Field-resolved high-order sub-cycle nonlinearities in a terahertz semiconductor laser.

The exploitation of ultrafast electron dynamics in quantum cascade lasers (QCLs) holds enormous potential for intense, compact mode-locked terahertz (THz) sources, squeezed THz light, frequency mixers, and comb-based metrology systems. Yet the important sub-cycle dynamics have been notoriously difficult to access in operational THz QCLs. Here, we employ high-field THz pulses to perform the first ultrafast two-dimensional spectroscopy of a free-running THz QCL. Strong incoherent and coherent nonlinearities up to eight-wave mixing are detected below and above the laser threshold. These data not only reveal extremely short gain recovery times of 2 ps at the laser threshold, they also reflect the nonlinear polarization dynamics of the QCL laser transition for the first time, where we quantify the corresponding dephasing times between 0.9 and 1.5 ps with increasing bias currents. A density-matrix approach reproducing the emergence of all nonlinearities and their ultrafast evolution, simultaneously, allows us to map the coherently induced trajectory of the Bloch vector. The observed high-order multi-wave mixing nonlinearities benefit from resonant enhancement in the absence of absorption losses and bear potential for a number of future applications, ranging from efficient intracavity frequency conversion, mode proliferation to passive mode locking.

Strong dose response after immunotherapy with PQ grass using conjunctival provocation testing.

BACKGROUND: Pollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose. METHODS: Patients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31-41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship. RESULTS: In total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature. CONCLUSIONS: PQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.

Structural integration and performance of inter-sectoral public health-related policy networks: An analysis across policy phases.

BACKGROUND: Inter-sectoral policy networks may be effective in addressing environmental determinants of health with interventions. However, contradictory results are reported on relations between structural network characteristics (i.e., composition and integration) and network performance, such as addressing environmental determinants of health. This study examines these relations in different phases of the policy process. METHODS: A multiple-case study was performed on four public health-related policy networks. Using a snowball method among network actors, overall and sub-networks per policy phase were identified and the policy sector of each actor was assigned. To operationalise the outcome variable, interventions were classified by the proportion of environmental determinants they addressed. RESULTS: In the overall networks, no relation was found between structural network characteristics and network performance. In most effective cases, the policy development sub-networks were characterised by integration with less interrelations between actors (low cohesion), more equally distributed distances between the actors (low closeness centralisation), and horizontal integration in inter-sectoral cliques. The most effective case had non-public health central actors with less connections in all sub-networks. CONCLUSION: The results suggest that, to address environmental determinants of health, sub-networks should be inter-sectorally composed in the policy development rather than in the intervention development and implementation phases, and that policy development actors should have the opportunity to connect with other actors, without strong direction from a central actor.

Establishment of a new human pneumococcal standard reference serum, 007sp.

Lot 89SF has been the reference standard serum pool used in pneumococcal enzyme-linked immunosorbent assays (ELISAs) since 1990. In 2005, it was estimated that there remained between 2 and 5 years' supply of lot 89SF. Since lot 89SF was the reference standard used in the evaluation of the seven-valent pneumococcal conjugate vaccine Prevnar (PCV7), the link to clinical efficacy would be severed if stocks became completely depleted. Furthermore, demonstration of immune responses comparable to those elicited by PCV7 is a licensure approach used for new pneumococcal conjugate vaccines, so a replacement reference standard was required. A total of 278 volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine Pneumovax II, and a unit of blood was obtained twice within 120 days following immunization. Plasma was prepared, pooled, and confirmed to be free from hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV. The pooled serum was poured at 6 ml per vial into 15,333 vials and lyophilized. Immunological bridging of 007sp to 89SF was used to establish equivalent reference values for 13 pneumococcal capsular serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) by five independent laboratories. Antibody concentrations in 007sp were established relative to the lot 89SF reference preparation using the WHO reference ELISA. Subsequently, 12 existing WHO calibration sera had concentrations reassigned for 13 pneumococcal serotypes using new serum 007sp as the reference, and these were compared to concentrations relative to the original reference serum. Agreement was excellent for the 12 WHO calibration sera. The 007sp preparation has replaced 89SF as the pneumococcal reference standard. Sufficient quantity of this new preparation is available such that, with judicious use, it should be available for at least 25 years.

The role of the general practitioner in the community care of people with HIV infection and AIDS: a comparative study of high- and low-prevalence areas in England.

