Inequalities in children's mental health care: analysis of routinely collected data on prescribing and referrals to secondary care.

BACKGROUND: One in eight children in the United Kingdom are estimated to have a mental health condition, and many do not receive support or treatment. The COVID-19 pandemic has negatively impacted mental health and disrupted the delivery of care. Prevalence of poor mental health is not evenly distributed across age groups, by sex or socioeconomic groups. Equity in access to mental health care is a policy priority but detailed socio-demographic trends are relatively under-researched. METHODS: We analysed records for all mental health prescriptions and referrals to specialist mental health outpatient care between the years of 2015 and 2021 for children aged 2 to 17 years in a single NHS Scotland health board region. We analysed trends in prescribing, referrals, and acceptance to out-patient treatment over time, and measured differences in treatment and service use rates by age, sex, and area deprivation. RESULTS: We identified 18,732 children with 178,657 mental health prescriptions and 21,874 referrals to specialist outpatient care. Prescriptions increased by 59% over the study period. Boys received double the prescriptions of girls and the rate of prescribing in the most deprived areas was double that in the least deprived. Mean age at first mental health prescription was almost 1 year younger in the most deprived areas than in the least. Referrals increased 9% overall. Initially, boys and girls both had an annual referral rate of 2.7 per 1000, but this fell 6% for boys and rose 25% for girls. Referral rate for the youngest decreased 67% but increased 21% for the oldest. The proportion of rejected referrals increased steeply since 2020 from 17 to 30%. The proportion of accepted referrals that were for girls rose to 62% and the mean age increased 1.5 years. CONCLUSIONS: The large increase in mental health prescribing and changes in referrals to specialist outpatient care aligns with emerging evidence of increasing poor mental health, particularly since the start of the COVID-19 pandemic. The static size of the population accepted for specialist treatment amid greater demand, and the changing demographics of those accepted, indicate clinical prioritisation and unmet need. Persistent inequities in mental health prescribing and referrals require urgent action.

A National Network of Safe Havens: Scottish Perspective.

For over a decade, Scotland has implemented and operationalized a system of Safe Havens, which provides secure analytics platforms for researchers to access linked, deidentified electronic health records (EHRs) while managing the risk of unauthorized reidentification. In this paper, a perspective is provided on the state-of-the-art Scottish Safe Haven network, including its evolution, to define the key activities required to scale the Scottish Safe Haven network's capability to facilitate research and health care improvement initiatives. A set of processes related to EHR data and their delivery in Scotland have been discussed. An interview with each Safe Haven was conducted to understand their services in detail, as well as their commonalities. The results show how Safe Havens in Scotland have protected privacy while facilitating the reuse of the EHR data. This study provides a common definition of a Safe Haven and promotes a consistent understanding among the Scottish Safe Haven network and the clinical and academic research community. We conclude by identifying areas where efficiencies across the network can be made to meet the needs of population-level studies at scale.

Magnetic Resonance Imaging Radiomics-Based Machine Learning Prediction of Clinically Significant Prostate Cancer in Equivocal PI-RADS 3 Lesions.

