Home Hospital Outcomes for Acute Decompensated Heart Failure and Factors Associated With Escalation of Care.

BACKGROUND: Overall outcomes and the escalation rate for home hospital admissions for heart failure (HF) are not known. We report overall outcomes, predict escalation, and describe care provided after escalation among patients admitted to home hospital for HF. METHODS: Our retrospective analysis included all patients admitted for HF to 2 home hospital programs in Massachusetts between February 2020 and October 2022. Escalation of care was defined as transfer to an inpatient hospital setting (emergency department, inpatient medical unit) for at least 1 overnight stay. Unexpected mortality was defined as mortality excluding those who desired to pass away at home on admission or transitioned to hospice. We performed the least absolute shrinkage and selection operator logistic regression to predict escalation. RESULTS: We included 437 hospitalizations; patients had a median age of 80 (interquartile range, 69-89) years, 58.1% were women, and 64.8% were White. Of the cohort, 29.2% had reduced ejection fraction, 50.9% had chronic kidney disease, and 60.6% had atrial fibrillation. Median admission Get With The Guidelines HF score was 39 (interquartile range, 35-45; 1%-5% predicted inpatient mortality). Escalation occurred in 10.3% of hospitalizations. Thirty-day readmission occurred in 15.1%, 90-day readmission occurred in 33.8%, and 6-month mortality occurred in 11.5%. There was no unexpected mortality during home hospitalization. Patients who experienced escalation had significantly longer median length of stays (19 versus 7.5 days, P<0.001). The most common reason for escalation was progressive renal dysfunction (36.2%). A low mean arterial pressure at the time of admission to home hospital was the most significant predictor of escalation in the least absolute shrinkage and selection operator regression. CONCLUSIONS: About 1 in 10 home hospital patients with HF required escalation; none had unexpected mortality. Patients requiring escalation had longer length of stays. A low mean arterial pressure at the time of admission to home hospital was the most important predictor of escalation of care in the least absolute shrinkage and selection operator logistic regression model.

A Public Health Critical Race Praxis Informed Congestive Heart Failure Quality Improvement Initiative on Inpatient General Medicine.

BACKGROUND: Prior evaluation at our hospital demonstrated that, compared to White patients, Black and Latinx patients with congestive heart failure (CHF) were less likely to be admitted to the cardiology service rather than the general medicine service (GMS). Patients admitted to GMS (compared to cardiology) had inferior rates of cardiology follow-up and 30-day readmission. OBJECTIVE: To develop and test the feasibility and impacts of using quality improvement (QI) methods, in combination with the Public Health Critical Race Praxis (PHCRP) framework, to engage stakeholders in developing an intervention for ensuring guideline-concordant inpatient CHF care across all patient groups. METHODS: We compared measures for all patients admitted with CHF to GMS between September 2019 and March 2020 (intervention group) to CHF patients admitted to GMS in the previous year (pre-intervention group) and those admitted to cardiology during the pre-intervention and intervention periods (cardiology group). Our primary measures were 30-day readmissions and 14- and 30-day post-discharge cardiology follow-up. RESULTS: There were 79 patients admitted with CHF to GMS during the intervention period, all of whom received the intervention. There were similar rates of Black and Latinx patients across the three groups. Compared to pre-intervention, intervention patients had a significantly lower 30-day readmission rate (18.9% vs. 24.8%; p=0.024), though the cardiology group also had a decrease in 30-day readmissions from the pre-intervention to intervention period. Compared to pre-intervention, intervention patients had significantly higher 14-day and 30-day post-discharge follow-up visits scheduled with cardiology (36.7% vs. 24.8%, p=0.005; 55.7% vs. 42.3%, p=0.0029), but no improvement in appointment attendance. CONCLUSION: This study provides a first test of applying the PHCRP framework within a stakeholder-engaged QI initiative for improving CHF care across races and ethnicities. Our study design cannot evaluate causation. However, the improvements in 30-day readmission, as well as in processes of care that may affect it, provide optimism that inclusion of a racism-conscious framework in QI initiatives is feasible and may enhance QI measures.

