Search

Hereditary angioedema (HAE), an inherited deficiency offunctional C1 esterase inhibitor (C1-INH), is characterized byrecurrent episodes of disabling and often painful swelling insubcutaneous and/or submucosal tissues.1HAE attacks aregenerally unpredictable, but triggers for an attack can includehaving a dental or medical procedure (eg, surgery), other trauma,or stress. A preemptive management plan for patients under-going these types of situations may reduce the risk of HAE at-tacks. Recommendations include administration of short-termprophylaxis in patients with HAE before invasive medical pro-cedures, especially those involving the upper airways or digestivetract, with C1-INH concentrate typically the medication ofchoice.

Optimal management of patients with combined immunodeficiency, especially pertaining to hematopoietic stem cell transplantation (HSCT), remains unclear.To identify factors influencing HSCT and mortality in the population with combined immunodeficiency in North America.We identified 337 participants in the United States Immunodeficiency Network database with diverse forms of combined immunodeficiency and their characteristics, including demographic characteristics, laboratory values, infectious history, comorbidities, and treatment strategies. Univariate analysis was performed using logistic regression, whereas multivariate analysis was performed using multiple Cox proportional hazards.On univariate analysis, disseminated invasive viral infections and variants in STAT3, GATA2, and, DOCK8 were associated with increased odds of HSCT. Mucocutaneous fungal infections and variants in STAT3 were associated with increased odds of survival, whereas disseminated/invasive fungal infections, disseminated/invasive viral infections, and parasitic infections were associated with decreased odds of survival. On multiple variable Cox proportional hazards analysis, variants in ZAP70, nonspecific bacterial, and disseminated/invasive viral infections were associated with increased hazards of transplantation, whereas variants in multiple genes (RMRP, NEMO, DOCK8, CD40L, and CARD9), disseminated/invasive viral infections, autoimmune disease, and higher absolute lymphocyte count were associated with increased hazards of death. Importantly, demographic characteristics, basic lymphocyte subset counts, and absence of genetic diagnosis were not associated with HSCT or mortality.We determined that specific genetic diagnoses and infection burden impacts the decision to undergo HSCT in this cohort. In addition, certain genetic diagnoses and invasive viral infections carry an increased risk of mortality.

Background: Primary immunodeficiency involving defective antibody formation requires antibody replacement therapy with immunoglobulin products to prevent and reduce infections. Immunoglobulin for intravenous use (IVIG) is a processed blood product with limited availability, and the various marketed IVIG products may have different tolerability among patients. New IVIG products are therefore necessary to offer options to patients and to reduce the risk of a product shortage. Methods: Forty-five adult and pediatric patients with primary immunodeficiency, documented agammaglobulinemia or hypogammaglobulinemia, and antibody deficiency were enrolled in a prospective, multi-centre, open-label, single-arm historically controlled Phase III study to evaluate the safety, efficacy, and pharmacokinetics of a new 10% IVIG produced by Kedrion. Results: Forty-four patients completed the study while one withdrew consent. Over the 12-month study period, only 2 episodes of acute serious bacterial infections (both bacterial pneumonias) were recorded, for a mean annual event rate of 0.04 per subject, with an upper one-sided 99% confidence limit of 0.11. Values for all secondary efficacy endpoints were comparable with those in similar studies. The primary safety endpoint was met as the rate of infusions temporally associated (i.e., within 72 hours) with ≥1 adverse event was 16% (upper 95% confidence limit 20.4%). Pharmacokinetics were assessed in 31 patients and found to be comparable with those published for other IVIG products. Conclusion: Kedrion IVIG 10% is safe, efficacious, and well tolerated by patients with primary immunodeficiency. Statement of novelty: This report describes the safety, efficacy, and pharmacokinetics of a new IVIG preparation.

