The data project: a shared approach between stakeholders of the healthcare system in definition of a therapeutic algorithm for inflammatory arthritis.

Rheumatic musculoskeletal diseases or RMD [rheumatoid arthritis (RA) and spondyloarthritis (SpA)] are systemic inflammatory diseases for which there are no biomarkers capable of predicting treatments with a higher likelihood of response in naive patients. In addition, the expiration of the anti-TNF blocking drugs' patents has resulted in the availability of anti-TNF biosimilar drugs with the same efficacy and safety than originators but at significantly reduced prices. To guarantee a personalized therapeutic approach to RMD treatment, a board of rheumatologists and stakeholders from the Campania region, Italy, developed a clinically applicable arthritis therapeutic algorithm to guide rheumatologists (DATA project). The general methodology relied on a Delphi technique forecast to produce a set of statements that summarized the experts' consensus. Selected clinical scenarios were discussed in light of the available evidence, and there were two rounds of voting on the therapeutic approaches. Separate discussions were held regarding rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The decision-making factors for each disease were clinical presentation, demographics, and comorbidities. In this paper, we describe a virtuous process between rheumatologists and healthcare system stakeholders that resulted in the development of a shared therapeutic algorithm for RMD patients naive to bDMARDs.

Size-dependent influence of NOx on the growth rates of organic aerosol particles.

Atmospheric new-particle formation (NPF) affects climate by contributing to a large fraction of the cloud condensation nuclei (CCN). Highly oxygenated organic molecules (HOMs) drive the early particle growth and therefore substantially influence the survival of newly formed particles to CCN. Nitrogen oxide (NOx) is known to suppress the NPF driven by HOMs, but the underlying mechanism remains largely unclear. Here, we examine the response of particle growth to the changes of HOM formation caused by NOx. We show that NOx suppresses particle growth in general, but the suppression is rather nonuniform and size dependent, which can be quantitatively explained by the shifted HOM volatility after adding NOx. By illustrating how NOx affects the early growth of new particles, a critical step of CCN formation, our results help provide a refined assessment of the potential climatic effects caused by the diverse changes of NOx level in forest regions around the globe.

Linac4 H⁻ ion sources.

CERN's 160 MeV H(-) linear accelerator (Linac4) is a key constituent of the injector chain upgrade of the Large Hadron Collider that is being installed and commissioned. A cesiated surface ion source prototype is being tested and has delivered a beam intensity of 45 mA within an emittance of 0.3 π ⋅ mm ⋅ mrad. The optimum ratio of the co-extracted electron- to ion-current is below 1 and the best production efficiency, defined as the ratio of the beam current to the 2 MHz RF-power transmitted to the plasma, reached 1.1 mA/kW. The H(-) source prototype and the first tests of the new ion source optics, electron-dump, and front end developed to minimize the beam emittance are presented. A temperature regulated magnetron H(-) source developed by the Brookhaven National Laboratory was built at CERN. The first tests of the magnetron operated at 0.8 Hz repetition rate are described.

Relation of left ventricular diastolic properties to systolic function in arterial hypertension.

BACKGROUND: It is unclear whether impairment of left ventricular (LV) diastolic characteristics is independent of systolic dysfunction. METHODS AND RESULTS: To address this issue, 159 consecutive hypertensive patients (44+/-11 years, 78 obese, 96 women) and 165 normotensive subjects (32+/-11 years, 84 obese, 110 women) were studied with the use of Doppler echocardiography. After adjustment for age, body mass index (BMI), and sex, we found that ejection fraction (EF; M-mode, z-derived) was higher in hypertensive (66. 6+/-5.2%) than in normotensive (63.9+/-4.4%, P<0.0001) subjects, whereas midwall shortening (MS) was lower (hypertensive patients 16. 9+/-2.0%, normotensive subjects 17.8+/-2.2%, P<0.02), even after correction for end-systolic wall stress (P<0.05). Isovolumic relaxation time (IVRT) was greater in hypertensive patients (103+/-14 ms) than in normotensive subjects (78+/-19 ms), as was deceleration time of E velocity and peak A velocity (all P<0.0001). In multivariate analysis, IVRT was unrelated to EF, but a negative relation was found with MS (P<0.001), independent of age, BMI, presence of arterial hypertension, LV geometry, and load (multiple R(2)=0.58). For comparable age, sex distribution, BMI, and blood pressure values, hypertensive patients with lower afterload-adjusted MS exhibited longer IVRT than patients with normal MS (P<0.005). However, IVRT remained higher than in normotensive control subjects after control for LV geometry and load. CONCLUSIONS: Doppler indices of delayed LV relaxation can be detected in the presence of normal or supranormal EF but are independently related to impaired MS. A less severely abnormal relaxation, however, can be also detected in the presence of normal midwall function, independent of LV geometry and load. Thus, diastolic abnormalities may occur before systolic dysfunction even when it is measured at the midwall.

Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in humans.

The disposal of a mixed meal was examined in 11 male subjects by multiple (splanchnic and femoral) catheterization combined with double-isotope technique (intravenous [2-3H]glucose plus oral U-[14C]starch). Glucose kinetics and organ substrate balance were measured basally and for 5 h after eating pizza (600 kcal) containing carbohydrates 75 g as starch, proteins 37 g, and lipids 17 g. The portal appearance of ingested carbohydrate was maximal (1.0 mmol/min) between 30 and 60 min after the meal and gradually declined thereafter, but was still incomplete at 300 min (0.46+/-0.08 mmol/min). The total amount of glucose absorbed by the gut over the 5 h of the study was 247+/-26 mmol (45+/-6 g), corresponding to 60+/-6% of the ingested starch. Net splanchnic glucose balance (-6.7+/-0.5 micromol x kg(-1) x min(-1), basal) rose by 250-300% between 30 and 60 min and then returned to baseline. Hepatic glucose production (HGP) was suppressed slightly and only tardily in response to meal ingestion (approximately 30% between 120 and 300 min). Splanchnic glucose uptake (3.7+/-0.6 micromol x kg(-1) x min(-1), basal) peaked to 9.8+/-2.0 micromol x kg(-1) x min(-1) (P<0.001) at 120 min and then returned slowly to baseline. Leg glucose uptake (34+/-5 micromol x leg(-1) x min(-1), basal) rose to 151+/-29 micromol x leg(-1) x min(-1) at 30 min (P<0.001) and remained above baseline until the end of the study, despite no increase in leg blood flow. The total amount of glucose taken up by the splanchnic area and total muscle mass was 161+/-16 mmol (29+/-3 g) and 128 mmol (23 g), respectively, which represent 39 and 30% of the ingested starch. Arterial blood lactate increased by 30% after meal ingestion. Net splanchnic lactate balance switched from a basal net uptake (3.2+/-0.6 micromol kg(-1) x min(-1) to a net output between 60 and 120 min and tended to zero thereafter. Leg lactate release (25+/-11 micromol x leg(-1) x min(-1), basal) drastically decreased postprandially. Arterial concentration of both branched-chain amino acids (BCAA) and non-branched-chain amino acids (N-BCAA) increased significantly after meal ingestion (P<0.001). The splanchnic area switched from a basal net amino acid uptake (31+/-16 and 92+/-48 micromol/min for BCAA and N-BCAA, respectively) to a net amino acid release postprandially. The net splanchnic amino acid release over 5 h was 11.3+/-4.2 mmol for BCAA and 37.8+/-9.7 mmol for N-BCAA. Basally, the net leg balance of BCAA was neutral (-3+/-5 micromol x leg(-1) x min(-1)), whereas that of N-BCAA indicated a net release (54+/-14 micromol x leg(-1) x min(-1)). After meal ingestion, there was a net leg uptake of BCAA (20+/-6 micromol x leg(-1) x min(-1)), whereas leg release of N-BCAA decreased by 50%. It is concluded that in human subjects, 1) the absorption of a natural mixed meal is still incomplete at 5 h after ingestion; 2) HGP is only marginally and tardily inhibited; 3) splanchnic and peripheral tissues contribute to the disposal of meal carbohydrate to approximately the same extent; 4) the splanchnic area transfers >30% of the ingested proteins to the systemic circulation; and 5) after meal ingestion, skeletal muscle takes up BCAA to replenish muscle protein stores.

