Multimode pumping of optical parametric oscillators

Cataloged from PDF version of article.Calculations suggest that optical parametric oscillators (OPO’s) can be efficiently pumped using multimode, divergent pump sources. The influence of pump beam divergence and mode structure upon OPO performance is measured for both noncritical phase-matching, and OPO’s with walkoff. Multimode OPO pumping is shown to be efficient, provided appropriate nonlinear crystals and OPO cavities are employed; the nonlinear crystal must have sufficient angular acceptance to tolerate a divergent pump; the OPO cavity must support modes that match the divergence and spatial intensity characteristics of the pump. For low-order pump modes, the OPO can be made to match the mode of the pump. Higher order pump modes reduce the OPO efficiency, and cause a saturation of efficiency with increasing pump power. The efficiency is degraded in a similar fashion in the presence of walkoff. Multimode pumping is more difficult in longer OPO cavities due to increased buildup time of higher order OPO modes

Protein Kinase A Regulates ATP Hydrolysis and Dimerization by a CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) Domain

Gating of the CFTRCl− channel is associated with ATP hydrolysis at the nucleotide-binding domains (NBD1, NBD2) and requires PKA (protein kinase A) phosphorylation of the R domain. The manner in which the NBD1, NBD2 and R domains of CFTR (cystic fibrosis transmembrane conductance regulator) interact to achieve a properly regulated ion channel is largely unknown. In this study we used bacterially expressed recombinant proteins to examine interactions between these soluble domains of CFTR in vitro. PKA phosphorylated a fusion protein containing NBD1 and R (NBD1–R–GST) on CFTR residues Ser-660, Ser-700, Ser- 712, Ser-737, Ser-768, Ser-795 and Ser-813. Phosphorylation of these serine residues regulated ATP hydrolysis by NBD1–R–GST by increasing the apparent Km for ATP (from 70 to 250 μM) and the Hill coefficient (from 1 to 1.7) without changing the Vmax. When fusion proteins were photolabelled with 8-azido- [α-32P]ATP, PKA phosphorylation increased the apparent kd for nucleotide binding and it caused binding to become co-operative. PKA phosphorylation also resulted in dimerization of NBD1– R–GST but not of R–GST, a related fusion protein lacking the NBD1 domain. Finally, an MBP (maltose-binding protein) fusion protein containing the NBD2 domain (NBD2–MBP) associated with and regulated the ATPase activity of PKA-phosphorylated NBD1–R–GST. Thus when the R domain in NBD1–R–GST is phosphorylated by PKA,ATP binding and hydrolysis becomes cooperative and NBD dimerization occurs. These findings suggest that during the activation of native CFTR, phosphorylation of the R domain by PKA can control the ability of the NBD1 domain to hydrolyse ATP and to interact with other NBD domains

First-to-Invent Versus First-to-File: International Patent Law Harmonization and Innovation

The U.S. has been under pressure to abandon the unique first-to-invent feature of its patent law for awarding patents. The opposition to reform however argues that switch to a first-to-file rule, the international norm, will undermine innovation. We evaluate this argument in a dynamic stochastic model of a patent race. The result generally supports the opposition's argument

If You Could Only Choose Five Psychotropic Medicines: Updating the Interagency Emergency Health Kit

Mark van Ommeren and colleagues describe how they chose five psychotropic medicines to add to the Interagency Emergency Health Kit, which is a box with medicines and medical supplies designed to help people in major humanitarian emergencies

International Harmonization of the Patent-Issuing Rules

With the America Invents Act of 2011, the U.S. changed its patent-issuing rule from first-to-invent to first-to-file, the international norm. We investigate the effect of such a policy change in a two-country model of R&D competition for two sequential (basic and final) inventions. We find that a switch never speeds up basic research. A delay is more likely especially in industries where the final product generates more value in the U.S. Simulations show that a delay in basic research also retards final invention, decreasing world welfare

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma:importance of immunoglobulin supplementation

Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received onceweekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P &lt; .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.</p

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma:importance of immunoglobulin supplementation

Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received onceweekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P &lt; .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.</p

