). They were more than 3 times as likely to demonstrate perfect technique for all inhaler devices (24% vs 7%; adjusted P = .01) and mastery of essential steps (40% vs 11%; adjusted P

Socioeconomically disadvantaged patients with chronic obstructive pulmonary disease (COPD) often face barriers to evidence-based care that are difficult to address in public care settings with limited resources.To determine the benefit of health coaching for patients with moderate to severe COPD relative to usual care.We conducted a randomized controlled trial of 9 months of health coaching versus usual care for English- or Spanish-speaking patients at least 40 years of age with moderate to severe COPD. Primary outcomes were COPD-related quality of life and the dyspnea subscale of the Chronic Respiratory Disease Questionnaire. Secondary outcomes were self-efficacy for managing COPD, exercise capacity (6-min walk test), and number of COPD exacerbations. Additional outcomes were COPD symptoms, lung function (forced expiratory volume in 1 s percent predicted), smoking status, bed days owing to COPD, quality of care (Patient Assessment of Chronic Illness Care), COPD knowledge, and symptoms of depression (Patient Health Questionnaire). Outpatient visits, emergency department visits, and hospitalizations were assessed by review of medical records. Generalized linear modeling was used to adjust for baseline values and account for clustering by clinic.Of 192 patients enrolled, 158 (82%) completed 9 months of follow-up. There were no significant differences between study arms for the primary or secondary outcomes. At 9 months, patients in the coached group reported better quality of care (mean Patient Assessment of Chronic Illness Care score, 3.30 vs. 3.18; adjusted P = 0.02) and were less likely to report symptoms of moderate to severe depression (Patient Health Questionnaire score, ≥15) than those in the usual care arm (6% vs. 20%; adjusted P = 0.01). During the study, patients in the coaching arm had 48% fewer hospitalizations related to COPD (0.27/patient/yr vs. 0.52/patient/yr), but this difference was not significant in the adjusted analysis.These results help inform expectations regarding the limitations and benefits of health coaching for patients with COPD. They may be useful to health policy experts in assessing the potential value of reimbursement and incentives for health coaching-type activities for patients with chronic disease. Clinical trial registered with www.clinicaltrials.gov (NCT02234284).

PURPOSE Levels of burnout among primary care clinicians and staff are alarmingly high, and there is widespread belief that burnout and lack of employee engagement contribute to high turnover of the workforce. Scant research evidence exists to support this assertion, however. METHODS We conducted a longitudinal cohort study using survey data on burnout and employee engagement collected in 2013 and 2014 from 740 primary care clinicians and staff in 2 San Francisco health systems, matched to employment roster data from 2016. RESULTS Prevalence of burnout, low engagement, and turnover were high, with 53% of both clinicians and staff reporting burnout, only 32% of clinicians and 35% of staff reporting high engagement, and 30% of clinicians and 41% of staff no longer working in primary care in the same system 2 to 3 years later. Burnout predicted clinician turnover (adjusted odds ratio = 1.57; 95% CI, 1.02-2.40); there was also a strong trend whereby low engagement predicted clinician turnover (adjusted odds ratio with high engagement = 0.58; 95% CI, 0.33-1.04). Neither measure significantly predicted turnover for staff. CONCLUSIONS High rates of burnout and turnover in primary care are compelling problems. Our findings provide evidence that burnout contributes to turnover among primary care clinicians, but not among staff. Although reducing clinician burnout may help to decrease rates of turnover, health care organizations and policymakers concerned about employee turnover in primary care need to understand the multifactorial causes of turnover to develop effective retention strategies for clinicians and staff.

BACKGROUND: Clinicians and healthcare staff report high levels of burnout. Two common burnout assessments are the Maslach Burnout Inventory (MBI) and a single-item, self-defined burnout measure. Relatively little is known about how the measures compare. OBJECTIVE: To identify the sensitivity, specificity, and concurrent validity of the self-defined burnout measure compared to the more established MBI measure. DESIGN: Cross-sectional survey (November 2016–January 2017). PARTICIPANTS: Four hundred forty-four primary care clinicians and 606 staff from three San Francisco Aarea healthcare systems. MAIN MEASURES: The MBI measure, calculated from a high score on either the emotional exhaustion or cynicism subscale, and a single-item measure of self-defined burnout. Concurrent validity was assessed using a validated, 7-item team culture scale as reported by Willard-Grace et al. (J Am Board Fam Med 27(2):229–38, 2014) and a standard question about workplace atmosphere as reported by Rassolian et al. (JAMA Intern Med 177(7):1036–8, 2017) and Linzer et al. (Ann Intern Med 151(1):28–36, 2009). KEY RESULTS: Similar to other nationally representative burnout estimates, 52% of clinicians (95% CI: 47–57%) and 46% of staff (95% CI: 42–50%) reported high MBI emotional exhaustion or high MBI cynicism. In contrast, 29% of clinicians (95% CI: 25–33%) and 31% of staff (95% CI: 28–35%) reported “definitely burning out” or more severe symptoms on the self-defined burnout measure. The self-defined measure’s sensitivity to correctly identify MBI-assessed burnout was 50.4% for clinicians and 58.6% for staff; specificity was 94.7% for clinicians and 92.3% for staff. Area under the receiver operator curve was 0.82 for clinicians and 0.81 for staff. Team culture and atmosphere were significantly associated with both self-defined burnout and the MBI, confirming concurrent validity. CONCLUSIONS: Point estimates of burnout notably differ between the self-defined and MBI measures. Compared to the MBI, the self-defined burnout measure misses half of high-burnout clinicians and more than 40% of high-burnout staff. The self-defined burnout measure has a low response burden, is free to administer, and yields similar associations across two burnout predictors from prior studies. However, the self-defined burnout and MBI measures are not interchangeable. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-018-4507-6) contains supplementary material, which is available to authorized users.