Current treatments for long-term prophylaxis in hereditary angioedema have limitations.To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P .001); -1.44 (95% CI, -1.84 to -1.04; P .001); and -1.71 (95% CI, -2.09 to -1.33; P .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Hereditary angioedema (HAE) is a rare disorder causing periodic attacks of nonpruritic swelling, for which highly effective subcutaneous and intravenous therapies are available. The need to seek ongoing medical attention for HAE attacks at clinics and hospitals adds to the already considerable burden of the disease. Recent international consensus treatment guidelines have emphasized home-based therapy as a preferred managed strategy whenever possible. Here, we review various strategies for facilitating home-based treatment with injectable HAE medications (plasma-derived C1 esterase inhibitor [C1-INH], ecallantide, icatibant, and recombinant C1-INH). Medical literature relating to home-based treatment of HAE is reviewed and strategies for implementing home-based therapy are presented. Home-based treatment of HAE has been shown to reduce the time to initiation of treatment, reduce the duration and severity of attacks, and improve patients' quality of life. Several options are available to facilitate home treatment of HAE. Medical staff in a primary care setting can be educated in the care of HAE patients and can teach the technique of parenteral drug administration. Home care agencies and specialty pharmacies are present in most communities and specialize in patient education. Infusion centers are skilled at working with patients with chronic diseases who perform extensive self-care. HAE comprehensive care clinics provide expert diagnosis and disease management and may become the patient's primary source of HAE care. Home-based therapy of HAE has been shown to be safe and clinically advantageous. Various strategies are available for equipping HAE patients to administer their treatments outside of a medical facility.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo. ispartof: ALLERGY vol:73 issue:9 pages:1871-1880 ispartof: location:Denmark status: published

Background: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. Objective: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). Methods: The international registry (2010–2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. Results: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500–3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH–treated attack of 72.0 hours (range, 0.0–166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH–treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). Conclusion: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.

Hereditary angioedema (HAE) is a rare disorder that causes periodic attacks of sometimes painful swelling that may affect any organ system. HAE results in significant morbidity and diminished quality of life and requires patients to seek urgent medical care. HAE can be treated with C1 esterase inhibitor concentrate (C1-INH), icatibant, and ecallantide. Recent consensus guidelines recommend that all HAE patients be considered for training in self-administration of therapy to treat acute attacks or to prevent attacks. Many patients have safely and successfully self-administered intravenous infusions of C1-INH, resulting in rapid treatment, shortened attacks, and improved quality of life. With proper patient selection and adequate guidance and follow-up, self-administered C1-INH therapy is a viable and favorable option to treat HAE, particularly in patients with a moderate to high frequency of attacks.

Introduction Patients with hereditary angioedema (HAE) are at risk for an acute attack after medical procedures. Short-term prophylaxis may minimize this risk. This study evaluated recombinant C1 esterase inhibitor (rhC1-INH) as short-term prophylaxis. Methods Patients with angioedema were treated with rhC1-INH prior to medical procedures/stressful life events; HAE attacks were recorded through 2 days and >2-7 days postprocedure. Results Fifty-one patients (median age, 44 years [range, 17-73 years]; 62.7% female; 92.2% HAE type 1) were included. A median rhC1-INH dose of 3075 IU (range, 2100-4200 IU) was administered as prophylaxis, median of 60 minutes prior, for 70 procedures (52.9% [n=37] dental [median, 60 minutes preprocedure]); 30.0% [n=21] surgical [median, 45 minutes preprocedure]; 15.7% [n=11] endoscopy [median, 30 minutes preprocedure, and 1.4% [n=1] stressful life event). Majority (n=48; 68.6%) of 70 cases had rhC1-INH administered 10-65 minutes preprocedure: 25 of 48 (52.1%) dental, 16 (33.3%) surgical, and 7 (14.6%) endoscopy. Nineteen (27.1%) cases involved long-term prophylaxis (danazol/tranexamic acid). Overall, 97.1% (68/70) of cases did not have an HAE attack within 2 days postprocedure; 91.4% (64/70) during >2-7 days postprocedure. For 2 attacks occurring within 2 days, rhC1-INH was administered 230 minutes and ≥24 hours preprocedure, respectively. No adverse events were reported. As a self-control group, 76.9% of 26 cases with no long-term/short-term prophylaxis preprocedure had an attack within 2 days postprocedure. Conclusions Short-term prophylaxis with rhC1-INH, administered within several hours preprocedure, was efficacious and safe in adolescents/adults and reduced the risk of an HAE attack postprocedure.