BACKGROUND: While Prostate Imaging Reporting and Data System (PI-RADS) 4 and 5 lesions typically warrant prostate biopsy and PI-RADS 1 and 2 lesions may be safely observed, PI-RADS 3 lesions are equivocal. PURPOSE: To construct and cross-validate a machine learning model based on radiomics features from T2 -weighted imaging (T2 WI) of PI-RADS 3 lesions to identify clinically significant prostate cancer (csPCa), that is, pathological Grade Group ≥ 2. STUDY TYPE: Single-center retrospective study. POPULATION: A total of 240 patients were included (training cohort, n = 188, age range 43-82 years; test cohort, n = 52, age range 41-79 years). Eligibility criteria were 1) magnetic resonance imaging (MRI)-targeted biopsy between 2015 and 2020; 2) PI-RADS 3 index lesion identified on multiparametric MRI; (3) biopsy performed within 1 year of MRI. The percentages of csPCa lesions were 10.6% and 15.4% in the training and test cohorts, respectively. FIELD STRENGTH/SEQUENCE: A 3 T; T2 WI turbo-spin echo, diffusion-weighted spin-echo echo planar imaging, dynamic contrast-enhanced MRI with time-resolved T1-weighted imaging. ASSESSMENT: Multislice volumes-of-interest (VOIs) were drawn in the PI-RADS 3 index lesions on T2 WI. A total of 107 radiomics features (first-order histogram and second-order texture) were extracted from the segmented lesions. STATISTICAL TESTS: A random forest classifier using the radiomics features as input was trained and validated for prediction of csPCa. The performance of the machine learning classifier, prostate specific antigen (PSA) density, and prostate volume for csPCa prediction was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The trained random forest classifier constructed from the T2 WI radiomics features good and statistically significant area-under-the-curves (AUCs) of 0.76 (P = 0.022) for prediction of csPCa in the test set. Prostate volume and PSA density showed moderate and nonsignificant performance (AUC 0.62, P = 0.275 and 0.61, P = 0.348, respectively) for csPCa prediction in the test set. CONCLUSION: The machine learning classifier based on T2 WI radiomic features demonstrated good performance for prediction of csPCa in PI-RADS 3 lesions. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: 2.

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.

A systematic review of global legal regulations on the permissible level of heavy metals in cosmetics with particular emphasis on skin lightening products.

BACKGROUND: There is an urgent need to address the safety problems caused by the use of skin lightening cosmetics. Evidence suggests that some of them may contain heavy metals. OBJECTIVES: We conducted a systematic review of global legal regulations regarding the permissible level of mercury, lead, arsenic, and cadmium in cosmetic products, with particular emphasis on skin lightening preparations. METHODS: The systematic search of documents was a two-stage process. First, official websites of 17 regional organizations and subsequently regulations for countries with a population over 100 million were searched. RESULTS: Fifteen legislative acts, encompassing more than 67·2% of the global population were reviewed. Regulations were identified for 44/59 high income countries, 16/55 upper middle income countries, 9/45 lower income countries, 0/34 low income countries. The median adult literacy rate was 91·4% and 64·2% in countries with and without regulations, respectively. The use of mercury, lead, arsenic, and cadmium has been banned in 67, 67, 65, and 65 out of 69 countries, respectively. CONCLUSIONS: While regulations exist in most of the high income countries, in low income countries there is a lack of similar standards. In most countries for which these legal regulations have been identified, restrictions on the permissible level of heavy metals are strict. There is a need for enforcement of existing rules, and rigorous assessment of the effectiveness of these regulations.

Use of an expert panel to identify domains and indicators of delirium severity.

PURPOSE: Our purpose was to create a content domain framework for delirium severity to inform item development for a new instrument to measure delirium severity. METHODS: We used an established, multi-stage instrument development process during which expert panelists discussed best approaches to measure delirium severity and identified related content domains. We conducted this work as part of the Better ASsessment of ILlness (BASIL) study, a prospective, observational study aimed at developing and testing measures of delirium severity. Our interdisciplinary expert panel consisted of twelve national delirium experts and four expert members of the core research group. Over a one-month period, experts participated in two rounds of review. RESULTS: Experts recommended that the construct of delirium severity should reflect both the phenomena and the impact of delirium to create an accurate, patient-centered instrument useful to interdisciplinary clinicians and family caregivers. Final content domains were Cognitive, Level of consciousness, Inattention, Psychiatric-Behavioral, Emotional dysregulation, Psychomotor features, and Functional. Themes debated by experts included reconciling clinical geriatrics and psychiatric content, mapping symptoms to one specific domain, and accurate capture of unclear clinical presentations. CONCLUSIONS: We believe this work represents the first application of instrument development science to delirium. The identified content domains are inclusive of various, wide-ranging domains of delirium severity and are reflective of a consistent framework that relates delirium severity to potential clinical outcomes. Our content domain framework provides a foundation for development of delirium severity instruments that can help improve care and quality of life for patients with delirium.

