Real-world evidence study on tolerance and growth in infants fed an infant formula with two human milk oligosaccharides vs mixed fed and exclusively breastfed infants.

INTRODUCTION: Human milk oligosaccharides (HMOs) are important components of human milk having diverse functions in the development of infants. Randomized controlled trials (RCTs) have demonstrated that infant formulas with the HMOs 2'-fucosyllactose (2'FL) and lacto-N-neotetraose (LNnT) are safe, well-tolerated, and support normal growth. This study aimed to generate real-world evidence (RWE) on growth and gastrointestinal (GI) tolerance in infants consuming a formula with 1 g/L 2'FL and 0.5 g/L LNnT, including a mixed feeding group not studied before in RCTs. PARTICIPANTS AND METHODS: This 8-week open-label prospective multicenter study was conducted in Germany and Austria, and included groups of healthy, exclusively breastfed infants (BF), exclusively formula-fed infants (FF) who received the HMO-formula, and infants mixed fed with both HMO formula and human milk (MF). Co-primary outcomes were anthropometry and gastrointestinal tolerance via validated Infant Gastrointestinal Symptom Questionnaire (IGSQ). Secondary outcomes included formula satisfaction and adverse events (AEs). RESULTS: One-hundred six infants completed the study (46 FF, 22 MF, and 38 BF). Mean anthropometric z-scores were comparable between groups and generally within ± 0.5 of WHO medians at week 8. IGSQ composite scores demonstrated good GI tolerance in all groups with no significant group differences at week 4 or 8. IGSQ composite scores in FF improved during the course of the study and parents provided high satisfaction ratings for the HMO-formula. Four potentially product-related AEs were reported in FF (no in MF). CONCLUSIONS: In this RWE study examining an infant formula with HMOs, growth and GI tolerance outcomes were confirming the good tolerance and safety of this early feeding option previously reported in RCTs.

Mechanistic and Kinetic Factors of ortho-Benzyne Formation in Hexadehydro-Diels-Alder (HDDA) Reactions.

With the rapid development of the hexadehydro-Diels-Alder reaction (HDDA) from its first discovery in 1997, the question of whether a concerted or stepwise mechanism better describes the thermally activated formation of ortho-benzyne from a diyne and a diynophile has been debated. Mechanistic and kinetic investigations were able to show that this is not a black or white situation, as minor changes can tip the balance. For that reason, especially, linked yne-diynes were studied to examine steric, electronic, and radical-stabilizing effects of their terminal substituents on the reaction mechanism and kinetics. Furthermore, the influence of the nature of the linker on the HDDA reaction was explored. The more recently discovered photochemical HDDA reaction also gives ortho-arynes, which display the same reactivity as the thermally generated ones, but their formation might not proceed by the same mechanism. This minireview summarizes the current state of mechanistic understanding of the HDDA reaction.

Highly Conjugated π-Systems Arising from Cannibalistic Hexadehydro-Diels-Alder Couplings: Cleavage of C-C Single and Triple Bonds.

We have investigated the cannibalistic self-trapping reaction of an ortho-benzyne derivative generated from 1,11-bis(p-tolyl)undeca-1,3,8,10-tetrayne in an HDDA reaction. Without adding any specific trapping agent, the highly reactive benzyne is trapped by another bisdiyne molecule in at least three different modes. We have isolated and characterized the resulting products and performed high-level calculations concerning the reaction mechanism. During the cannibalistic self-trapping process, either a C≡C triple bond or an sp-sp3 C-C single bond is cleaved. Up to seven rings and nine C-C bonds are formed starting from two 1,11-bis(p-tolyl)undeca-1,3,8,10-tetrayne molecules. Our experiments and calculations provide considerable insight into the variety of reaction pathways which the ortho-benzyne derivative, generated from a bisdiyne, can take when reacting with another bisdiyne molecule.

Regio- and Stereoselective Synthesis of 1,1-Diborylalkenes via Brønsted Base-Catalyzed Mixed Diboration of Alkynyl Esters and Amides with BpinBdan.