Hospital-Level Care at Home for Patients With Acute Respiratory Disease: A Descriptive Analysis.

BACKGROUND: Home hospital (HH) care is hospital-level substitutive care delivered at home for acutely ill patients who traditionally would be cared for in the hospital. Despite HH care programs operating successfully for years and scientific evidence of similar or better outcomes compared with bricks-and-mortar care, HH care outcomes in the United States for respiratory disease have not been evaluated. RESEARCH QUESTION: Do outcomes differ between patients admitted to HH care with acute respiratory illness vs those with other acute general medical conditions? STUDY DESIGN AND METHODS: This was a retrospective evaluation of prospectively collected data of patients admitted to HH care (2017-2021). We compared patients requiring admission with respiratory disease (asthma exacerbation [26%], acute exacerbation of COPD [33%], and non-COVID-19 pneumonia [41%]) to all other patients admitted to HH care. During HH care, patients received two nurse and one physician visit daily, IV medications, advanced respiratory therapies, and continuous heart and respiratory rate monitoring. Main outcomes were acute and postacute health care use and safety. RESULTS: We analyzed 1,031 patients; 24% were admitted for respiratory disease. Patients with and without respiratory disease were similar: mean age, 68 ± 17 years, 62% women, and 48% White. Patients with respiratory disease more often were active smokers (21% vs 9%; P < .001). Eighty percent of patients showed an FEV1 to FVC ratio of ≤ 70; 28% showed a severe or very severe obstructive pattern (n = 118). During HH care, patients with respiratory disease showed less health care use: length of stay (mean, 3.4 vs 4.6 days), laboratory orders (median, 0 vs 2), IV medication (43% vs 73%), and specialist consultation (2% vs 7%; P < .001 for all). Ninety-six percent of patients completed the full admission at home with no mortality in the respiratory group. Within 30 days of discharge, both groups showed similar readmission, ED presentation, and mortality rates. INTERPRETATION: HH care is as safe and effective for patients with acute respiratory disease as for those with other acute general medical conditions. If scaled, it can generate significant high-value capacity for health systems and communities, with opportunities to advance the complexity of care delivered.

Remote vs In-home Physician Visits for Hospital-Level Care at Home: A Randomized Clinical Trial.

Importance: Home hospital care is the substitutive provision of home-based acute care services usually associated with a traditional inpatient hospital. Many home hospital models require a physician to see patients at home daily, which may hinder scalability. Whether remote physician visits can safely substitute for most in-home visits is unknown. Objective: To compare remote and in-home physician care. Design, Setting, and Participants: This randomized clinical trial assessed 172 adult patients at an academic medical center and community hospital who required hospital-level care for select acute conditions, including infection, heart failure, chronic obstructive pulmonary disease, and asthma, between August 3, 2019, and March 26, 2020; follow-up ended April 26, 2020. Interventions: All patients received acute care at home, including in-home nurse or paramedic visits, intravenous medications, remote monitoring, and point-of-care testing. Patients were randomized to receive physician care remotely (initial in-home visit followed by daily video visit facilitated by the home hospital nurse) vs in-home care (daily in-home physician visit). In the remote care group, the physician could choose to see the patient at home beyond the first visit if it was felt to be medically necessary. Main Outcomes and Measures: The primary outcome was the number of adverse events, compared using multivariable Poisson regression at a noninferiority threshold of 10 events per 100 patients. Adverse events included a fall, pressure injury, and delirium. Secondary outcomes included the Picker Patient Experience Questionnaire 15 score (scale of 0-15, with 0 indicating worst patient experience and 15 indicating best patient experience) and 30-day readmission rates. Results: A total of 172 patients (84 receiving remote care and 88 receiving in-home physician care [control group]) were randomized; enrollment was terminated early because of COVID-19. The mean (SD) age was 69.3 (18.0) years, 97 patients (56.4%) were female, 77 (45.0%) were White, and 42 (24.4%) lived alone. Mean adjusted adverse event count was 6.8 per 100 patients for remote care patients vs 3.9 per 100 patients for control patients, for a difference of 2.8 (95% CI, -3.3 to 8.9), supporting noninferiority. For remote care vs control patients, the mean adjusted Picker Patient Experience Questionnaire 15 score difference was -0.22 (95% CI, -1.00 to 0.56), supporting noninferiority. The mean adjusted 30-day readmission absolute rate difference was 2.28% (95% CI, -3.23% to 7.79%), which was inconclusive. Of patients in the remote group, 16 (19.0%) required in-home visits beyond the first visit. Conclusions and Relevance: In this study, remote physician visits were noninferior to in-home physician visits during home hospital care for adverse events and patient experience, although in-home physician care was necessary to support many patients receiving remote care. Our findings may allow for a more efficient, scalable home hospital approach but require further research. Trial Registration: ClinicalTrials.gov Identifier: NCT04080570.