Changing Paradigms for Acute Dental Pain: Prevention Is Better Than PRN.

A B S T R A C T The drugs available for the management of acute orofacial pain have changed very little since the introduction of ibuprofen into practice 40 years ago. Orally effective opioids, acetaminophen, aspirin and NSAIDs remain the mainstay of analgesic therapy. Increased recognition of the societal and personal impact of opioid diversion and abuse requires re-examination of the traditional approach of prescribing an opioid-containing analgesic combination to be administered by the patient "as needed" (PRN) starting postoperatively.

The role and timing of palliative medicine consultation for women with gynecologic malignancies: association with end of life interventions and direct hospital costs.

OBJECTIVE: Aggressive care interventions at the end of life (ACE) are reported metrics of sub-optimal quality of end of life care that are modifiable by palliative medicine consultation. Our objective was to evaluate the association of inpatient palliative medicine consultation with ACE scores and direct inpatient hospital costs of patients with gynecologic malignancies. METHODS: A retrospective review of medical records of the past 100 consecutive patients who died from their primary gynecologic malignancies at a single institution was performed. Timely palliative medicine consultation was defined as exposure to inpatient consultation ≥ 30 days before death. Metrics utilized to tabulate ACE scores were ICU admission, hospital admission, emergency room visit, death in an acute care setting, chemotherapy at the end of life, and hospice admission <3 days. Inpatient direct hospital costs were calculated for the last 30 days of life from accounting records. Data were analyzed using Fisher's Exact, Mann-Whitney U, Kaplan-Meier, and Student's T testing. RESULTS: 49% of patients had a palliative medicine consultation and 18% had timely consultation. Median ACE score for patients with timely palliative medicine consultation was 0 (range 0-3) versus 2 (range 0-6) p=0.025 for patients with untimely/no consultation. Median inpatient direct costs for the last 30 days of life were lower for patients with timely consultation, $0 (range 0-28,019) versus untimely, $7729 (0-52,720), p=0.01. CONCLUSIONS: Timely palliative medicine consultation was associated with lower ACE scores and direct hospital costs. Prospective evaluation is needed to validate the impact of palliative medicine consultation on quality of life and healthcare costs.

Mental health service use in children at risk of significant harm: A record linkage study of a child protection register.

Children with experience of maltreatment, abuse or neglect have higher prevalence of poor mental health. In the United Kingdom, child protection services identify children at risk of significant harm on the Child Protection Register (CPR) and intervene to reduce risk. Prevalence and incidence of mental health service use among this population of children are not well understood. We analysed records from one Scottish Local Authority's CPR, linked to electronic health records for all children in the broader health board region aged 0-17 years. We described mental health service use among children with a CPR registration using measures of mental health prescribing and referrals to child and adolescent mental health services (CAMHS). We calculated age- and sex-specific incidence rates for comparison with the general population. Between 2012 and 2022, we found 1498 children with a CPR registration, with 69% successfully linked to their health records. 20% were registered before birth and median age at registration was 3 years. Incidence rates in all measures of mental health service use were higher in children with a CPR record across all ages (at outcome) and genders compared to the general population. The largest absolute difference was for boys aged 5-9 with a CPR record, who had 31.8 additional mental health prescriptions per 1000 person-years compared to the general population (50.4 vs. 18.6 prescriptions per 1000 person-years, IRR: 2.7). Girls aged 0-4 years with a CPR registration had the largest relative difference, with a rate of CAMHS referral 5.4 times higher than the general population (12.3 vs. 2.3 per 1000 person-years). Our reproducible record linkage of the CPR to health records reveals an increased risk of mental health service use during childhood. Our findings have relevance to public mental health surveillance, service prioritisation and wider policy aiming to reduce childhood exposure to risk of harm.

Evidence-based clinical practice guideline for the pharmacologic management of acute dental pain in adolescents, adults, and older adults: A report from the American Dental Association Science and Research Institute, the University of Pittsburgh, and the University of Pennsylvania.