Objective: This case report aims to highlight the challenges faced by mental health clinicians in managing complex medical and psychiatric presentation, with a particular interest in intravenous (IV) olanzapine use outside the emergency department (ED) and intensive care unit setting. Conclusion: There is no current prescribing guideline regarding the use of IV olanzapine for acute agitation associated with schizophrenia and bipolar disorder. Most of the literature available regarding the use of IV olanzapine has originated from studies performed in the ED setting, with the majority of studies reporting a favourable efficacy and safety profile for IV olanzapine. Further research on the utilization of IV olanzapine in the general medical ward is required. Until more data is available, use of IV olanzapine in the acute arousal setting on a general medical ward remains off-label.

Background Chronic obstructive pulmonary disease (COPD) severely hinders quality of life for those affected and is costly to the health care system. Care gaps in areas such as pharmacotherapy, inhaler technique, and knowledge of disease are prevalent, particularly for vulnerable populations served by community clinics. Non-professionally licensed health coaches have been shown to be an effective and cost-efficient solution in bridging care gaps and facilitating self-management for patients with other chronic diseases, but no research to date has explored their efficacy in improving care for people living with COPD. Method This is multi-site, single blinded, randomized controlled trial evaluates the efficacy of health coaches to facilitate patient self-management of disease and improve quality of life for patients with moderate to severe COPD. Spirometry, survey, and an exercise capacity test are conducted at baseline and at 9 months. A short survey is administered by phone at 3 and 6 months post-enrollment. The nine month health coaching intervention focuses on enhancing disease understanding and symptom awareness, improving use of inhalers; making personalized plans to increase physical activity, smoking cessation, or otherwise improve disease management; and facilitating care coordination. Discussion The results of this study will provide evidence regarding the efficacy and feasibility of health coaching to improve self-management and quality of life for urban underserved patients with moderate to severe COPD. Trial registration ClinicalTrials.gov identifier NCT02234284 . Registered 12 August 2014.

Aims and Method We aimed to assess the contents and tone of articles on mental health care in the UK print media by comparing them with reporting in the USA and Australia. Two broadsheets from each country were analysed using the Internet for a random 4 months over a 1-year period. The number of articles, their content and the views expressed in them were identified and compared. Results A total of 118 articles on mental health care issues were found. The predominant tone of the articles in all three countries was negative, though there were slightly more positive articles in the USA and Australian media. Positive articles highlighted in the UK media covered mostly medical conferences and research findings. Clinical Implications Efforts to achieve a more positive attitude towards people with mental illnesses in the public, such as anti-stigma campaigns, operate against a background of predominantly negative coverage of mental health care issues in broadsheets. The coverage in the UK may tend to be even less positive than in the USA and Australia. Medical conferences and research findings can, however, be used to promote positive views of mental health care in the media.

Congenital anomalies occur up to four times more frequently in diabetic pregnancy than in the nondiabetic population. Although past work has shown that maternal hyperglycemia and hyperketonemia may increase embryonic abnormalities, recent experimental evidence suggests that low insulin levels may also contribute to diabetic embryopathy. This study investigated the effects of guinea pig serum (whose insulin is inactive in rat systems) on rat embryonic growth and development in culture. Supplementation of guinea pig serum with pork insulin at low (1 ng/ml) and high (5 ng/ml) physiological concentrations and insulinlike growth factors (IGF) I and II were also studied. Culture of rat embryos from the early headfold stage in guinea pig serum resulted in poor embryonic growth and development with a 92% rate of anomalies. Supplementation of guinea pig serum with zinc-binding pork insulin significantly improved rat embryonic growth and development (46% anomaly rate) especially between the first 5 and 21 h of the period of organogenesis. This evidence supports our most recent findings that low insulin levels, as encountered in untreated diabetic pregnancy, may contribute to the increased risk of congenital abnormality. Insulin at low physiological concentrations improved growth, whereas higher physiological concentrations were required to increase growth and development. IGF-I or IGF-II supplementation improved rat embryonic growth and development but failed to match that of the controls, indicating that other growth factors including insulin may also be required.