Lactoferrin for the Prevention of Post-antibiotic Diarrhoea

Antibiotic-associated diarrhoea (AAD) is a common cause of morbidity and mortality. Older individuals in long-term care facilities are particularly vulnerable due to multisystem illnesses and the prevailing conditions for nosocomial infections. Lactoferrin, an antimicrobial protein in human breastmilk, was tested to determine whether it would prevent or reduce AAD, including Clostridium difficile in tube-fed long-term care patients. Thirty patients were enrolled in a randomized double-blind study, testing eight weeks of human recombinant lactoferrin compared to placebo for the prevention of antibiotic-associated diarrhoea in long-term care patients. Fewer patients in the lactoferrin group experienced diarrhoea compared to controls (p=0.023). Based on the findings, it is concluded that human lactoferrin may reduce post-antibiotic diarrhoea

Lactoferrin for the Prevention of Post-antibiotic Diarrhoea

Antibiotic-associated diarrhoea (AAD) is a common cause of morbidity and mortality. Older individuals in long-term care facilities are particularly vulnerable due to multisystem illnesses and the prevailing conditions for nosocomial infections. Lactoferrin, an antimicrobial protein in human breastmilk, was tested to determine whether it would prevent or reduce AAD, including Clostridium difficile in tube-fed long-term care patients. Thirty patients were enrolled in a randomized double-blind study, testing eight weeks of human recombinant lactoferrin compared to placebo for the prevention of antibiotic-associated diarrhoea in long-term care patients. Fewer patients in the lactoferrin group experienced diarrhoea compared to controls (p=0.023). Based on the findings, it is concluded that human lactoferrin may reduce post-antibiotic diarrhoea

Divergence via Europeanisation: rethinking the origins of the Portuguese debt crisis

A founding myth of the euro was that profound economic convergence could be achieved across the core and periphery of Europe. Scholarship from within Comparative Political Economy (CPE) has compellingly pointed to this myth of convergence as the fundamental mistake of the euro project (Regan, “Imbalance of Capitalisms”). Economic and Monetary Union was applied across a range of incompatible varieties of capitalism with little appreciation for how difficult it would be for peripheral economies to overcome long-standing institutional stickiness. Yet, while institutional stickiness tells us much about the causes of declining competitiveness, it tells us much less about the origins of brand new patterns of debt-led growth. This article modifies this CPE account by drawing attention to the much overlooked case of Portugal. In contrast to CPE’s emphasis on institutional stickiness, this paper explores the ways in which negotiation of European integration has been generative of institutional transformation leading to debt-led growth in Portugal. By combining Europeanisation with CPE, this article shows that, far from an inability to do so, in the case of Portugal, it has been the attempt to ‘follow the rules’ of European Integration that explains its damaging patterns of debt-led growth

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Health Care Utilization and Cost Outcomes of a Comprehensive Dementia Care Program for Medicare Beneficiaries.