BACKGROUND: A panel convened by the American Dental Association Science and Research Institute, the University of Pittsburgh, and the University of Pennsylvania conducted systematic reviews and meta-analyses and formulated evidence-based recommendations for the pharmacologic management of acute dental pain after simple and surgical tooth extraction(s) and for the temporary management (ie, definitive dental treatment not immediately available) of toothache associated with pulp and periapical diseases in adolescents, adults, and older adults. TYPES OF STUDIES REVIEWED: The panel conducted 4 systematic reviews to determine the effect of opioid and nonopioid analgesics, local anesthetics, corticosteroids, and topical anesthetics on acute dental pain. The panel used the Grading of Recommendations, Assessment, Development and Evaluation approach to assess the certainty of the evidence and the Grading of Recommendations, Assessment, Development and Evaluation Evidence-to-Decision Framework to formulate recommendations. RESULTS: The panel formulated recommendations and good practice statements using the best available evidence. There is a beneficial net balance favoring the use of nonopioid medications compared with opioid medications. In particular, nonsteroidal anti-inflammatory drugs alone or in combination with acetaminophen likely provide superior pain relief with a more favorable safety profile than opioids. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Nonopioid medications are first-line therapy for managing acute dental pain after tooth extraction(s) and the temporary management of toothache. The use of opioids should be reserved for clinical situations when the first-line therapy is insufficient to reduce pain or there is contraindication of nonsteroidal anti-inflammatory drugs. Clinicians should avoid the routine use of just-in-case prescribing of opioids and should exert extreme caution when prescribing opioids to adolescents and young adults.

Lipid peroxidation product 4-hydroxy-trans-2-nonenal causes endothelial activation by inducing endoplasmic reticulum stress.

Lipid peroxidation products, such as 4-hydroxy-trans-2-nonenal (HNE), cause endothelial activation, and they increase the adhesion of the endothelium to circulating leukocytes. Nevertheless, the mechanisms underlying these effects remain unclear. We observed that in HNE-treated human umbilical vein endothelial cells, some of the protein-HNE adducts colocalize with the endoplasmic reticulum (ER) and that HNE forms covalent adducts with several ER chaperones that assist in protein folding. We also found that at concentrations that did not induce apoptosis or necrosis, HNE activated the unfolded protein response, leading to an increase in XBP-1 splicing, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α, and the induction of ATF3 and ATF4. This increase in eukaryotic translation initiation factor 2α phosphorylation was prevented by transfection with protein kinase-like ER kinase siRNA. Treatment with HNE increased the expression of the ER chaperones, GRP78 and HERP. Exposure to HNE led to a depletion of reduced glutathione and an increase in the production of reactive oxygen species (ROS); however, glutathione depletion and ROS production by tert-butyl-hydroperoxide did not trigger the unfolded protein response. Pretreatment with a chemical chaperone, phenylbutyric acid, or adenoviral transfection with ATF6 attenuated HNE-induced monocyte adhesion and IL-8 induction. Moreover, phenylbutyric acid and taurine-conjugated ursodeoxycholic acid attenuated HNE-induced leukocyte rolling and their firm adhesion to the endothelium in rat cremaster muscle. These data suggest that endothelial activation by HNE is mediated in part by ER stress, induced by mechanisms independent of ROS production or glutathione depletion. The induction of ER stress may be a significant cause of vascular inflammation induced by products of oxidized lipids.

End-of-life care of women with gynecologic malignancies: a pilot study.

