A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients

PurposeDespite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include.MethodsTo inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT.ResultsWe identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria.ConclusionOpportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.     

Breast and prostate cancer risk: The interplay of polygenic risk,rare pathogenic germline variants,and family history

PurposeWe aimed to investigate to what extent polygenic risk scores (PRS), rare pathogenic germline variants (PVs), and family history jointly influence breast cancer and prostate cancer risk.MethodsA total of 200,643 individuals from the UK Biobank were categorized as follows: (1) heterozygotes or nonheterozygotes for PVs in moderate to high-risk cancer genes, (2) PRS strata, and (3) with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio across groups and the cumulative incidence through life.ResultsCumulative incidence by age 70 years among the nonheterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast cancer and prostate cancer, respectively. Among the PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history was always associated with an increased cancer odds ratio.ConclusionPRS alone provides a meaningful risk gradient leading to a cancer risk stratification comparable to PVs in moderate risk genes, whereas acts as a risk modifier when considering high-risk genes. Including family history along with PV and PRS further improves cancer risk stratification.     

High detection rate from genetic testing in BRCA-negative women with familial epithelial ovarian cancer

PurposeEpithelial ovarian cancer (EOC) is associated with pathogenic variants (PVs) in homologous recombination and/or mismatch repair genes. We aimed to review the testing of women with familial EOC at our center.MethodsWomen with familial EOC (≥2 EOC in family, including index case) referred to our center between 1993 and 2021 were included. Genetic testing (BRCA/Lynch syndrome screening, exome sequencing, panel testing, 100,000 Genome Project, and NIHR BioResource genome sequencing) and clinical demographic, diagnosis, and survival data were reviewed.ResultsOf 277, 128 (46.2%) women were BRCA heterozygotes (BRCA1: 89, BRCA2: 39). The detection rate in BRCA-negative women was 21.8%; the most commonly affected gene was BRIP1 (5.9%). The non-BRCA detection rate was significantly higher in families with 2 affected members with EOC only (22.4%) than the families with ≥3 (11.1%) affected members (odds ratio = 9.9, 95% CI = 1.6-105.2, P = .0075). Overall, 112 different PVs in 12 homologous recombination/mismatch repair genes were detected in 150 of 277 (54.2%) unrelated women.ConclusionThis is the largest report of women with familial EOC undergoing wider testing to date. One-fifth of BRCA-negative women were heterozygous for a PV in a potentially actionable gene. Wider genetic testing of women with familial EOC is essential to optimize their treatment and prevention of disease in family members.     

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals

PurposeTo measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.MethodsWe used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards.ResultsOne in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders.ConclusionMedically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.     

The role of patient education and physician support in self-efficacy for skin self-examination among patients with melanoma

ObjectiveThis project aims to elucidate the relationships between skin self-examination (SSE), perceived physician support of SSE, and self-efficacy for SSE among melanoma patients.MethodsA longitudinal study of patients diagnosed with melanoma was conducted over the span of 18 months. Participants filled out questionnaires at four assessment points and participated in an SSE education about the early signs of melanoma.ResultsAmong the 242 patients enrolled, the level of self-efficacy for SSE was 23% higher immediately after the educational intervention (p < .001) and the increase was retained three months (p < .001) and twelve months later (p < .001). Additionally, a one-way repeated measures ANOVA revealed that the perceived physician support of SSE positively corresponded to the level of patient self-efficacy with higher patient-reported physician support being related to higher self-efficacy (p = .001).ConclusionPatient education and perceived physician support of SSE are positively associated with patients’ level of self-efficacy.Practice implicationsPhysicians caring for melanoma survivors should be aware that, both SSE education and patients’ perception of high physician support of SSE may be associated with higher self-efficacy for checking one’s own skin for signs of cancer recurrence.     

Does maternal fermented dairy products consumption protect against cow's milk protein allergy in toddlers?