Randomized Study of Bedside vs Hallway Rounding: Neurology Rounding Study.

Over the last century, attending rounds have shifted away from the bedside. Despite evidence for greater patient satisfaction rates and improved nursing perception of teamwork with bedside presentations, residents and attending physicians are apprehensive of the bedside approach. There is lack of data to guide rounding practices within neurology, and therefore, optimal rounding methods remain unclear. The objective of this study was to compare bedside rounding with hallway rounding on an academic neurology inpatient service and assess efficiency, trainee education, and satisfaction among patients and staff. We conducted a single-center prospective randomized study of bedside vs hallway rounding on new inpatient neurology admissions over 1-week blocks. The bedside team presented patients at the bedside, whereas the hallway team presented patients outside of the patient's room. We evaluated the 2 approaches with time-motion analysis, which investigated the rounding style's effect on composition and timing of rounds (primary outcome) and surveys of patients, nurses, residents, and attending physicians on both teams (secondary outcomes). The mean rounding time per newly admitted patient in the bedside group (n = 38 patients) and hallway group (n = 41 patients) was 23 minutes and 23.2 minutes, respectively (p = 0.93). The bedside group spent on average 56.4% of patient rounding time in the patient's room, whereas the hallway group spent 39.5% of rounding time in the patient's room (p = 0.036). Residents perceived hallway rounding to be more efficient and associated it with a superior educational experience and more effective data review. Nurses had improved perception of their participation in bedside rounds. Although patients' views of bedside and hallway rounds were similar, patients who had experienced bedside rounds preferred it. In conclusion, bedside rounding was perceived less favorably by most residents but was as efficient as hallway rounding. Although bedside rounding limited the use of technology for data review, it promoted nursing participation and resulted in more time spent with the patient. CLINICAL TRIAL REGISTRATION NUMBER: Registered retrospectively per the editors' suggestion (NCT04754828).

Remote Patient Monitoring Program for Hospital Discharged COVID-19 Patients.