Background Administration of subcutaneous immunoglobulin (SCIG) via rapid push, an alternative to infusion pump delivery, can offer heightened simplicity and convenience for patients with primary immunodeficiency disease (PIDD). Objective To assess dosing and administration patterns, serum IgG responses, safety, and tolerability of the subcutaneous (SC) rapid push technique. Methods A retrospective medical record review captured data on 173 patients with PIDD (1,140 follow-up visits) who self-administered SCIG (16% or 20%) via infusion pump or SC rapid push. Results Serum IgG levels increased from a mean (SD) trough of 903.8 (285.4) mg/dL during intravenous immunoglobulin use to a steady-state mean (SD) of 1,121.6 (257.6) mg/dL on SCIG. Mean frequency of weekly SCIG administration was 2.3 days per week with pump and 2.8 days per week with SC rapid push. Mean serum IgG levels were higher among push vs pump users (1,164 vs 1,048 mg/dL). Mean (SD) SCIG volume administered per infusion site with SC rapid push was 15.0 (7.3) mL (maximum, 60.0 mL). Most patients using SC rapid push infused in 9 minutes or less; median pump infusion duration was 49 minutes. Use of 20% SCIG was associated with smaller mean weekly product volumes vs 16% SCIG (41.7 vs 51.0 mL) and fewer mean dosing days per week (2.0 vs 2.8 days). Adverse events, primarily local, were reported on fewer visits with SC rapid push (15.6%) than with infusion pump (20.7%). Conclusion The SC rapid push technique is a safe, viable alternative to an infusion pump, seemingly preferred by patients and offering more rapid administration.

Immunoglobulin (IgG) replacement is a life-saving treatment for individuals with primary immunodeficiency disease (PIDD). Today, there are many options for IgG replacement, and the choice is an individual one based on many factors. My preference for most patients is the subcutaneous (SCIG) route. It offers many advantages not offered by the intravenous (IVIG) route. These include: 1) independence from hospital-based infusion settings; 2) an alternative for patients with poor venous access; 3) better tolerability in those patients who are not able to tolerate IVIG; 4) flexibility of dosing; 5) ease of administration; 6) a very low side-effect profile; 7) a comparatively more even, almost physiological, IgG level; 8) less cost to administer than IVIG; and 9) improved quality of life in patients treated with SCIG compared with those treated with IVIG. For most patients with PIDD who require IgG replacement, SCIG offers advantages not available with IVIG.

Many factors need to be considered when choosing the mode of delivery of immunoglobulin (IgG) replacement therapy for a given patient with primary immunodeficiency disease (PIDD). Despite some general guidance as provided in the previous discussions, a number of ongoing questions remain. This article attempts to provide some answers and clarification for clinical situations in which the choice of intravenous IgG (IVIG) or subcutaneous IgG (SCIG) may be ambiguous.

Decisions by third-party payors that are restricting delivery of appropriate IgG treatment for primary immunodeficiency disease (PIDD) are summoning action from patients, physicians, and their organizations to ensure that high quality treatment remains accessible. Some of the strongest advocacy to date is from patient organizations, such as the Immune Deficiency Foundation (IDF), which strive to educate stakeholders on key issues that determine patient access to appropriate IgG treatment. These issues include the ability to choose the appropriate site of care based on a patient’s experience and circumstance and greater awareness of product choice. Advocacy by physicians on these issues at the local level is needed, as are national efforts by organizations such as the American Academy of Allergy, Asthma & Immunology and their regional societies.