Validity of self-assessment of hallux valgus using the Manchester scale

<p>Abstract</p> <p>Background</p> <p>Hallux valgus (HV) is a common condition involving the progressive subluxation of the first metatarsophalangeal joint due to lateral deviation of the hallux and medial deviation of the first metatarsal. The objective of this study was to evaluate the re-test reliability and validity of self-assessment of HV using a simple clinical screening tool involving four standardised photographs (the Manchester scale), in order to determine whether this tool could be used for postal surveys of the condition.</p> <p>Methods</p> <p>HV was assessed with the Manchester scale in 138 people aged 65 to 93 years of age (102 women and 36 men) as part of a larger randomised controlled trial. At the six month follow-up assessment, HV was reassessed to determine re-test reliability, and participants were asked to self-assess their degree of HV independent of the examiners. Associations between (i) baseline and follow-up assessments of the examiners and (ii) participant and examiner assessments were performed using weighted kappa statistics. Analyses were then repeated after HV was dichotomised as present or absent using unweighted kappa, and sensitivity and specificity of self-assessment of HV was determined.</p> <p>Results</p> <p>Re-test reliability of the examiners was substantial to almost perfect (weighted kappa = 0.78 to 0.90), and there was a substantial level of agreement between observations of the participants and the examiners (weighted kappa = 0.71 to 0.80). Overall, there was a slight tendency for participants to rate their HV as less severe than the examiners. When the Manchester scale scores were dichotomised, agreement was substantial to almost perfect for both re-test comparisons (kappa = 0.80 to 0.89) and substantial for comparisons between participants and examiners (kappa = 0.64 to 0.76). The sensitivity and specificity of self-assessment of HV using the dichotomous scale were 85 and 88%, respectively.</p> <p>Conclusions</p> <p>The Manchester scale demonstrates high re-test reliability, and self-assessment scores obtained by participants are strongly associated with scores obtained by examiners. These findings indicate that the tool can be used with confidence in postal surveys to document the presence and severity of HV.</p> <p>Trial registration</p> <p>ACTRN12608000065392</p

Conflict in the Indian Kashmir Valley II: psychosocial impact

ABSTRACT: BACKGROUND: India and Pakistan have disputed ownership of the Kashmir Valley region for many years, resulting in high level of exposure to violence among the civilian population of Kashmir (India). A survey was done as part of routine programme evaluation to assess confrontation with violence and its consequences on mental health, health service usage, and socio-economic functioning. METHODS: We undertook a two-stage cluster household survey in two districts of Kashmir (India) using questionnaires adapted from other conflict areas. Analysis was stratified for gender. RESULTS: Over one-third of respondents (n=510) were found to have symptoms of psychological distress (33.3%, CI: 28.3-38.4); women scored significantly higher (OR 2.5; CI: 1.7-3.6). A third of respondents had contemplated suicide (33.3%, CI: 28.3-38.4). Feelings of insecurity were associated with higher levels of psychological distress for both genders (males: OR 2.4, CI: 1.3-4.4; females: OR 1.9, CI: 1.1-3.3). Among males, violation of modesty, (OR 3.3, CI: 1.6-6.8), forced displacement, (OR 3.5, CI: 1.7-7.1), and physical disability resulting from violence (OR 2.7, CI: 1.2-5.9) were associated with greater levels of psychological distress; for women, risk factors for psychological distress included dependency on others for daily living (OR 2.4, CI: 1.3-4.8), the witnessing of killing (OR 1.9, CI: 1.1-3.4), and torture (OR 2.1, CI: 1.2-3.7). Self-rated poor health (male: OR 4.4, CI: 2.4-8.1; female: OR 3.4, CI: 2.0-5.8) and being unable to work (male: OR 6.7, CI: 3.5-13.0; female: OR 2.6, CI: 1.5-4.4) were associated with mental distress. CONCLUSIONS: The ongoing conflict exacts a huge toll on the communities' mental well-being. We found high levels of psychological distress that impacts on daily life and places a burden on the health system. Ongoing feelings of personal vulnerability (not feeling safe) were associated with high levels of psychological distress. Community mental health programmes should be considered as a way reduce the pressure on the health system and improve socio-economic functioning of those suffering from mental health problems