The NaOtBu-catalyzed mixed 1,1-diboration of terminal alkynes using the unsymmetrical diboron reagent BpinBdan (pin = pinacolato; dan = 1,8-diaminonaphthalene) proceeds in a regio- and stereoselective fashion affording moderate to high yields of 1,1-diborylalkenes bearing orthogonal boron protecting groups. It is applicable to gram-scale synthesis without loss of yield or selectivity. The mixed 1,1-diborylalkene products can be utilized in Suzuki-Miyaura cross-coupling reactions which take place selectivly at the C-B site. DFT calculations suggest the NaOtBu-catalyzed mixed 1,1-diboration of alkynes occurs through deprotonation of the terminal alkyne, stepwise addition of BpinBdan to the terminal carbon followed by protonation with tBuOH. Experimentally observed selective formation of (Z)-diborylalkenes is supported by our theoretical studies.

Direct observation of o-benzyne formation in photochemical hexadehydro-Diels-Alder (hν-HDDA) reactions.

Reactive ortho-benzyne derivatives are believed to be the initial products of liquid-phase [4 + 2]-cycloadditions between a 1,3-diyne and an alkyne via what is known as a hexadehydro-Diels-Alder (HDDA) reaction. The UV/VIS spectroscopic observation of o-benzyne derivatives and their photochemical dynamics in solution, however, have not been reported previously. Herein, we report direct UV/VIS spectroscopic evidence for the existence of an o-benzyne in solution, and establish the dynamics of its formation in a photoinduced reaction. For this purpose, we investigated a bis-diyne compound using femtosecond transient absorption spectroscopy in the ultraviolet/visible region. In the first step, we observe excited-state isomerization on a sub-10 ps time scale. For identification of the o-benzyne species formed within 50-70 ps, and the corresponding photochemical hexadehydro-Diels-Alder (hν-HDDA) reactions, we employed two intermolecular trapping strategies. In the first case, the o-benzyne was trapped by a second bis-diyne, i.e., self-trapping. The self-trapping products were then identified in the transient absorption experiments by comparing their spectral features to those of the isolated products. In the second case, we used perylene for trapping and reconstructed the spectrum of the trapping product by removing the contribution of irrelevant species from the experimentally observed spectra. Taken together, the UV/VIS spectroscopic data provide a consistent picture for o-benzyne derivatives in solution as the products of photo-initiated HDDA reactions, and we deduce the time scales for their formation.

Does it matter who places the intravenous? An inter-professional comparison of prehospital intravenous access difficulties between physicians and paramedics.

OBJECTIVES: Depending on the specific national emergency medical systems, venous cannulations may be performed by physicians, paramedics or both alike. Difficulties in the establishment of vascular access can lead to delayed treatment and transport. Our study investigates possible inter-professional differences in the difficulties of prehospital venous cannulation. METHODS: Paramedics were interviewed for their personal attitudes towards and experiences in venous access. We analysed 47 candidate predictor variables in terms of cannulation failure and exceedance of a 2 min time threshold. Multivariable logistic regression models were fitted for variables of potential predictive value (P<0.25) and evaluated by the area under the curve (AUC>0.60) of their respective receiver operating characteristic curve. Results were compared with previously published data from emergency physicians. RESULTS: A total of 552 cannulations were included in our study. All 146 participants voted that paramedics should be eligible to perform venous catheterizations. Despite ample experience in the task, almost half of them considered prehospital venous cannulations more difficult than those performed in hospital. However, the multivariable logistic regression found only patient-related and puncture site factors to be predictive of cannulation failure (patient age, vein palpability with tourniquet, insufficient ambient lighting: model AUC: 0.72) or cannulation delay (vein palpability with tourniquet: model AUC: 0.60). CONCLUSION: Our study shows that venous cannulation is well established among paramedics. It presents itself with similar difficulties across medical professions. Not the numerous specific circumstances of prehospital emergency care, but universal factors inherent to the task will influence the success at venous catheterization.

Early detection of temporomandibular joint arthritis in children with juvenile idiopathic arthritis - the role of contrast-enhanced MRI.