OBJECTIVE: We deployed a Remote Patient Monitoring (RPM) program to monitor patients with coronavirus disease 2019 (COVID-19) upon hospital discharge. We describe the patient characteristics, program characteristics, and clinical outcomes of patients in our RPM program. METHODS: We enrolled COVID-19 patients being discharged home from the hospital. Enrolled patients had an app, and were provided with a pulse oximeter and thermometer. Patients self-reported symptoms, O2 saturation, and temperature daily. Abnormal symptoms or vital signs were flagged and assessed by a pool of nurses. Descriptive statistics were used to describe patient and program characteristics. A mixed-effects logistic regression model was used to determine the odds of a combined endpoint of emergency department (ED) or hospital readmission. RESULTS: A total of 295 patients were referred for RPM from five participating hospitals, and 225 patients were enrolled. A majority of enrolled patients (66%) completed the monitoring period without triggering an abnormal alert. Enrollment was associated with a decreased odds of ED or hospital readmission (adjusted odds ratio: 0.54; 95% confidence interval: 0.3-0.97; p = 0.039). Referral without enrollment was not associated with a reduced odds of ED or hospital readmission. CONCLUSION: RPM for COVID-19 provides a mechanism to monitor patients in their home environment and reduce hospital utilization. Our work suggests that RPM reduces readmissions for patients with COVID-19 and provides scalable remote monitoring capabilities upon hospital discharge. RPM for postdischarge patients with COVID-19 was associated with a decreased risk of readmission to the ED or hospital, and provided a scalable mechanism to monitor patients in their home environment.

Interactive Digital Health Tools to Engage Patients and Caregivers in Discharge Preparation: Implementation Study.

BACKGROUND: Poor discharge preparation during hospitalization may lead to adverse events after discharge. Checklists and videos that systematically engage patients in preparing for discharge have the potential to improve safety, especially when integrated into clinician workflow via the electronic health record (EHR). OBJECTIVE: This study aims to evaluate the implementation of a suite of digital health tools integrated with the EHR to engage hospitalized patients, caregivers, and their care team in preparing for discharge. METHODS: We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to identify pertinent research questions related to implementation. We iteratively refined patient and clinician-facing intervention components using a participatory process involving end users and institutional stakeholders. The intervention was implemented at a large academic medical center from December 2017 to July 2018. Patients who agreed to participate were coached to watch a discharge video, complete a checklist assessing discharge readiness, and request postdischarge text messaging with a physician 24 to 48 hours before their expected discharge date, which was displayed via a patient portal and bedside display. Clinicians could view concerns reported by patients based on their checklist responses in real time via a safety dashboard integrated with the EHR and choose to open a secure messaging thread with the patient for up to 7 days after discharge. We used mixed methods to evaluate our implementation experience. RESULTS: Of 752 patient admissions, 510 (67.8%) patients or caregivers participated: 416 (55.3%) watched the video and completed the checklist, and 94 (12.5%) completed the checklist alone. On average, 4.24 concerns were reported per each of the 510 checklist submissions, most commonly about medications (664/2164, 30.7%) and follow-up (656/2164, 30.3%). Of the 510 completed checklists, a member of the care team accessed the safety dashboard to view 210 (41.2%) patient-reported concerns. For 422 patient admissions where postdischarge messaging was available, 141 (33.4%) patients requested this service; of these, a physician initiated secure messaging for 3 (2.1%) discharges. Most patient survey participants perceived that the intervention promoted self-management and communication with their care team. Patient interview participants endorsed gaps in communication with their care team and thought that the video and checklist would be useful closer toward discharge. Clinicians participating in focus groups perceived the value for patients but suggested that low awareness and variable workflow regarding the intervention, lack of technical optimization, and inconsistent clinician leadership limited the use of clinician-facing components. CONCLUSIONS: A suite of EHR-integrated digital health tools to engage patients, caregivers, and clinicians in discharge preparation during hospitalization was feasible, acceptable, and valuable; however, important challenges were identified during implementation. We offer strategies to address implementation barriers and promote adoption of these tools. TRIAL REGISTRATION: ClinicalTrials.gov NCT03116074; https://clinicaltrials.gov/ct2/show/NCT03116074.

Use, Perceived Usability, and Barriers to Implementation of a Patient Safety Dashboard Integrated within a Vendor EHR.