BackgroundCow's milk protein allergy (CMPA) is the most common immunoglobulin E-mediated food allergy in childhood.ObjectiveTo investigate the potential impact on the disease of the frequency, amount, and diversity of maternal consumption of fermented dairy products (FDP) during pregnancy and lactation in children with immunoglobulin E-mediated CMPA.MethodsOne hundred sixty toddlers (80 with physician-diagnosed CMPA and 80 healthy controls) and their mothers participated in this case-control study. The data were collected using a structured questionnaire and were compared between the 2 groups.ResultsThe most commonly consumed FDP were cheese, yogurt, and tarhana. The amounts of maternal yogurt, tarhana, and kefir consumed during pregnancy (P < .001, P < .001, and P = .04, respectively) in addition to yogurt and tarhana consumption during lactation (P < .001 and P = .001, respectively) were lower in toddlers with CMPA. The frequency of maternal consumption of yogurt, cheese, and tarhana during lactation (P = .001, P = .003, and P = .02, respectively) and the diversity of FDP were also lower in toddlers with CMPA (P = .001). At multivariate logistic regression analysis, maternal weight gain during pregnancy (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.04-1.18; P = .001), maternal age (OR, 1.20; 95% CI, 1.09-1.31; P < .001), and gestational age at birth (OR, 1.23; 95% CI, 1.03-1.48; P = .02) increased the odds of the baby having CMPA. The diversity of FDP consumed during lactation was protective against CMPA (OR, 0.439; 95% CI, 0.272-0.711; P = .001).ConclusionWeekly maternal consumption of FDP was low during pregnancy and lactation in toddlers with CMPA. Although the diversity of FDP consumed during lactation may reduce the risk of CMPA, this effect was not observed during pregnancy.     

Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer

PurposeCTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied.MethodsDe-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers.ResultsFifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers.ConclusionCTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.     

Real-world tree nut consumption in peanut-allergic individuals

BackgroundIndividuals with peanut allergy often avoid tree nuts, yet true rates of tree nut allergy in peanut-allergic individuals are as low as 7%.ObjectiveTo examine tree nut sensitization patterns in peanut-allergic individuals, patient and family choice regarding tree nut consumption, and factors that influence consumption of tree nuts.MethodsAll patients presenting for peanut allergy evaluation to an outpatient allergy office were included during a 4-month period. In addition to demographic information, sensitization to tree nuts and tree nut consumption were collected. Logistic regression was performed to generate odds ratios with 95% CIs in univariate and multivariate analyses for variables that predict tree nut consumption.ResultsA total of 258 individuals with peanut allergy were enrolled. Ninety-five (36.8%) consumed all tree nuts ad libitum, 63 (24.4%) consumed some but not all tree nuts, and 100 (38.8%) consumed no tree nuts. Of the 100 electively avoiding all tree nuts, the most commonly reported reason was fear of cross-contact (50%). Although there was no difference between rates of sensitization between individual tree nuts (P = .056), cashew and pistachio had higher serum specific IgE levels compared with other tree nuts (P < .001). The tree nut most commonly consumed by peanut-allergic individuals was almond (P < .001). Consumption of foods with precautionary labeling was the strongest predictor of tree nut consumption in peanut allergic individuals (P < .001)ConclusionOur data highlight the potential for safe introduction of tree nuts in peanut-allergic individuals and indicate that peanut-allergic individuals who consume foods with precautionary labeling are most likely to consume tree nuts.     

A clinical scoring system for early onset (neonatal) Marfan syndrome

PurposeThis study aimed to develop objective diagnostic criteria for early onset Marfan syndrome (eoMFS) to facilitate early diagnosis and timely interventions.MethodsOn the basis of an extensive literature review and the responses from a survey distributed among providers with expertise in the diagnosis and management of eoMFS, we developed an age-based, diagnostic scoring system encompassing 10 features common to eoMFS (9 clinical + 1 laboratory) and divided them into cardiac, systemic, and FBN1 (on the basis of the location of the pathogenic FBN1 variant) scores.ResultsIn total, 77 individuals with eoMFS (13 newly reported) and 49 individuals diagnosed with classical Marfan syndrome during early childhood were used to validate the criteria. Median cardiac (8 vs 0, P < .001), systemic (11 vs 3, P < .001), FBN1 (5 vs 0, P < .001), and total (23 vs 4, P < .001) scores were significantly higher in individuals with eoMFS than in those without. A proposed clinical score (cardiac + systemic) cutoff of ≥14 points showed excellent sensitivity (100%), specificity (92%), and reliability (correctly classified = 94%).ConclusionDistinct from classical Marfan syndrome in phenotype and morbidity, eoMFS can be diagnosed clinically using an objective scoring system encompassing the typical physical features and cardiac disease manifestations. Although genetic testing can be suggestive of eoMFS, genetic testing alone is insufficient for diagnosis.     