BACKGROUND: Policy for the care of people suffering from HIV and AIDS has changed over the past decade. Schemes for shared primary and secondary care have been met with varying success, and patients may be reluctant to become involved. No systematic evaluation comparing the views of primary care providers and users in areas of varying HIV prevalence has been published. AIM: To examine the role of general practice in areas of England with low and high human immunodeficiency virus (HIV) prevalence and to compare barriers to general practice care in each area. METHOD: We used focus groups, semistructured questionnaires and interviews in north London (high HIV prevalence) and Nottingham (low HIV prevalence). RESULTS: Four focus groups took place in London. A total of 411 general practitioners (GPs) in London and 405 in Nottingham replied to postal questionnaires. Overall, 121 primary care staff in 40 London practices and 26 staff in five Nottingham practices were interviewed. In all, 54 people infected with HIV were interviewed in London and 20 in Nottingham. Providers and users regarded the 24-hour availability and the familiar environment of general practice as its key assets. Lack of expertise and time were its disadvantages. Providers were concerned about inadequate communication with specialist services. Although providers were concerned about confidentiality, whether they had liberal and sympathetic attitudes was more important in deciding whether people with HIV used the service. In the low-prevalence area, general practice involvement was the result of individual initiatives, and practices were not integrated into specialist care. In the high-prevalence area, HIV care was more usual in general practice, but there was also little integration with HIV services. CONCLUSIONS: In high-prevalence districts, a strategy to make HIV care routine for all GPs may be appropriate. In low-prevalence areas, a network of selected, strategically located, relatively high-involvement practices may be more effective in meeting the primary care needs of people with HIV infection and acquired immunodeficiency syndrome (AIDS).

Radiofrequency catheter ablation of right ventricular tachycardia late after repair of congenital heart defects.

BACKGROUND: Ventricular arrhythmias after repair of congenital heart defects are a common finding and possibly contribute to sudden death in these patients. Optimal antiarrhythmic management has not yet been defined. METHODS AND RESULTS: The study population consisted of 16 patients in whom ventricular arrhythmias occurred 11 to 42 years after complete surgical repair of congenital heart defects. Fifteen patients had a history of symptomatic sustained or nonsustained ventricular tachycardia, and 1 had frequent nonsustained ventricular tachycardia. The diagnostic mapping procedure to identify the origin of the arrhythmia included pace mapping during sinus rhythm, activation mapping, and pacing interventions during ventricular tachycardia. Catheter ablation was carried out by means of radiofrequency energy in the temperature-controlled mode. The follow-up period was 6 to 33 months (mean, 16 months). A right ventricular origin of the tachycardia in the surgically corrected area could be determined in all patients. Catheter ablation was carried out without complications. Immediate noninducibility was achieved in 15 of the 16 patients. One patient in whom the tachycardia was again inducible at repeat stimulation 1 week later was successfully treated with amiodarone. Eleven patients were taken off antiarrhythmic drugs. During follow-up, none of them had a recurrence of the tachycardia that had been ablated. CONCLUSIONS: In patients with symptomatic or frequent ventricular tachycardia late after complete surgical repair of congenital heart defects, catheter ablation by means of radiofrequency energy is feasible and safe and thus might be taken into consideration for these patients. Short-term follow-up results are promising.

Modulation of the immunologic response to acute stress in humans by beta-blockade or benzodiazepines.

Acute stress evokes immediate responses in the cardiovascular endocrine, and immune systems. In particular, the number and activity of natural killer (NK) lymphocytes increase after stress. Here, we investigate the possibility to pharmacologically interfere with these stress-induced immunologic changes. Twenty-five healthy males were subjected to an acute stressor, a first-time tandem parachute jump. Subjects were randomly assigned to a beta-adrenoceptor antagonist (propranolol), a benzodiazepine (alprazolam), or placebo group. To analyze the role of the spleen in lymphocyte redistribution, splenectomized subjects performed a parachute jump. Propranolol, but no alprazolam, inhibited the heart rate increase during jumping. Increases in epinephrine and cortisol in the propranolol group were comparable to placebo, but were attenuated by alprazolam. The number and activity of NK cells significantly increased in the placebo group but not in the propranolol group immediately after stress. Alprazolam treatment did not alter the increase in NK cell numbers but did inhibit the increase in NK activity. In splenectomized subjects, NK cell numbers, but not NK activity, increased as in placebo subjects. We conclude that stress-induced changes in the immune system are controlled by beta-adrenergic mechanisms and only partly depend on the spleen; central interference with alprazolam differentially affects stress-induced changes in the NK cell compartment.