Hyper-IgM syndrome and Common Variable Immunodeficiency are heterogeneous disorders characterized by a predisposition to serious infection and impaired or absent neutralizing antibody responses. Although a number of single gene defects have been associated with these immune deficiency disorders, the genetic basis of many cases is not known. To facilitate mutation screening in patients with these syndromes, we have developed a custom 300-kb resequencing array, the Hyper-IgM/CVID chip, which interrogates 1,576 coding exons and intron-exon junction regions from 148 genes implicated in B-cell development and immunoglobulin isotype switching. Genomic DNAs extracted from patients were hybridized to the array using a high-throughput protocol for target sequence amplification, pooling, and hybridization. A Web-based application, SNP Explorer, was developed to directly analyze and visualize the single nucleotide polymorphism (SNP) annotation and for quality filtering. Several mutations in known disease-susceptibility genes such as CD40LG, TNFRSF13B, IKBKG, AICDA, as well as rare nucleotide changes in other genes such as TRAF3IP2, were identified in patient DNA samples and validated by direct sequencing. We conclude that the Hyper-IgM/CVID chip combined with SNP Explorer may provide a cost-effective tool for high-throughput discovery of novel mutations among hundreds of disease-relevant genes in patients with inherited antibody deficiency.

Subcutaneous immunoglobulin (SCIg) replacement therapy for primary immune deficiency disease (PIDD) is a safe, effective, and convenient alternative to intravenous Ig (IVIg) therapy. Although SCIg is typically administered weekly by infusion pump, administration by a rapid push technique may provide a greater degree of convenience. Rapid push administration has been an option at the author's clinic for several years. We report experience with a cohort of patients given a choice between rapid push and standard pump administration. This was a retrospective chart review of PIDD patients at a single site who initiated treatment with SCIg (16% solution) therapy between January 1, 2006 and April 1, 2008. Patients selected either infusion pump or rapid push administration after receiving a description and demonstration of each method and training for home self-administration. Demographics, dose, adverse events (AEs), serum immunoglobulin G (IgG) levels, and therapy disposition (discontinued, switched technique) were recorded on a standardized data collection form. Charts for 104 patients (45 male, 59 female; mean age, 21.1 years; range, 0.5–67.6 years; SD = 17.9 years) were reviewed. Seventy-four patients (71%) chose rapid push. Mean SCIg dose was 32.11 g/month (range, 1.92–89.6 g/month; SD = 8.3 g/month) split into an average of 3.11 times per week. Volume per site ranged from 3 to 20 mL, typically administered over 5–20 min and at one site. Mean serum IgG levels did not differ significantly by administration method: pump, 1,153.06 mg/dL (SD = 240.8); rapid push, 1,225.8 mg/dL (SD = 299.8). Local infusion-site reactions were the most common AEs and were experienced by one third of patients in each group. Only two patients discontinued therapy because of an AE. The results suggest that PIDD patients prefer SCIg administered as a rapid push rather than as conventional pump infusion. Serum IgG levels were comparable between methods, and safety was similar, if not slightly better, with rapid push. Rapid push offers the potential for even greater convenience than the pump infusion technique, although these results should be confirmed in prospective studies.

For patients with the most frequent type of primary immunodeficiency diseases (PIDD) characterized by antibody production defects, treatment with immunoglobulin (IgG) replacement therapy is the mainstay of treatment. Since 1982, intravenous immunoglobulin (IGIV) therapy has been the standard treatment in the United States. However, interest in subcutaneous immunoglobulin (IGSC) therapy has increased over the past 5 to 10 years based largely on the extensive use of this approach in Scandinavia and the development of new IGSC products in the US that led to FDA approval of IGSC for the treatment of PIDD in 2006. At the center of management of PIDD with IgG therapy are two main issues. The first is helping patients choose the appropriate IgG delivery modality best suited for them based on the benefits and limitations of each type of treatment. The second involves a new paradigm that has emerged that emphasizes individualizing therapy for each patient to prevent infection versus achieving a standard IgG dose or trough level for all patients. The articles in this supplement examine both these issues as part of an overall discussion of the latest research on IgG therapy for PIDD. The articles are based on presentations given by leading immunologists on these issues at a CME symposia series that was offered in five major US cities in 2011. This supplement is supported by an educational grant from Baxter, which also supported the symposia series. We hope that ultimately the issues discussed in this supplement will offer physicians not only expert perspective but practical clinical guidance on strategies to individualize IgG therapy for their patients with PIDD. Ralph Shapiro, MD Midwest Immunology Center Plymouth, Minnesota