OBJECTIVE: There are limited data regarding the end-of-life care for women with gynecologic malignancies. We set out to generate pilot data describing the care that women with gynecologic malignancies received in the last 6 months of life. Patient demographics, patterns of care, and utilization of palliative medicine consultation services were evaluated. METHODS: One hundred patients who died of gynecologic malignancies were identified in our institutional database. Only patients who had received treatment with a gynecologic oncologist within 1 year of death were included. Medical records were reviewed for relevant information. Data were abstracted from the electronic medical record, and analyses were made using Student t test and Mann-Whitney U test with SPSS software. RESULTS: The mean age of patients was 60 years (range, 30-94 years). Racial/ethnic distribution was as follows: 38%, white; 34%, black; and 15%, Hispanic. Seventy-five percent of patients received chemotherapy within the last 6 months of life, and 30% received chemotherapy within the last 6 weeks of life. The median number of days hospitalized during the last 6 months of life was 24 (range, 0-183 days). During the last 6 months of life, 19% were admitted to the intensive care unit, 17% were intubated, 5% had terminal extubation, and 13% had cardiopulmonary resuscitative efforts. Sixty-four percent had a family meeting, 50% utilized hospice care, and 49% had palliative medicine consultations. There was a significant difference in hospice utilization when comparison was made between patients who had 14 days or more from consultation until death versus patients who had 14 days or less or no consultation, 21 (72%) versus 29 (41%), P = 0.004. Patients who were single were less likely to have a palliative medicine consultation, P = 0.005. CONCLUSIONS: End-of-life care for patients with gynecologic malignancies often includes futile, aggressive treatments and invasive procedures. It is unknown whether these measures contribute to longevity or quality of life. These pilot data suggest that factors for implementation of timely hospice referral, family support, and legacy building should include specialists trained in palliative medicine.

A case report of an 18-year-old receiving nebulized lidocaine for treatment of COVID-19 cough.

An 18-year-old girl presenting with respiratory and gastrointestinal symptoms was found to have COVID-19 pneumonia and severe acute respiratory distress syndrome (ARDS). She was transferred to our pediatric intensive care unit (PICU) for ongoing mechanical ventilation and initiation of venovenous extracorporeal membrane oxygenation (VV-ECMO) for management of progressive hypoxic respiratory failure. She developed a worsening cough with associated life-threatening desaturation events that impaired ECMO flow and required deep sedation. Despite multiple sedative agents, our patient continued to have frequent coughing episodes with associated tachycardia, hypertension, and hypoxemia. The PICU team started nebulized lidocaine 1% 4 mL (40 mg) every 6 hours with albuterol pretreatment, gabapentin, and scheduled ipratropium. Lidocaine levels were <1 mcg/mL throughout the treatment duration. Nebulized lidocaine was stopped after 18 days given improvement in coughing episode severity. Our patient is one of the first reports of an adolescent patient receiving nebulized lidocaine for COVID-19 associated cough. Administration of nebulized lidocaine was well tolerated in this patient without adverse effects and was associated with decreased sedation needs. Given the widespread impact of the COVID-19 pandemic and its sequelae in pediatric, adolescent, and adult patients, additional research is warranted to explore options for management of COVID-19 associated cough.

Use of Continuous Ketamine Infusion as an Adjunctive Agent in Young Infants With Refractory and Super Refractory Status Epilepticus: A Case Series.

Continuous ketamine infusions have been studied as an adjunctive agent for refractory status epilepticus (RSE) and super refractory status epilepticus (SRSE) in older children and adults. However, minimal information exists on the efficacy, safety, and dosing for continuous ketamine in young infants. We present the clinical course of 3 young infants with RSE and SRSE who received continuous ketamine in conjunction with other antiseizure medications. The condition of these patients was refractory to an average of 6 antiseizure medications before initiation of continuous ketamine infusion. For each patient, a continuous ketamine infusion was initiated at a rate of 1 mg/kg/hr with 1 patient requiring titration to a maximum of 6 mg/kg/hr. In 1 case, the concomitant use of continuous ketamine allowed for a reduction in the benzodiazepine continuous infusion rate. In all cases, ketamine was well tolerated especially in the setting of hemodynamic instability. Ketamine may provide a safe adjunct in the acute setting in severe RSE and SRSE. This is the first case series to document the use of continuous ketamine as a treatment modality in young infants with RSE or SRSE secondary to various underlying etiologies, without adverse events. Further studies are needed to evaluate the long-term safety and efficacy of continuous ketamine in this patient population.

Evidence-based clinical practice guideline for the pharmacologic management of acute dental pain in children: A report from the American Dental Association Science and Research Institute, the University of Pittsburgh School of Dental Medicine, and the Center for Integrative Global Oral Health at the University of Pennsylvania.