Role of insulin and free fatty acid (FFA) availability on regional FFA kinetics in the human forearm.

To determine the role of insulin and free fatty acid (FFA) concentration in the regulation of FFA metabolism, forearm FFA fluxes were quantified in 16 healthy volunteers by combining the forearm perfusion technique with the infusion of [3H]palmitate. Three groups of studies were performed. In study 1 (n = 6), a systemic insulin infusion (1.2 mU/kg.min) was performed for 120 min while euglycemia was maintained by a variable glucose infusion. In Study 2 (n = 5), insulin (0.05 mU/kg.min) was infused into the brachial artery to expose the forearm tissues to the same insulin level as in study 1. In study 3 (n = 5), heparin was infused to raise plasma FFA concentration to 1-1.5 mmol/L. At 60 min, an intrabrachial insulin infusion was added as in study 2 and maintained for 60 min. During systemic insulin infusion, plasma FFA concentration fell to 0.09 +/- 0.02 mmol/L. Forearm FFA uptake (FFA-U) decreased from the basal value of 2.54 +/- 0.52 to 0.95 +/- 0.10 mumol/L.min (P < 0.05). Likewise, forearm FFA release (FFA-R) fell to 1.0 +/- 0.31 mumol/L.min (P < 0.05). With local insulin administration, both FFA levels and FFA-U remained unchanged, whereas FFA-R was markedly inhibited (from 1.78 +/- 0.23 to 1.04 +/- 0.24 mumol/L.min; P < 0.05). In study 3 (heparin infusion), FFA levels rose to 1.17 +/- 0.12 mmol/L due to a 4-fold increase in FFA-R (from 1.18 +/- 0.36 to 6.92 +/- 2.40 mumol/L.min; P < 0.05). FFA-U rose from the basal value of 2.50 +/- 0.82 to 6.92 +/- 1.95 mumol/L.min (P < 0.05). Addition of intrabrachial insulin did not modify FFA-U, whereas heparin activation of FFA-R was only partially antagonized (4.53 +/- 2.40 mumol/L.min; 0.01 < P < 0.05 vs. heparin alone). The data demonstrate that plasma FFA concentration is the main determinant of forearm FFA transport. Insulin exerts a direct inhibitory effect on FFA release and affects tissue FFA transport only indirectly through the fall in circulating FFA.

Muscle sympathetic nerve activity in patients with acromegaly.

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 +/- 4 yr; body mass index, 28 +/- 2 kg/m2) and eight healthy subjects (age, 32 +/- 3 yr; body mass index, 25 +/- 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method [infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (approximately 90 mg/dL) by means of the euglycemic clamp. Arterial plasma NE was similar in the two groups at rest (197 +/- 28 and 200 +/- 27 pg/mL (-1) and slightly increased during insulin infusion. Forearm NE release was 2.33 +/- 0.55 ng x liter(-1) x min(-1) in healthy subjects and 2.67 +/- 0.61 ng x liter(-1) x min(-1) in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 +/- 0.71 and 3.32 +/- 0.75 ng x L(-1) x min(-1), P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 +/- 0.4 mg x L(-1) x min(-1)) than in control subjects (7.9 +/- 1.3 mg x L(-1) x min(-1), P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism. Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms.

Tonsillectomy and adenoidectomy: an inpatient or outpatient procedure?