Preservation of peristaltic reflex in hypertrophied ileum of guinea pig.

Chronic obstruction of the guinea pig ileum leads to distension and muscular hypertrophy, but how this affects passive biomechanical and nerve-mediated contractions and clearance known as peristaltic reflex is unclear. Ileum of controls had a diameter of 3.0 +/- 1.1 mm and a circular muscle thickness of 37.2 +/- 11.2 microns; 4 wk after placement of a nonconstricting Gore-Tex band, the ileum was distended to 10.0 +/- 0.19 mm, and its muscle had hypertrophied to 195.0 +/- 61.2 microns. Hypertrophied segments exceeded controls in capacity (e.g., 5.1 +/- 1.1 vs. 1.1 +/0 0.2 ml at 6 cm), compliance, and hysteresis. Threshold volumes and pressures that triggered the reflex were 3.3 +/- 1.3 ml and 3.1 +/- 0.01 mmHg in hypertrophied vs. 0.7 +/- 0.2 ml and 1.5 +/- 0.2 mmHg in controls. The diameter increase that triggered the reflex was 1.4 +/- 0.1 mm in hypertrophied segments and 0.6 +/- 0.1 mm in controls. Hypertrophied segments generated fewer contractions of virtually double the amplitude and failed to generate a pressure differential between up- and downstream sites as controls did. Hypertrophied segments generated larger stroke volumes and cumulative clearance than controls. The ratio of antegrade to retrograde clearance was similar in hypertrophied and control segments. The length of the occluding segment in hypertrophied preparations exceeded that of controls. Control contractions indented the antimesenteric border and propagated antegrade from their site of origin; bizarre writhing movements of hypertrophied segments made their contractions difficult to monitor. Thus distension and muscular hypertrophy do not interfere with the ability of the chronically obstructed guinea pig ileum to generate a peristaltic reflex at least as readily and as powerful and as effective in clearing the lumen as controls.

Dynamic imaging of obstructed opossum esophagus. From altered load to altered contractility.

We studied by barium contrast the dynamics of experimental obstruction in the opossum esophagus. Immediately after banding the gastroesophageal junction, entrapment of the bolus between the band and the peristaltic contraction led to esophageal bulging, forceful retropulsion of the bolus at the band, and the repeated triggering of peristaltic contractions by the retropelled bolus. In ensuing weeks, triggering of contractions became more difficult and contractions led to bizarre "corkscrew" movements of the increasingly distended and tortuous esophagus. A tight contraction ring that moved very slowly retrograde was occasionally observed in the chronically distended esophagus. Computer-assisted analysis showed that the area and perimeter of the bolus were abnormally large in chronic obstruction and that during its passage through the esophagus the compactness of the bolus increased no longer. Configurational analysis of the cone that the peristaltic contraction shapes at the tail of the barium column showed this to narrow progressively on passage through the normal esophagus and, paradoxically, to widen in both acute and chronic obstruction.

A controlled investigation of right hemispheric processing enhancement after restricted environmental stimulation (REST) with floatation.

Two groups of 16 subjects, 8 of each gender, were examined on two occasions, one group before and after restricted environmental stimulation with floatation, and the other group without floatation was the control group. They were examined with a tactile object discrimination task carried out with each hand separately while blindfolded, and with a recognition memory test for words and unfamiliar faces, a test validated on neurological patients with left and right hemispheric lesions respectively. Consistent with both tasks the floatation group showed a significantly greater enhancement of right hemispheric processing after floatation than was found when retesting the controls. The results were distinguished from previous research on hypnosis where the same relative state of hemispheric imbalance was achieved with the same tasks, but largely through inhibitory influences on the left hemisphere.

Metabolic cost of grade running in dogs.

Dogs (Canis familiaris) were run up and down 7.4, 11.8, and 20.4% grades as well as on the horizontal at speeds of 3 and 6 km/h while their steady-state oxygen comsumption was measured. On positive grades the metabolism was directly dependent on both grade and speed. On the negative grades the metabolic rates were dependent only on speed and for each dog were depressed about the same amount below the metabolism needed for horizontal running at each speed. The clustering of the metabolic rates for the downhill slopes means that to cover a given distance gorizontally and downhill the dog will use the minimum energy if it descends via the gentlest grade. This is so because such a route allows the animal to maintain the lowest metabolism for the longest time. There is no best uphill route. The grade metabolism of the dogs was an almost exact duplicate of that found for humans running on grades which implies similarity of mechanical and biochemical aspects of running.