BACKGROUND: A guideline panel convened by the American Dental Association Council on Scientific Affairs, American Dental Association Science and Research Institute, University of Pittsburgh School of Dental Medicine, and Center for Integrative Global Oral Health at the University of Pennsylvania conducted a systematic review and meta-analyses and formulated evidence-based recommendations for the pharmacologic management of acute dental pain after 1 or more simple and surgical tooth extractions and the temporary management of toothache (that is, when definitive dental treatment not immediately available) associated with pulp and furcation or periapical diseases in children (< 12 years). TYPES OF STUDIES REVIEWED: The authors conducted a systematic review to determine the effect of analgesics and corticosteroids in managing acute dental pain. They used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence and the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework to formulate recommendations. RESULTS: The panel formulated 7 recommendations and 5 good practice statements across conditions. There is a small beneficial net balance favoring the use of nonsteroidal anti-inflammatory drugs alone or in combination with acetaminophen compared with not providing analgesic therapy. There is no available evidence regarding the effect of corticosteroids on acute pain after surgical tooth extractions in children. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Nonopioid medications, specifically nonsteroidal anti-inflammatory drugs like ibuprofen and naproxen alone or in combination with acetaminophen, are recommended for managing acute dental pain after 1 or more tooth extractions (that is, simple and surgical) and the temporary management of toothache in children (conditional recommendation, very low certainty). According to the US Food and Drug Administration, the use of codeine and tramadol in children for managing acute pain is contraindicated.

Delirium: a very common problem you may not recognize.

Older adults with multiple pre-existing conditions are admitted to hospitals with acute illnesses and injuries every day. Delirium is not recognized by clinicians across health care settings. With awareness of risk factors and knowledge of delirium, nurses can play a pivotal role in the early identification, treatment, and, most important, prevention of delirium in older adults. Nurses often display a lack of knowledge related to delirium and the complex symptoms that appear differently in the presence of other complicating co-morbid conditions in aging adults. Nurses play a crucial role in keeping patients safe and ensuring optimal outcomes, regardless of the setting. With the growing population of older adults and the expected increases in chronic illness and dementia, delirium is a problem nurses are likely to experience in all practice settings. Knowing what to look for facilitates recognizing the risk and acting early to minimize (or even prevent) delirium.

Implementation and analysis of an enhanced screening and testing protocol for prediabetes in a dental school patient population.

OBJECTIVES: This project aimed to enhance the identification of patients at-risk for prediabetes or diabetes within a dental school patient population by introduction of a modified screening tool and related training of dental residents and students. METHODS: The American Diabetes Association Risk Tool (ADART) was modified by addition of three diabetes-linked oral health questions. Of the 1477 dental patients screened, 551 (37.3%) indicated an at-risk status using the modified tool. A subset of 138 patients received follow-up chairside HbA1c blood testing conducted by dental residents and students. Data was analysed to determine a) the influence of the modifications on the tool's discrimination strength and b) change in the tool's predictive value. RESULTS: The addition of the 3 oral health questions to the 7-item ADART resulted in a 9.4% increase in identification of patients at-risk for pre-diabetes/diabetes. The predictive value of the tool remained stable. Residents and students successfully incorporated the new screening activities within their assigned clinics. CONCLUSIONS: This project demonstrates that screening for risk for prediabetes/diabetes is both prudent and practical in the dental setting. Dental personnel, including trainees, can successfully incorporate enhanced screening methods within their traditional activities. Further, screening tools used in the dental setting might be enhanced by inclusion of certain oral health variables associated with diabetes. These findings add to emerging knowledge on the importance of screening for prediabetes/diabetes in dental settings and have particular relevance and application to institutional practice.

Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.