BACKGROUND: Preventable adverse events continue to be a threat to hospitalized patients. Clinical decision support in the form of dashboards may improve compliance with evidence-based safety practices. However, limited research describes providers' experiences with dashboards integrated into vendor electronic health record (EHR) systems. OBJECTIVE: This study was aimed to describe providers' use and perceived usability of the Patient Safety Dashboard and discuss barriers and facilitators to implementation. METHODS: The Patient Safety Dashboard was implemented in a cluster-randomized stepped wedge trial on 12 units in neurology, oncology, and general medicine services over an 18-month period. Use of the Dashboard was tracked during the implementation period and analyzed in-depth for two 1-week periods to gather a detailed representation of use. Providers' perceptions of tool usability were measured using the Health Information Technology Usability Evaluation Scale (rated 1-5). Research assistants conducted field observations throughout the duration of the study to describe use and provide insight into tool adoption. RESULTS: The Dashboard was used 70% of days the tool was available, with use varying by role, service, and time of day. On general medicine units, nurses logged in throughout the day, with many logins occurring during morning rounds, when not rounding with the care team. Prescribers logged in typically before and after morning rounds. On neurology units, physician assistants accounted for most logins, accessing the Dashboard during daily brief interdisciplinary rounding sessions. Use on oncology units was rare. Satisfaction with the tool was highest for perceived ease of use, with attendings giving the highest rating (4.23). The overall lowest rating was for quality of work life, with nurses rating the tool lowest (2.88). CONCLUSION: This mixed methods analysis provides insight into the use and usability of a dashboard tool integrated within a vendor EHR and can guide future improvements and more successful implementation of these types of tools.

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

BACKGROUND: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality. RESULTS: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race. CONCLUSIONS: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.

Effect of default order set settings on telemetry ordering.

OBJECTIVE: To investigate the effects of adjusting the default order set settings on telemetry usage. MATERIALS AND METHODS: We performed a retrospective, controlled, before-after study of patients admitted to a house staff medicine service at an academic medical center examining the effect of changing whether the admission telemetry order was pre-selected or not. Telemetry orders on admission and subsequent orders for telemetry were monitored pre- and post-change. Two other order sets that had no change in their default settings were used as controls. RESULTS: Between January 1, 2017 and May 1, 2018, there were 1, 163 patients admitted using the residency-customized version of the admission order set which initially had telemetry pre-selected. In this group of patients, there was a significant decrease in telemetry ordering in the post-intervention period: from 79.1% of patients in the 8.5 months prior ordered to have telemetry to 21.3% of patients ordered in the 7.5 months after (χ2 = 382; P < .001). There was no significant change in telemetry usage among patients admitted using the two control order sets. DISCUSSION: Default settings have been shown to affect clinician ordering behavior in multiple domains. Consistent with prior findings, our study shows that changing the order set settings can significantly affect ordering practices. Our study was limited in that we were unable to determine if the change in ordering behavior had significant impact on patient care or safety. CONCLUSION: Decisions about default selections in electronic health record order sets can have significant consequences on ordering behavior.

User-Centered Collaborative Design and Development of an Inpatient Safety Dashboard.

Patient safety remains a key concern in hospital care. This article summarizes the iterative participatory development, features, functions, and preliminary evaluation of a patient safety dashboard for interdisciplinary rounding teams on inpatient medical services. This electronic health record (EHR)-embedded dashboard collects real-time data covering 13 safety domains through web services and applies logic to generate stratified alerts with an interactive check-box function. The technological infrastructure is adaptable to other EHR environments. Surveyed users perceived the tool as highly usable and useful. Integration of the dashboard into clinical care is intended to promote communication about patient safety and facilitate identification and management of safety concerns.

All Together Now: Impact of a Regionalization and Bedside Rounding Initiative on the Efficiency and Inclusiveness of Clinical Rounds.