Importance:An estimated 4 to 5 million Americans have Alzheimer disease or another dementia. Objective:To determine the health care utilization and cost outcomes of a comprehensive dementia care program for Medicare fee-for-service beneficiaries. Design, Setting, and Participants:In this case-control study, we used a quasiexperimental design to compare health care utilization and costs for 1083 Medicare fee-for-service beneficiaries enrolled in the University of California Los Angeles Health System Alzheimer and Dementia Care program between July 1, 2012, and December 31, 2015, with those of 2166 similar patients with dementia not participating in the program. Patients in the comparison cohort were selected using the zip code of residence as a sampling frame and matched with propensity scores, which included demographic characteristics, comorbidities, and prior-year health care utilization. We used Medicare claims data to compare utilization and cost outcomes for the 2 groups. Interventions:Patients in the dementia care program were comanaged by nurse practitioners and physicians, and the program consisted of structured needs assessments of patients and their caregivers, creation and implementation of individualized dementia care plans with input from primary care physicians, monitoring and revising care plans, referral to community organizations for dementia-related services and support, and access to a clinician for assistance and advice 24 hours per day, 7 days per week. Main Outcomes and Measures:Admissions to long-term care facilities; average difference-in-differences per quarter over the 3-year intervention period for all-cause hospitalization, emergency department visits, 30-day hospital readmissions, and total Medicare Parts A and B costs of care. Program costs were included in the cost estimates. Results:Program participants (n = 382 men, n = 701 women; mean [SD] age, 82.10 [7.90] years; age range 54-101 years) were less likely to be admitted to a long-term care facility (hazard ratio, 0.60; 95% CI, 0.59-0.61) than those not participating in the dementia care program (n = 759 men, n = 1407 women; mean [SD] age, 82.42 [8.50] years; age range, 34-103 years). There were no differences between groups in terms of hospitalizations, emergency department visits, or 30-day readmissions. The total cost of care to Medicare, excluding program costs, was $601 less per patient per quarter (95$1198 to -$5). After accounting for the estimated program costs of$317 per patient per quarter, the program was cost neutral for Medicare, with an estimated net cost of -$284 (95$881 to $312) per program participant per quarter. Conclusions and Relevance:Comprehensive dementia care may reduce the number of admissions to long-term care facilities, and depending on program costs, may be cost neutral or cost saving. Wider implementation of such programs may help people with dementia stay in their communities

Health Care Utilization and Cost Outcomes of a Comprehensive Dementia Care Program for Medicare Beneficiaries.

Importance:An estimated 4 to 5 million Americans have Alzheimer disease or another dementia. Objective:To determine the health care utilization and cost outcomes of a comprehensive dementia care program for Medicare fee-for-service beneficiaries. Design, Setting, and Participants:In this case-control study, we used a quasiexperimental design to compare health care utilization and costs for 1083 Medicare fee-for-service beneficiaries enrolled in the University of California Los Angeles Health System Alzheimer and Dementia Care program between July 1, 2012, and December 31, 2015, with those of 2166 similar patients with dementia not participating in the program. Patients in the comparison cohort were selected using the zip code of residence as a sampling frame and matched with propensity scores, which included demographic characteristics, comorbidities, and prior-year health care utilization. We used Medicare claims data to compare utilization and cost outcomes for the 2 groups. Interventions:Patients in the dementia care program were comanaged by nurse practitioners and physicians, and the program consisted of structured needs assessments of patients and their caregivers, creation and implementation of individualized dementia care plans with input from primary care physicians, monitoring and revising care plans, referral to community organizations for dementia-related services and support, and access to a clinician for assistance and advice 24 hours per day, 7 days per week. Main Outcomes and Measures:Admissions to long-term care facilities; average difference-in-differences per quarter over the 3-year intervention period for all-cause hospitalization, emergency department visits, 30-day hospital readmissions, and total Medicare Parts A and B costs of care. Program costs were included in the cost estimates. Results:Program participants (n = 382 men, n = 701 women; mean [SD] age, 82.10 [7.90] years; age range 54-101 years) were less likely to be admitted to a long-term care facility (hazard ratio, 0.60; 95% CI, 0.59-0.61) than those not participating in the dementia care program (n = 759 men, n = 1407 women; mean [SD] age, 82.42 [8.50] years; age range, 34-103 years). There were no differences between groups in terms of hospitalizations, emergency department visits, or 30-day readmissions. The total cost of care to Medicare, excluding program costs, was $601 less per patient per quarter (95$1198 to -$5). After accounting for the estimated program costs of$317 per patient per quarter, the program was cost neutral for Medicare, with an estimated net cost of -$284 (95$881 to $312) per program participant per quarter. Conclusions and Relevance:Comprehensive dementia care may reduce the number of admissions to long-term care facilities, and depending on program costs, may be cost neutral or cost saving. Wider implementation of such programs may help people with dementia stay in their communities