Serial Measurement of WT1 Expression and Decrement Ratio Until Hematopoietic Cell Transplantation as a Marker of Residual Disease in Patients with Cytogenetically Normal Acute Myelogenous Leukemia

Using real-time quantitative PCR, we monitored Wilms tumor gene 1 (WT1) expression from diagnosis to hematopoietic stem cell transplantation (HSCT) in adult patients with cytogenetically normal acute myelogenous leukemia (CN-AML) and FLT3-ITD and NPM1 mutations. The values at diagnosis were evaluated in 104 patients. Data collected after induction chemotherapy were available for all patients, but only 68 patients were treated with HSCT. Significant WT1 expression cut-offs were determined by receiver operation characteristic curve analysis, and rates of overall survival (OS) and disease-free survival (DFS) were estimated. WT1 decrement ratios (DR) at postinduction chemotherapy and at pre- and post-HSCT compared with the diagnostic level were calculated. Higher WT1 expression at diagnosis, postinduction chemotherapy, and pre-HSCT showed inferior OS (P = .015, <.001, and .002) and DFS (P = .006, <.001, and .003). The cut-offs were determined at the median for diagnostic WT1 expression and at the 25% level from the top for other time points excluding post-HSCT. The WT1 DR ≥ 1-log after induction chemotherapy showed superior OS and DFS (P = .009 and .002) and WT1 DR ≥ 1-log preceding HSCT also showed superior OS and DFS (P = .009 and .003). Results of WT1 DR were consistently applicable in each subgroup with higher (≥1.0) and lower (<1.0) WT1 expression at diagnosis and also in NPM1-wild-type/FLT3-ITD–negative CN-AML. The WT1 DR therefore predicted survival outcomes after HSCT more accurately than did the diagnostic WT1 expression. WT1 expression may serve as a reliable marker for residual disease and WT1 DR as a prognostic indicator, particularly in NPM1-wild-type/FLT3-ITD–negative CN-AML. These measures may be applied throughout the course of treatment and even after HSCT.     

Efficacy and safety of grass sublingual immunotherapy tablet,MK-7243: a large randomized controlled trial

BackgroundIn North America, few studies have evaluated sublingual immunotherapy for allergic rhinitis with or without conjunctivitis (AR/C); pediatric data are sparse. The authors report findings from the largest published immunotherapy trial yet conducted in adults and children.ObjectiveTo evaluate grass sublingual immunotherapy tablet (MK-7243) treatment in subjects with AR/C.MethodsNorth American subjects (5–65 years old) with grass allergy were randomized 1:1 to once-daily MK-7243 (2,800 BAU Phleum pratense) or placebo. The first dose was given at the investigator's office; subsequent doses were self-administered at home. The primary end point was total combined score (TCS; rhinoconjunctivitis daily symptom score [DSS] plus daily medication score [DMS]) over the entire grass pollen season (GPS). Key secondary end points included entire-season DSS, DMS, peak-season TCS, and rhinoconjunctivitis quality-of-life questionnaire scores. Safety outcomes included adverse events (AEs).ResultsOne thousand five hundred one subjects were randomized (85% polysensitized, 25% had asthma). MK-7243 yielded improvements vs placebo of 23% in entire-season TCS (median difference −0.98, P < .001), 29% in peak-season TCS (median difference −1.33, P < .001), 20% in entire-season DSS (median difference −0.64, P = .001), 35% in entire-season DMS (mean difference −0.48, P < .001), and 12% in peak-season rhinoconjunctivitis quality-of-life questionnaire (median difference −0.13, P = .027). Efficacy between children and adults was similar. Most AEs were transient local application-site reactions, with no serious treatment-related AEs or anaphylactic shock. Three subjects (1 placebo, 2 MK-7243) had moderate systemic allergic reactions.ConclusionMK-7243 was effective in polysensitized grass-allergic North American children and adults with AR/C in this large trial, confirming previous research.     