BACKGROUND: Early treatment of temporomandibular joint (TMJ) arthritis is crucial in children with juvenile idiopathic arthritis (JIA) to prevent permanent functional impairment. As involvement of TMJs is often asymptomatic, contrast-enhanced MRI is regarded as the most sensitive noninvasive diagnostic tool. OBJECTIVE: To evaluate the degree of contrast enhancement in TMJs of children and adolescents with JIA in comparison to normal controls from a previous study. MATERIALS AND METHODS: Dynamic contrast-enhanced MRI of 50 children and adolescents with JIA (6.3 to 18 years of age; mean: 12 years) were retrospectively analysed. We assessed morphological abnormalities and postcontrast time-intensity curves of the soft joint tissue and the mandibular condyle. Ratios were calculated to quantify postcontrast signal intensities (SI) in relation to precontrast SI at initial (1 min postcontrast) and maximum (6 min postcontrast) increase. RESULTS: Time-intensity curves followed similar biphasic patterns in normal and pathological joints. In joints with morphological signs of arthritis, mean SI ratios were on average higher than in normal joints of the reference group, but ranges of values widely overlapped. Arthritis: mean initial increase of SI 62% (±2 S.D. 18-105%), mean maximum SI 106% higher than precontrast (±2 S.D. 46-166%). Normal: mean initial increase of SI 49% (±2 S.D. 14- 85%), mean maximum of SI 73% (±2 S.D. 23-123%). CONCLUSIONS: Given this considerable overlap of results in dynamic contrast-enhanced MRI, the degree of contrast enhancement alone did not allow differentiation between TMJs with and without signs of inflammation. Thickening of the soft joint tissue seems to remain the earliest sign to reliably indicate TMJ arthritis.

Cervical spine involvement in patients with juvenile idiopathic arthritis - MRI follow-up study.

BACKGROUND: To describe MRI and clinical findings in patients with juvenile idiopathic arthritis with cervical spine involvement at onset and follow-up under therapy. METHODS: 13 patients with signs of cervical spine involvement in juvenile idiopathic arthritis with a median disease duration of 1.7 years were included in the study. Clinical records and MR images were retrospectively analyzed according to symptoms and findings concerning the cervical spine. RESULTS: At the onset of cervical spine involvement all patients showed limited range of motion, whereas only 5 of them complained of pain. In MR images joint hyperintensity, contrast enhancement, malalignment, ankylosis, erosion and narrowing of the spinal canal at cranio-cervical junction were found at 28, 32, 15, 2, 2 and 3 sites in 12 (93%), 13 (100%), 8 (62%), 2 (15%), 2 and 3 (20%) patients respectively. 3 of the 5 patients with pain (60%) showed ankylosis, erosions or narrowing of the spinal canal at cranio-cervical junction on MRI. At follow-up - after a median disease duration of cervical spine arthritis of 2.1 years and a variable duration of treatment with methotrexate (all patients) and biological agents (12 patients) - joint hyperintensity, enhancement and malalignment decreased to 15, 19 and 6 sites in 10 (77%), 11 (85%) and 3 (20%) patients respectively whereas ankylosis, erosion and narrowing of the spinal canal at cranio-cervical junction increased to 7, 6 and 4 sites in 3 (20%), 4 (31%) and 4 patients respectively. Pain was no longer reported, but 9 of 13 (69%) patients still had a limited range of motion with 6 of them (46%) showing skeletal changes on MRI. CONCLUSIONS: This first MRI based follow-up study shows that cervical spine arthritis can follow a severe disease course in juvenile arthritis. While malalignments and inflammation sites decreased osseous changes with erosions, ankylosis, and narrowing of the spinal canal increased under treatment despite only minor subjective complaints. Therefore close MRI monitoring of these patients appears to be reasonable.

Impaired suppression of synovial fluid CD4+CD25- T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ Treg cells.