An emerging paradigm for the treatment of primary immunodeficiency disease (PIDD) with immunoglobulin (IgG) replacement therapy emphasizes the tailoring of treatments to each patient with the goal of preventing infections and minimizing side effects. Increasing evidence shows that the IgG dose needed to prevent infection varies with each patient, and both intravenous immunoglobulin (IGIV) and subcutaneous immunoglobulin (IGSC) have emerged as feasible modes of delivery. Although IGIV is currently the routine treatment, IGSC is increasingly being chosen as the preferred route of delivery due to greater flexibility and reduced side effects.

Immunology and Allergy Clinics of North America - In Press.Proof corrected by the author Available online since vendredi 6 juillet 2012

Since 2005, when changes in Medicare reimbursement for IgG replacement therapy went into effect, physicians and patients with primary immunodeficiency disease (PIDD) have encountered a number of challenges to administering and receiving appropriate immunoglobulin therapy. A 2006 membership survey conducted by the American Academy of Allergy, Asthma & Immunology found that 95 % of responders thought that the health of their patients was at risk due to Medicare changes; many patient surveys also found a significant number adversely affected by these changes. Decisions critical for optimal care being made by third-party payors are often in conflict with guidelines on recommended standard of care. Many payors, for example, are dictating where infusions can occur despite evidence clearly demonstrating that choice of the site of care needs to be determined by the particular patient’s circumstance and experience. Another critical issue is the lack of product availability due to the determination by payors of which IgG products appear on formularies. Patients, physicians, and payors all bring their own perspective to these issues, and finding a solution to these challenges requires balancing the needs of all three groups.

Analysis of the genomic termini of Epstein-Barr virus can provide valuable insight into the cofactor role of EBV in the development of B cell lymphomas and lymphoproliferative disease. We report EBV genomic findings in pathologic specimens from 10 patients who developed lymphoma or lymphoproliferative disease after renal or bone marrow transplantation. Endonuclease restriction patterns of EBV genomic termini are highly variable in size in both the episomal and linear configuration. This variability in fragment size permits direct assessment of tissue clonality in EBV-infected material. Hybridization with terminus-specific probes also reveals configuration of viral genome (circular and latent vs. linear and replicative). Nine of 10 patients had tumors with mono- or biclonal episomal markers, and 4 of 10 had evidence of linear or replicative virus. Analyses of virally determined markers were compared to immunoglobulin gene rearrangement studies, histologic immunophenotyping, cytogenetics, and clinical outcome. These 10 cases represent a spectrum of lymphoproliferative disorders ranging from benign polyclonal to malignant monoclonal disease. The molecular data lend credence to two important aspects of viral pathogenesis: (1) the finding of a homogeneous episomal population in the monoclonal tumors suggests that EBV infection is an early event in tumorigenesis that occurs before clonal expansion; and (2) therapeutic efficacy of acyclovir has been shown only in presence of polyclonal disease but may impact on intermediate stages where linear replicative virus can be found. Finally, the various assessments of tumor clonality were compared, and although heterogeneity was seen among patients and among diagnostic methods, analyses at the molecular level using virus and immunoglobulin gene specific probes were concurrent and provide the more sensitive means for detection of clonality.