Concern over the rising cost of health care has created a trend toward outpatient surgery. Because adenotonsillectomy is such a frequently performed procedure, there is pressure on many otolaryngologists to do this operation on an ambulatory basis. A prospective study was undertaken to evaluate the incidence and severity of postoperative hemorrhage, protracted emesis, and fever at specified times within the first 24 hours after surgery. Over a 1-year period, 1000 tonsillectomy and/or adenoidectomy patients were studied. There was a 2.1% incidence of serious complications within the first 6 postoperative hours. The incidence of serious hemorrhage, fever, and protracted emesis was 0.7% each. The incidence of significant complications between the 6th and 24th postoperative hours was 1.7%. Hemorrhage occurred in 0.4% of the patients, fever in 0.7%, and protracted emesis in 0.6%. The total incidence of hemorrhage during this time period was 1.1%. There were no deaths. The greatest percentage of complications occurred within the first 6 postoperative hours. Based on this study, outpatient tonsil and adenoid surgery should be followed by at least 6 hours of postoperative observation before discharge. The choice to perform ambulatory tonsil and adenoid surgery depends on the professional judgment of the operating physician based on this and other recent studies, the sophistication of the physician's ambulatory surgery center, and the medical and social background of the patient.

Mycobacterial cervical lymphadenitis: a persistent diagnostic problem.

The most common manifestation of mycobacterial infection encountered in otolaryngologic practice is cervical lymphadenitis. Mycobacterial cervical lymphadenitis, or scrofula, remains a diagnostic and therapeutic challenge because it mimics other pathologic processes, and because of the inconsistent reliability of physical and laboratory findings. Twenty-five cases of scrofula were treated at our institution from 1973 to 1986. Positive chest x-ray was exhibited by five (20%) patients. Histologic examination of the excisional biopsy was the most reliable test with 100% positive specimens. This study emphasizes the marked variability in clinical presentation of scrofula and the importance of surgical excisional biopsy for histologic diagnosis.

Autologous free dermal fat graft. Reconstruction of facial contour defects.

OBJECTIVE: To examine the use of autologous free dermal fat grafts (FDFGs) in the reconstruction of soft-tissue facial contour defects, an 8-year, retrospective, computerized medical chart review was conducted for 21 patients who underwent reconstruction with FDFGs. SETTING: Section of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology, Oregon Health Sciences University, Portland, or affiliated hospitals. PATIENTS: Twenty-one patients identified in the chart review were included in the retrospective evaluation. Follow-up periods ranged from 11 to 94 months. Five patients were unavailable for follow-up at the chart review, but all five had satisfactory results at their last evaluation. DESIGN: Soft-tissue augmentation was performed using autologous FDFGs harvested from the abdomen following in situ de-epithelialization with a high-speed dermabrader. Facial contour defects resulted from tumor extirpation, congenital deformity, trauma, or degenerative disease. MAIN OUTCOME MEASURES: Outcome was considered satisfactory when the patient and the surgeon were pleased with the long-term results at the last evaluation. RESULTS: Complications, including graft resorption (five patients) and epithelial cyst formation (two patients), were observed in seven patients and resulted in an unsatisfactory outcome. The remaining 14 patients demonstrated satisfactory results as determined by the patient and the surgeon at the last evaluation. CONCLUSIONS: Successful long-term augmentation of facial contour defects may be achieved with autologous FDFGs in an appropriate patient population. Careful patient selection and proper surgical technique are essential for satisfactory long-term results. Guidelines are provided for the augmentation of facial contour defects with autologous FDFGs.

Nasal reconstruction with articulated irradiated rib cartilage.

Nasal structural reconstruction is a formidable task in cases where there is loss of support to both the nasal dorsum and tip. A multitude of surgical approaches and materials have been used for the correction of the saddle-nose deformity with varying degrees of success. Articulated irradiated rib cartilage inserted through an external rhinoplasty approach was used to reconstruct nasal deformities in 18 patients over a 6-year period. Simultaneous use of a midline forehead flap to reconstruct the overlying soft tissue was required in four cases. Follow-up ranged from 1 to 6 years (mean, 2.8 years). Results were rewarding in most cases with marked improvement in nasal support and airway. Revision and/or replacement secondary to trauma or warping of the graft was required in four cases. None of the patients exhibited infection, extrusion, or noticeable resorption. A description of the surgical technique, review of all the cases, and recommendation for continued use of this graft material are discussed.

Head and neck lymphoma in patients with the acquired immune deficiency syndrome.