OBJECTIVE: Natural CD4+CD25+FoxP3+ Treg cells play a crucial role in maintaining immune homeostasis and controlling autoimmunity. In patients with juvenile idiopathic arthritis (JIA), inflammation occurs despite the increased total numbers of Treg cells in the synovial fluid (SF) compared to the peripheral blood (PB). This study was undertaken to investigate the phenotype of CD4+ T cells in PB and SF from JIA patients, the function of synovial Treg cells, and the sensitivity of PB and SF CD4+CD25- effector T cells to the immunoregulatory properties of Treg cells, and to study the suppression of cytokine secretion from SF effector T cells by Treg cells. METHODS: The phenotypes of effector T cells and Treg cells of PB and SF from JIA patients and healthy donors were determined by flow cytometry. The functionality of isolated Treg cells and effector T cells was quantified in (3) H-thymidine proliferation assays. Cytokine levels were analyzed using Bio-Plex Pro assay. RESULTS: Compared to PB, SF showed significantly elevated numbers of activated and differentiated CD4+CD45RO+ T cells. Sensitivity of SF effector T cells to the suppressive effects of Treg cells from both PB and SF was impaired, correlating inversely with the expression of CD69 and HLA-DR. However, SF effector T cell cytokine secretion was partly suppressed by SF Treg cells. CONCLUSION: Our findings indicate that regulation is impaired in the SF of patients with JIA, as shown by the resistance of effector T cells to immunoregulation by functional Treg cells. This resistance of the SF effector T cells might be due to their activated phenotype.

Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate.

There are only a few studies that address the frequency and type of spinal involvement in patients with chronic recurrent multifocal osteomyelitis (CRMO) as well as the outcome of these patients treated with pamidronate (PAM). We performed a retrospective study on patients with CRMO and analyzed clinical and pain assessments as well as regional and whole body MRI findings and compared with posttreatment findings. Of 102 children and adolescents with CRMO, 27 (26%) had involvement of the spine. Vertebral deformities were seen in 14 of these 27 patients, scoliosis or kyphosis in 6. After routine whole body MRI, 19 complained of back pain, whereas eight were asymptomatic with spinal lesions detected incidentally. A total of 72 spinal lesions were detected, thoracic vertebrae being the most commonly affected. Seven patients were treated with PAM; all of whom had vertebral deformities and ongoing back pain. Pain resolution was achieved within 3 months of PAM treatment in every case. One patient subsequently developed a pain amplification syndrome. Repeat MRI performed at a mean interval of 13 months revealed partial or complete resolution of vertebral hyperintensities in every patient. Improvement of vertebral height was seen in a total of three vertebrae in two patients. Severe side effects were not observed. In conclusion, we demonstrated that spinal involvement and associated vertebral deformities with or without kyphoscoliosis are not rare in CRMO, and PAM appears to be an effective and safe treatment for this condition. Although controlled studies are urgently needed, the use of PAM for refractory CRMO with extended spinal involvement (vertebral deformities, kyphosis, and scoliosis) should be considered, especially after failing of conventional therapy.

Discussions about preventive services: a qualitative study.

BACKGROUND: Elderly minority patients are less likely to receive influenza vaccination and colorectal cancer screening than are other patients. Communication between primary care providers (PCPs) and patients may affect service receipt. METHODS: Encounters between 7 PCPs and 18 elderly patients were observed and audiotaped at 2 community health centers. Three investigators coded transcribed audiotapes and field notes. We used qualitative analysis to identify specific potential barriers to completion of preventive services and to highlight examples of how physicians used patient-centered communication and other facilitation strategies to overcome those barriers. RESULTS: Sharing of power and responsibility, the use of empathy, and treating the patient like a person were all important communication strategies which seemed to help address barriers to vaccination and colonoscopy. Other potential facilitators of receipt of influenza vaccine included (1) cultural competence, (2) PCP introduction of the discussion, (3) persistence of the PCP (revisiting the topic throughout the visit), (4) rapport and trust between the patient and PCP, and (5) PCP vaccination of the patient. PCP persistence as well as rapport and trust also appeared to facilitate receipt of colorectal cancer screening. CONCLUSION: Several communications strategies appeared to facilitate PCP communications with older patients to promote acceptance of flu vaccination and colorectal cancer screening. These strategies should be studied with larger samples to determine which are most predictive of compliance with prevention recommendations.

Alternative comorbidity adjustors for the Medicare inpatient psychiatric facility PPS.