BACKGROUND: Attending rounds at academic medical centers are often disconnected from patients and team members who are not physicians. Regionalization of care teams may facilitate bedside rounding and more frequent interactions among doctors, nurses, and patients. OBJECTIVE: We used time-motion analysis to investigate how regionalization of medical teams and encouragement of bedside rounds affect participants on rounds and rounding time. DESIGN AND SETTING: We used pre-post analysis to study the effects of care redesign on teams' daily rounds on a general medicine service at an academic medical center. PARTICIPANTS: Four general medical teams were evaluated before the intervention and 5 teams afterward. INTERVENTIONS: General medical teams were regionalized to specific units, the admitting structure was changed to facilitate regionalization, and teams were encouraged to round bedside. MEASUREMENTS: Primary outcomes included proportion of time each team member was present on rounds and proportion of bedside rounding time. Secondary outcomes included round duration and non-patient time during rounds. RESULTS: Proportion of time the nurse was present on rounds increased from 24.1% to 67.8% (P ⟨ 0.001), and proportion of total bedside rounding time increased from 39.9% to 55.8% (P ⟨ 0.001). Mean total rounding time decreased from 3.0 hours to 2.4 hours (P = 0.01), despite a higher patient census. CONCLUSIONS: Creating regionalized care teams and encouraging interdisciplinary bedside rounds increased the proportion of bedside rounding time and the presence of nurses on rounds while decreasing total rounding time. Journal of Hospital Medicine 2017;12:150-156.

Impact of regionalized care on concordance of plan and preventable adverse events on general medicine services.

BACKGROUND: Dispersion of inpatient care teams across different medical units impedes effective team communication, potentially leading to adverse events (AEs). OBJECTIVE: To regionalize 3 inpatient general medical teams to nursing units and examine the association with communication and preventable AEs. DESIGN: Pre-post cohort analysis. SETTING: A 700-bed academic medical center. PATIENTS: General medicine patients on any of the participating nursing units before and after implementation of regionalized care. INTERVENTION: Regionalizing 3 general medical physician teams to 3 corresponding nursing units. MEASUREMENTS: Concordance of patient care plan between nurse and intern, and adjusted odds of preventable AEs. RESULTS: Of the 414 included nurse and intern paired surveys, there were no significant differences pre- versus postregionalization in total mean concordance scores (0.65 vs 0.67, P = 0.26), but there was significant improvement in agreement on expected discharge date (0.56 vs 0.68, P = 0.003), knowledge of the other provider's name (0.56 vs 0.86,P < 0.001), and daily care plan discussions (0.73 vs 0.88, P < 0.001). Of the 392 reviewed patient medical records, there was no significant difference in the adjusted odds of preventable AEs pre- versus postregionalization (adjusted odds ratio: 1.37, 95% confidence interval: 0.69, 2.69). CONCLUSIONS: We found that regionalization of care teams improved recognition of care team members, discussion of daily care plan, and agreement on estimated discharge date, but did not significantly improve nurse and physician concordance of the care plan or reduce the odds of preventable AEs. Our findings suggest that regionalization alone may be insufficient to effectively promote communication and lead to patient safety improvements. Journal of Hospital Medicine 2016;11:620-627. © 2016 Society of Hospital Medicine.

Readability of patient discharge instructions with and without the use of electronically available disease-specific templates.

OBJECTIVE: Low health literacy is common, leading to patient vulnerability during hospital discharge, when patients rely on written health instructions. We aimed to examine the impact of the use of electronic, patient-friendly, templated discharge instructions on the readability of discharge instructions provided to patients at discharge. MATERIALS AND METHODS: We performed a retrospective cohort study of 233 patients discharged from a large tertiary care hospital to their homes following the implementation of a web-based "discharge module," which included the optional use of diagnosis-specific templated discharge instructions. We compared the readability of discharge instructions, as measured by the Flesch Reading Ease Level test (FREL, on a 0-100 scale, with higher scores indicating greater readability) and the Flesch-Kincaid Grade Level test (FKGL, measured in grade levels), between discharges that used templated instructions (with or without modification) versus discharges that used clinician-generated instructions (with or without available templated instructions for the specific discharge diagnosis). RESULTS: Templated discharge instructions were provided to patients in 45% of discharges. Of the 55% of patients that received clinician-generated discharge instructions, the majority (78.1%) had no available templated instruction for the specific discharge diagnosis. Templated discharge instructions had higher FREL scores (71 vs. 57, P < .001) and lower FKGL scores (5.6 vs. 7.6, P < .001), compared to clinician-generated discharge instructions. DISCUSSION: The use of electronically available templated discharge instructions was associated with better readability (a higher FREL score and a lower FKGL score) than the use of clinician-generated discharge instructions. The main reason for clinicians to create discharge instructions was the lack of available templates for the patient's specific discharge diagnosis. CONCLUSIONS: Use of electronically available templated discharge instructions may be a viable option to improve the readability of written material provided to patients at discharge, although the library of available templates requires expansion.

Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.

Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.

Akt is required for Stat5 activation and mammary differentiation.

INTRODUCTION: The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2-deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. METHODS: In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation. RESULTS: Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1(-/-);Akt2(+/-) mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. CONCLUSIONS: Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.

Therapeutic efficacy of chloroquine and sequence variation in pfcrt gene among patients with falciparum malaria in central India.

OBJECTIVES: To assess the therapeutic efficacy of chloroquine (CQ) treatment against uncomplicated Plasmodium falciparum infections in a tribal population of central India (Madhya Pradesh) and to investigate the prevalence of mutant P. falciparum chloroquine-resistant transporter (pfcrt) gene in the parasite population. METHODS: Clinical and parasitological response was determined by in-vivo testing. For molecular testing, the parasite DNA was extracted from blood samples and used to amplify and sequence parts of the pfcrt (44-177 codons), MSP1 (block 2) and MSP2 (central repeat region) genes. RESULTS: Of 463 patients presenting fever, 137 tested positive for P. falciparum. They were treated with CQ. Of these, 58% participated in the study. Overall, treatment failure occurred in 53% of participants. Children under 5 years of age showed significantly more CQ resistance than adults. Mutant genotype S(72)V(73)M(74)N(75)T(76) was prevalent among both CQ responders (61.29%) and non-responders (66.7%). Interestingly, several patients from the CQ non-responder group (33.3%, n = 39) were harbouring parasite with wild type C(72)V(73)M(74)N(75)K(76) genotype of the pfcrt gene. Microsatellite sequences downstream of exon 2 varied widely among both wild type and mutant pfcrt haplotypes. CONCLUSION: The high rate of treatment failure in the present study clearly indicates the need to reassess the use of CQ as first-line antimalarial therapy in central India. This is supported by the presence of mutant pfcrt genotype among majority of the parasite population of the CQ non-responder group of patients. However, the presence of wild type amino acid at codon 76 of the pfcrt gene among several patients with CQ non-responders requires further investigations.

Food allergies: detection and management.

Family physicians play a central role in the suspicion and diagnosis of immunoglobulin E-mediated food allergies, but they are also critical in redirecting the evaluation for symptoms that patients are falsely attributing to allergies. Although any food is a potential allergen, more than 90 percent of acute systemic reactions to food in children are from eggs, milk, soy, wheat, or peanuts, and in adults are from crustaceans, tree nuts, peanuts, or fish. The oral allergy syndrome is more common than anaphylactic reactions to food, but symptoms are transient and limited to the mouth and throat. Skin-prick and radioallergosorbent tests for particular foods have about an 85 percent sensitivity and 30 to 60 percent specificity. Intradermal testing has a higher false-positive rate and greater risk of adverse reactions; therefore, it should not be used for initial evaluations. The double-blind, placebo-controlled food challenge remains the most specific test for confirming diagnosis. Treatment is through recognition and avoidance of the responsible food. Patients with anaphylactic reactions need emergent epinephrine and instruction in self-administration in the event of inadvertent exposure. Antihistamines can be used for more minor reactions.