A marked increase has recently been noted in the incidence of lymphoma in patients with AIDS. These lymphomas are generally high-grade, of B-cell origin, and often involve extranodal sites. Reported here are twenty patients with AIDS in whom symptoms and physical findings developed related to the head and neck region as a result of lymphoma. The tumor was observed in a variety of sites, including the nasopharynx, orbit, submandibular triangle, anterior and posterior cervical triangles, supraclavicular fossa, and the hypopharynx. Sixteen tumors were large cell nonHodgkin's B-cell lymphomas, three were small cell nonHodgkin's B-cell lymphomas, and one was Hodgkin's disease, mixed cellularity. All were treated with combination chemotherapy. A high degree of suspicion for lymphoma is required in treating any patient with AIDS who has a rapidly enlarging mass in the head and neck. If needle aspiration is nondiagnostic, excisional biopsy should be performed after a complete head and neck evaluation. Although the development of lymphoma associated with AIDS portends a grave prognosis, prompt diagnosis will allow an improved chance of remission of the lymphoma.

Assessment of survival and microscopic changes in porcine skin flaps undergoing immediate intraoperative tissue expansion.

The technique of rapid intraoperative tissue expansion has been used with increasing frequency in the clinical setting over the last several years. This technique takes advantage of the skin's ability to immediately stretch and increase in surface area when expanded under a constant load. Sixteen random-pattern, rapidly expanded skin flaps on 10 domestic male pigs were studied to assess the predictive value of the fluorescein test for flap viability after rapid intraoperative tissue expansion. Partial fluorescence was found to be a more accurate predictor of flap survival in the experimental rapidly expanded flaps when compared to full fluorescence. Partial fluorescence was found to under-predict flap survival by 0.3 to 0.5 cm, whereas full fluorescence was found to under-predict flap survival by 2.5 cm. Additionally, histologic and ultrastructural changes were examined in rapidly expanded skin from the hip region in three pigs. The only microscopic change noted between control and experimental flaps was dilated capillaries in the dermis of expanded skin, which was noted by electron microscopy. Collagen and elastic tissue changes were not demonstrated in rapidly expanded pig skin by electron microscopy, direct immunofluorescence, collagen, and elastic tissue stains.

Linac4 low energy beam measurements with negative hydrogen ions.

Linac4, a 160 MeV normal-conducting H(-) linear accelerator, is the first step in the upgrade of the beam intensity available from the LHC proton injectors at CERN. The Linac4 Low Energy Beam Transport (LEBT) line from the pulsed 2 MHz RF driven ion source, to the 352 MHz RFQ (Radiofrequency Quadrupole) has been built and installed at a test stand, and has been used to transport and match to the RFQ a pulsed 14 mA H(-) beam at 45 keV. A temporary slit-and-grid emittance measurement system has been put in place to characterize the beam delivered to the RFQ. In this paper a description of the LEBT and its beam diagnostics is given, and the results of beam emittance measurements and beam transmission measurements through the RFQ are compared with the expectation from simulations.

Status and operation of the Linac4 ion source prototypes.

CERN's Linac4 45 kV H(-) ion sources prototypes are installed at a dedicated ion source test stand and in the Linac4 tunnel. The operation of the pulsed hydrogen injection, RF sustained plasma, and pulsed high voltages are described. The first experimental results of two prototypes relying on 2 MHz RF-plasma heating are presented. The plasma is ignited via capacitive coupling, and sustained by inductive coupling. The light emitted from the plasma is collected by viewports pointing to the plasma chamber wall in the middle of the RF solenoid and to the plasma chamber axis. Preliminary measurements of optical emission spectroscopy and photometry of the plasma have been performed. The design of a cesiated ion source is presented. The volume source has produced a 45 keV H(-) beam of 16-22 mA which has successfully been used for the commissioning of the Low Energy Beam Transport (LEBT), Radio Frequency Quadrupole (RFQ) accelerator, and chopper of Linac4.

Civilian external peer review: lessons learned.

Since 1986, the Department of Defense has contracted with an outside agency for Civilian External Peer Review (CEPR). From January, 1986 to December, 1988, records indicate that approximately 350,000 discharges from Army hospitals have been included in the study. Initially, the small number of positive findings prevented generalizations; as the total number of cases screened has increased, several valuable lessons have been learned suggesting avenues for improving care. Additionally, a great deal has been elucidated concerning the process of large-scale clinical peer review.