RATIONALE: Studies have shown that reducing sedation of critically ill patients shortens time on the ventilator and in the intensive care unit (ICU). Little is known, however, of how such strategies affect long-term cognitive, psychological, and functional outcomes. OBJECTIVES: To determine the long-term effects of a wake up and breathe protocol that interrupts and reduces sedative exposure in the ICU. METHODS: In this a priori planned substudy conducted at one tertiary care hospital during the Awakening and Breathing Controlled Trial, a multicenter randomized controlled trial, we assessed cognitive, psychological, and functional/quality-of-life outcomes 3 and 12 months postdischarge among 180 medical ICU patients randomized to paired daily spontaneous awakening trials with spontaneous breathing trials (SBTs) or to sedation per usual care plus daily SBTs. MEASUREMENTS AND MAIN RESULTS: Cognitive impairment was less common in the intervention group at 3-month follow-up (absolute risk reduction, 20.2%; 95% confidence interval, 1.5-36.1%; P = 0.03) but not at 12-month follow-up (absolute risk reduction, -1.9%; 95% CI, -21.3 to 27.1%; P = 0.89). Composite cognitive scores, alternatively, were similar in the two groups at 3-month and 12-month follow-up (P = 0.80 and 0.61, respectively), as were symptoms of depression (P = 0.59 and 0.82) and posttraumatic stress disorder (P = 0.59 and 0.97). Activities of daily living, functional status, and mental and physical quality of life were similar between groups throughout follow-up. CONCLUSIONS: In this trial, management of mechanically ventilated medical ICU patients with a wake up and breathe protocol resulted in similar cognitive, psychological, and functional outcomes among patients tested 3 and 12 months post-ICU. The proven benefits of this protocol, including improved 1-year survival, were not offset by adverse long-term outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 00097630).

Is necrotizing enterocolitis the same disease in term and preterm infants?

INTRODUCTION: Necrotizing enterocolitis predominantly affects preterm (PT) infants. The paucity of data regarding the clinical course in term infants makes it difficult to predict outcomes and counsel families. To identify predisposing factors and gain a better understanding of the clinical course of NEC in term infants, we reviewed our experience with term infants and compared it to outcomes in PT infants. METHODS: We performed a 10 year retrospective review of all infants admitted to our NICU with Bell stage 2 NEC or greater. Infants < 37 weeks gestation were considered PT. Term and PT infant comorbidities, outcomes and intraoperative findings were compared. RESULTS: Fifteen (12%) of 125 infants were term. Compared to PT infants, term infants were more likely to have congenital heart disease (33% term vs. 10% PT, p = 0.02) and develop NEC sooner (4 days in term vs. 17 days in PT, p < 0.001) but were less likely to require operative intervention (20% term vs. 38% PT; p = 0.17). There was no significant difference in Bell stage, survival and development of intestinal failure. NEC totalis occurred exclusively in PT infants. CONCLUSIONS: NEC in term infants has unique clinical features that distinguishes it from NEC in PT infants.

The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation.

Nitrogen-containing bisphosphonates (N-BPs) are effective antiosteolytic agents in patients with multiple myeloma. Preclinical studies have also demonstrated that these agents have direct antitumor effects in vitro and can reduce tumor burden in a variety of animal models, although it is not clear whether such effects are caused by direct actions on tumor cells or by inhibition of bone resorption. N-BPs prevent bone destruction in myeloma by inhibiting the enzyme farnesyl pyrophosphate synthase in osteoclasts, thereby preventing the prenylation of small GTPase signaling proteins. In this study, utilizing a plasmacytoma xenograft model without complicating skeletal lesions, treatment with zoledronic acid (ZOL) led to significant prolongation of survival in severe combined immunodeficiency mice inoculated with human INA-6 plasma cells. Following treatment with a clinically relevant dose of ZOL, histological analysis of INA-6 tumors from the peritoneal cavity revealed extensive areas of apoptosis associated with poly (ADP-ribose) polymerase cleavage. Furthermore, Western blot analysis of tumor homogenates demonstrated the accumulation of unprenylated Rap1A, indicative of the uptake of ZOL by nonskeletal tumors and inhibition of farnesyl pyrophosphate synthase. These studies provide, for the first time, clear evidence that N-BPs have direct antitumor effects in plasma cell tumors in vivo and this is executed by a molecular mechanism similar to that observed in osteoclasts.