A critical examination is given of two recent claims of association between solar and meteorological variability. One of these claims (Markson, 1971, 1978a) was chosen for examination because it invokes a possible physical mechanism, the other (Wilcox et al., 1974, 1976) because it has received widespread attention and acceptance. The evidence offered here, while not addressed to any physical mechanism, clearly indicates that the claims of association are unsubstantiated and most likely have arisen from statistical sampling fluctuations.

An attempt is made to find a relationship between solar variability and weather using the skill scores of an objective weather forecasting procedure as the basis of analysis. The hypothesis being tested rests on the nature of a numerical weather prediction model as an initial value problem and on the fact that the model does not include, either explicitly or implicitly, the effects of solar variability which occur between the time of the initial input data and the time of forecast verification. Therefore, solar disturbance, if it affects the weather, is expected to result in forecasts which are less skillful than average and the lack of solar disturbance, in more skillful forecasts. Geomagnetically disturbed and quiet days are used as measures of solar disturbance and solar quiet, respectively. In addition, the interplanetary magnetic sector structure is also used as a measure of organized solar activity. Although some of the results may be interpreted as indicating a real solar effect, that are ...

The Northern Hemisphere 700 mb contour heights from 20 N to 70 N for the period 1947-1970 are studied in conjunction with 272 key days, where the daily increase of the Ci index equals or exceeds 1.0. The superposed epoch method is applied from 33 days before to 66 days after the key day for a variety of zonal and meridional indices. It is shown that the 700 mb height difference between 20 N and 55 N increases significantly in winter 4 days following geomagnetic disturbance (in summer a less prominent but statistically significant increase is found 2 days earlier). The effect is most clear in winter in the quadrant 90-175 W and corresponds to a 7% increase in the mean geostrophic westerly flow. The statistical significance of the results is established by applying Student's t-test to the difference of each daily mean from the continuum.

The nondivergent barotropic vorticity equation on a sphere supplies the framework for a series Of experiments designed to study the suitability of numerical methods commonly used in the modeling and prediction of the atmosphere. Specifically, making use of idealized initial conditions and a scale-dependent spatial filter we investigate the capabilities and limitations of a typical second-order finite-difference approximation in numerical time integrations. From comparisons with analytic solutions, it is found that for dynamically stable flows numerical methods such as second-order finite-difference approximations, together with a Shapiro-type filter, are adequate in yielding approximate solutions to the modeling differential equations. For dynamically unstable flows, numerical errors are amplified as part of the dynamics of the unstable system. The use of finite-difference approximations may yield solutions which bear no resemblance whatsoever to the true solution of the differential equations in...

The solar magnetic sector structure has recently been reported to be related to the atmospheric absolute vorticity (Wilcox et al., 1973, 1974). An examination of some of the statistics of this association shows that it may not be as highly significant as had been postulated, and raises serious question of its physical reality. A comparable analysis of the atmospheric relative vorticity shows that it responds in a more consistent fashion to the solar sector structure. The implication of this analysis is that if a physically real association exists, the solar sector structure is more likely to he related to the relative vorticity rather than the absolute vorticity.

An assay procedure has been developed for virginiamycin in mash-type feeds which includes removing fat interferences from the feeds by a rapid petroleum ether wash, a citric acid extraction, an acetone extraction, and the use of the pad-plate diffusion system. The procedure eliminates the need for compensatory curves prepared from feeds of the same or similar composition. Recoveries from 10 laboratory-prepared feeds containing 11.0 μg virginiamycin/g averaged 89.3% with a coefficient of variation (CV) of 5.76%. Recoveries from a laboratory-prepared feed containing 13.2 μg virginiamycin/g averaged 89.9% (CV 9.92%). The procedure is simple, reasonably accurate, and precise.

An improved amplitude restoring interpolation operator is specialized into a form that corrects the phase error as well as the amplitude damping introduced by two-point linear interpolation. The efficiency and accuracy of the operator is demonstrated by a series of test comparisons with amplitude restoring interpolation and cubic spline interpolation.