Sympathetic deactivation by growth hormone treatment in patients with dilated cardiomyopathy.

AIMS: We examined the effects of growth hormone administration on the sympathetic nervous system in patients with idiopathic dilated cardiomyopathy. BACKGROUND: Growth factor therapy is emerging as a new potential option in the treatment of heart failure. Although growth hormone provides functional benefit in the short term, it is unknown whether it affects the sympathetic nervous system, which plays a role in the progression of heart failure. METHODS: Seven patients with idiopathic cardiomyopathy received 3 months treatment with recombinant human growth hormone (0.15-0.20 IU.kg-1.week-1). Standard medical therapy was unchanged. Myocardial norepinephrine release, both at rest and during submaximal physical exercise, plasma aldosterone, and plasma volume were measured before and after growth hormone treatment. Myocardial norepinephrine release was assessed from arterial and coronary venous plasma concentrations of unlabelled and tritiated norepinephrine and coronary plasma flow (thermodilution). RESULTS: Growth hormone induced a significant fall in myocardial norepinephrine release in response to physical exercise (from 180 +/- 64 to 99 +/- 34 ng.min-1; P < 0.05). Basally, plasma aldosterone was 189 +/- 28 and 311 +/- 48 pg.ml-1 in the supine and upright position, respectively, and fell to 106 +/- 16 (P < 0.01) and 182 +/- 29 pg.ml-1 (P < 0.05) after growth hormone therapy. Growth hormone increased plasma volume from 3115 +/- 493 ml to 3876 +/- 336 ml (P < 0.05), whereas serum sodium and potassium concentrations were unaffected. CONCLUSIONS: The data demonstrate that growth hormone administration to patients with idiopathic cardiomyopathy reduces myocardial sympathetic drive and circulating aldosterone levels. This neurohormonal deactivation may be relevant to the potential, long-term use of growth hormone in the treatment of patients with heart failure.

A preliminary study of growth hormone in the treatment of dilated cardiomyopathy.

BACKGROUND: Cardiac hypertrophy is a physiologic response that allows the heart to adapt to an excess hemodynamic load. We hypothesized that inducing cardiac hypertrophy with recombinant human growth hormone might be an effective approach to the treatment of idiopathic dilated cardiomyopathy, a condition in which compensatory cardiac hypertrophy is believed to be deficient. METHODS: Seven patients with idiopathic dilated cardiomyopathy and moderate-to-severe heart failure were studied at base line, after three months of therapy with human growth hormone, and three months after the discontinuation of growth hormone. Standard therapy for heart failure was continued throughout the study. Cardiac function was evaluated with Doppler echocardiography, right-heart catheterization, and exercise testing. RESULTS: When administered at a dose of 14 IU per week, growth hormone doubled the serum concentrations of insulin-like growth factor I. Growth hormone increased left-ventricular-wall thickness and reduced chamber size significantly. Consequently, end-systolic wall stress (a function of both wall thickness and chamber size) fell markedly (from a mean [+/-SE] of 144+/-11 to 85+/-8 dyn per square centimeter, P<0.001). Growth hormone improved cardiac output, particularly during exercise (from 7.4+/-0.7 to 9.7+/-0.9 liters per minute, P=0.003), and enhanced ventricular work, despite reductions in myocardial oxygen consumption (from 56+/-6 to 39+/-5 ml per minute, P=0.005) and energy production (from 1014+/-100 to 701+/-80 J per minute, P=0.002). Thus, ventricular mechanical efficiency rose from 9+/-2 to 21+/-5 percent (P=0.006). Growth hormone also improved clinical symptoms, exercise capacity, and the patients' quality of life. The changes in cardiac size and shape, systolic function, and exercise tolerance were partially reversed three months after growth hormone was discontinued. CONCLUSIONS: Recombinant human growth hormone administered for three months to patients with idiopathic dilated cardiomyopathy increased myocardial mass and reduced the size of the left ventricular chamber, resulting in improvement in hemodynamics, myocardial energy metabolism, and clinical status.