The inpatient psychiatric facility prospective payment system (IPF-PPS), provides per diem payments for psychiatric hospitals and units, including 17 comorbid condition payment adjustors that cover 11 percent of patients. This study identifies an alternative set of 16 adjustors identifying three times as many high-cost patients and evaluates the improved predictive power in log per diem cost regression models. A model using the IPF-PPS adjustors achieved 8.8 percent of the feasible improvement from a no-adjustor baseline, while the alternative adjustors achieved 22.1 percent of the feasible improvement. The current adjustors may therefore be too restrictive, resulting in systematic over- or underpayment for many patients.

Economic grand rounds: Variation in staffing and activities in psychiatric inpatient units.

In 1999 the Balanced Budget Refinement Act mandated the development of a per diem prospective payment for all psychiatric inpatients. To assist Medicare in developing a per diem patient-based payment system, this study surveyed a representative sample of psychiatric inpatient units in 40 facilities for one week in 2001 through 2003 to determine how units are staffed and how staff members spend their time caring for patients. On general adult units, psychiatric staff averaged ten hours per patient per 24-hour day, roughly 55 percent of staff time was involved in psychiatric care, medical-related nursing and personal care accounted for 10 percent of staff time, and milieu time took up 34 percent of staff time. Small general adult and geriatric units required 50 percent more staff time per patient than large units. More research is needed to determine how recent changes in the method of payment affect these facilities.

Patient casemix classification for medicare psychiatric prospective payment.

OBJECTIVE: For a proposed Medicare prospective payment system for inpatient psychiatric facility treatment, the authors developed a casemix classification to capture differences in patients' real daily resource use. METHOD: Primary data on patient characteristics and daily time spent in various activities were collected in a survey of 696 patients from 40 inpatient psychiatric facilities. Survey data were combined with Medicare claims data to estimate intensity-adjusted daily cost. Classification and Regression Trees (CART) analysis of average daily routine and ancillary costs yielded several hierarchical classification groupings. Regression analysis was used to control for facility and day-of-stay effects in order to compare hierarchical models with models based on the recently proposed payment system of the Centers for Medicare & Medicaid Services. RESULTS: CART analysis identified a small set of patient characteristics strongly associated with higher daily costs, including age, psychiatric diagnosis, deficits in daily living activities, and detox or ECT use. A parsimonious, 16-group, fully interactive model that used five major DSM-IV categories and stratified by age, illness severity, deficits in daily living activities, dangerousness, and use of ECT explained 40% (out of a possible 76%) of daily cost variation not attributable to idiosyncratic daily changes within patients. A noninteractive model based on diagnosis-related groups, age, and medical comorbidity had explanatory power of only 32%. CONCLUSIONS: A regression model with 16 casemix groups restricted to using "appropriate" payment variables (i.e., those with clinical face validity and low administrative burden that are easily validated and provide proper care incentives) produced more efficient and equitable payments than did a noninteractive system based on diagnosis-related groups.

Variation in patient routine costliness in U.S. psychiatric facilities.