A simple linear smoothing operator of general order p is constructed for discretized functions. It is particularly suited for problems in numerical integration where it is necessary or desirable to suppress two-grid-interval waves. The operator is ideal in the sense that for the class of damping operators of order p, which remove two-grid-interval waves without changing the phase of any wave component, this operator produces the least damping of the amplitudes of all other waves.

The hypothesis that the ejection of solar corpuscles is influenced by interactions of ‘active region’ magnetic fields is tested empirically. The results do not support the hypothesis.

Power spectra and cross spectra of surface pressure variations in polar regions compared to solar emission, noting Antarctic-Arctic relationship

A high-resolution power spectrum of 72 years of daily values of the international magnetic character figure, Ci, shows two subsidiary peaks on either side of the well-known 27-day period. The larger of the two subsidiary peaks is situated close to the lunar synodic period of 29.53 days. The origin of the subsidiary peaks is examined. A lunar association is rejected as a significant causal agent, along with various errors and bias. It is concluded that the subsidiary peaks represent some real phenomenon and are probably produced by solar activity, although perhaps indirectly.

By subjecting functions of known spectral constitution to a conventional procedure of obtaining the spectral estimates, the combined effect of the observation system and the method of interpolation on the spectral estimates are statistically assessed. The results suggest that linear interpolation applied on currently available observations may produce spectral estimates that yield an overestimated value for the slope of the spectral profile in the range 10 ≲ k ≲ 20, where k is the hemisphere wavenumber.

The relationship between geomagnetic activity and the intensity of the 5577 A [O I] line in the night airglow is presented. The correlation that is used accounts for missing data in the airglow time-series and, what is more important, allows for the effects of the high correlation between successive data points. The results for the period studied (1953–1960) indicate an inverse relationship between airglow intensity and the geomagnetic index Kp for values of the index between 0 and 7 and a direct relationship for index values of 8 and 9. Statistical tests show the inverse relationship to be marginally significant at the 5 per cent confidence level. The direct relationship for values of Kp equal to 8 or 9 depends on a total of 10 data points; although much emphasis on this result is premature, it is not inconsistent with previous results.

Observations of the persistence of the surface pressure distribution are compared for two regions of the northern hemisphere. One region covers most of North America ; the other region is comparable in size and is centered on the Greenwich meridian. The linear correlation coefficient is used as a quantitative measure of persistence. The European pressure distribution is found to have considerably greater persistence up to periods of three days. Comparison of the monthly means of the persistence observations and crude measures of the vertical wind shear indicate that the atmosphere behaves in a manner which is consistent with the conclusions of theoretical studies on the growth of atmospheric disturbances.

Variance (power) spectra of time series (7⅓ yr) of the individual Fourier components of the meridional geostrophic kinetic energy at 500 mb are presented. The spectra show a pronounced annual period. No other significant periodicities are found.

In a recent paper Shapiro and Ward [1966] showed that the 27-day variation of geomagnetic disturbance indices possesses two prominent side lobes: one at about 29.4 days and the other at about 26.0 days. Coleman and Smith [1966] have claimed that the side lobes are produced by an annual amplitude modulation of the 27-day variation. Such a modulation of the principal peak at 27.4 days would in fact produce side lobes at 29.6 and 25.5 days, which are in reasonably close agreement with the observed peaks. However, Coleman and Smith did not show that such an annual amplitude modulation was in fact taking place nor did they inquire as to the amount of modulation that might be necessary to produce side lobes as large as those observed in the Ci spectrum.

An analysis of the sea-level pressure distribution over North America for 47 years (1899–1945) provides what appears to be firm evidence of a solar-weather effect and tends to confirm an earlier pilot study. A pronounced decrease in a persistence correlation is found to occur about two weeks after large increases in geomagnetic activity. A qualitative interpretation of the observed effect is advanced in the light of some recent experimental and theoretical work.