BACKGROUND: The Balanced Budget Refinement Act of 1999 included a Congressional mandate to develop a patient-level case mix prospective payment system (PPS) for all Medicare beneficiaries treated in PPS-exempt psychiatric facilities. Payment levels by case mix category have been proposed by the government based on claims and facility cost reports. Because of claims data limitations, these levels do not account for patient-specific staffing costs within a facility's routine units, nor are certain key patient characteristics considered for higher payment. AIMS OF THE STUDY: This study uses novel primary data to quantify heretofore unmeasured differences in daily staffing intensity on routine units among Medicare patients. The data are used to test for compression (or narrowing) in case mix payment weights that would result from using only Medicare claims and facility cost reports to quantify daily routine costliness. METHODS: Primary data on patient and staff times in over 20 activities were collected from 40 psychiatric facilities and 66 psychiatric units, nation-wide. Patient times were reported on all inpatients on each shift over a 7-day study period. A resource intensity measure (in Registered Nurse (RN)-equivalent minutes) was constructed on a daily basis for 4,149 Medicare and 4,667 non-Medicare patient days. The routine measure is converted into daily cost using cost report per diems and ancillary costs added using submitted claims. Descriptive tables isolate key cost drivers for Medicare patients. Classification and Regression Trees (CART) clustering identifies 16 potential case mix groups. Multivariate regression is used to compare case mix, day-of-stay, and facility effects using 4 alternative measures of daily routine and ancillary costs. RESULTS: Patient daily routine intensity of care is found to vary by a factor of 3 or more between the top and bottom 10% of days. Medicare patient days were 12.5% more staff intensive than non-Medicare days, which may have been due to age and other differences. Older dementia and "residual diagnosis" patients are more intensive while schizophrenia and substance-related patients are less intensive. Age, psychiatric and medical severity, deficits in Activities in Daily Living (ADLs), dangerous behaviors, and electroconvulsive therapy (ECT) also contribute substantially to higher staffing intensity. Other patient characteristics were insignificant within broad diagnostic groups. Routine costs based on a single facility per diem produced narrower case mix cost differences--often by a factor of 2 or more--for 10 of 12 groups with significantly higher costs. Adding patient-specific ancillary to uniform per diem costs only marginally decompressed costs. Day of-stay costs were similarly compressed when using only cost reports. DISCUSSION: Claims-based costing using Medicare cost reports unduly compresses (narrows) estimates of inter-group case mix cost differences. Also, by not capturing ADL deficits and dangerous behaviors, administrative data sets fail to identify small, but very resource intensive, patient groups. ECT treatment regimens, although rare, significantly increase costs on a daily basis. IMPLICATIONS FOR HEALTH POLICIES: Medicare's recently proposed prospective payment system for psychiatric inpatients uses claims-based costing methods based on widely available administrative data. Consequently, fewer high cost groups are identified due to non-reported patient characteristics such as ADL deficits. Moreover, inter-group relative cost differences are likely understated. It is also possible that any standardized dollar amount applied to group relative weights is understated because Medicare patients appear more intensive per day on routine units. IMPLICATIONS FOR FUTURE RESEARCH: Larger primary samples of special psychiatric units (e.g., med-psych, child/adolescent) could improve estimates of daily routine costliness. Larger samples could also support stronger tests of case mix and cost differences by facility type and teaching status. Medical records information on non-Medicare patients could quantify any systematic differences in average daily costs holding case mix constant. Similar primary studies of psychiatric patients treated outside PPS-exempt units in acute general hospitals could result in a fully integrated payment system for all mentally ill Medicare patients, thereby avoiding payment inefficiencies and inequities.

Characteristics of high staff intensive Medicare psychiatric inpatients.

Previous analyses of the costs of Medicare psychiatric inpatients have been limited by the use of claims and provider cost reports that fail to quantify differences in patient characteristics and routine costs. This article uses new primary data from 66 psychiatric inpatient units in 40 facilities nationwide to measure the times staff spend in therapeutic and other activities caring for Medicare patients. Patient days are divided into two groups of very high and low staff intensity and patient characteristics compared in each group. Results identify key patient characteristics associated with high staffing days, including old age, dementia and cognitive impairment, severe psychiatric diagnosis, deficits in activities of daily living (ADLs), and assaultive or agitated behaviors. Policy implications and suggested enhancements are made with regard to the proposed CMS case-mix classification system based on claims data alone.

Possible association of non-binding of HSP70 to HLA-DRB1 peptide sequences and protection from rheumatoid arthritis.

The beta-chains of HLA-DR molecules associated with susceptibility to rheumatoid arthritis (RA) share a common amino acid sequence in their third hypervariable region at position 70-74. This shared epitope could either contribute to preferential binding of a given disease-associated peptide, be involved in disease-induction by molecular mimicry or, by binding to heat shock proteins, influence antigen presentation. It is known that the Escherichia coli M(r)70,000 heat shock protein DnaK can bind peptides from the shared epitope. Using a highly sensitive method, we show that peptides covering the third hypervariable region of associated, but also most of the non-associated HLA-DR alleles, bind to DnaK. Similar binding specificities could be found for the constitutively expressed mammalian M(r)70,000 heat shock protein Hsc73 and the inducible mammalian Hsp72. However, peptides containing the amino acid sequence DERAA, found in HLA-DR alleles and strongly associated with protection from RA, did not bind any HSP70. Thus, our results suggest a possible association of non-binding of HSP70 to HLA-DR molecules or its 70-74 fragments and protection from RA.