Trends in eczema,rhinitis, and rye grass sensitization in a longitudinal asthma cohort

BackgroundAtopic conditions are prevalent in the Western world, with limited long-term data on atopic trends in patients with asthma.ObjectiveTo describe the trends in eczema, rhinitis, and allergic sensitization in a longitudinal childhood asthma cohort.MethodsFour hundred eighty-four patients were recruited at 7 years of age and followed regularly to 50 years of age. Subjects completed an interviewer-administered questionnaire to define current eczema and rhinitis. Skin prick testing to rye grass also was performed.ResultsThe participation rate over the past 4 decades has been maintained at 72% to 91%. There was a decrease in the prevalence of eczema in the past 12 months in groups with viral-associated wheeze (21% to 8%, P = .002), asthma (47% to 18%, P < .001), and severe asthma (69% to 28%, P < .001) from 14 to 21 years of age. Conversely, there was an increase in the prevalence of rhinitis in the previous 12 months in groups without asthma (1% to 6%, P = .04; 1% to 20%, P = .008), with viral-associated wheeze (16% to 28%, P = .006; 16% to 49%, P < .001), and with asthma (45% to 56%, P = .2; 45% to 73%, P = .014) from recruitment to 10 and 14 years of age, respectively. There were 2 peaks in prevalence in the sensitization to rye grass in this cohort from 7 to 10 years of age and from 14 to 21 years of age in all groups.ConclusionThe adolescence phase appears to be an important period in the body's response to allergens whereby eczema decreases in prevalence, whereas rhinitis and rye grass sensitization increase in prevalence.     

Incidence of and risk factors for perioperative or periprocedural anaphylaxis in the United States from 2005 to 2014

BackgroundThe estimated worldwide incidence of perioperative or periprocedural anaphylaxis (PA) is between 1 in 1250 and 1 in 20,000 procedures.ObjectiveTo evaluate the incidence of PA in the United States and compare patient characteristics and underlying risk factors using a large national database.MethodsUsing deidentified data from the nationwide inpatient sample from 2005 to 2014, we identified cases of PA through the International Classification of Diseases, Ninth Revision, Clinical Modification codes and conducted a retrospective analysis.ResultsAmong 35,647,347 surgeries and procedures, there were 5458 (0.015%) PA cases identified. The incidence of PA was 15.3 cases per 100,000 procedures. When compared with controls, PA cases had an increased mortality (3.4% vs 1.4%; P < .001), median length of stay (5 vs 3 days; P < .001), and median hospital cost ($45,155 vs $24,734; P < .001). The age group between 18 and 34 years (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.13-1.58; P < .001) and female sex (OR, 1.40; 95% CI, 1.31-1.49; P < .001) were associated with increased odds of PA. Transplant (OR, 3.35; 95% CI, 2.59-4.34; P < .001), hematologic (OR, 1.63; 95% CI, 1.30-2.05; P < .001), vascular (OR, 1.49; 95% CI, 1.30-1.67; P < .001), and cardiac (OR, 1.47; 95% CI, 1.30-1.67; P < .001) procedures were at increased risk for PA. Several comorbidities were associated with PA including chronic pulmonary disease (OR, 1.41; 95% CI, 1.31-1.51; P < .001).ConclusionThe incidence of PA is 1 in 6531 procedures, with a mortality of 1 in 191,652 procedures. PA has worsening outcomes compared with controls. The risk factors of PA include age, sex, procedure type, and comorbidities.     

Changes in cat specific IgE and IgG antibodies with decreased cat exposure

BackgroundCurrent understanding of the effects of reducing exposure to cat allergens is limited. It has also become clear that there are different forms of immune response to cat allergens.ObjectiveTo investigate changes in skin tests and cat specific IgG and IgE antibodies when students from a home with a cat move to a college dormitory.MethodsNinety-seven college students participated in a prospective study that consisted of allergy skin prick testing and serum measurement of IgE and IgG antibodies to cat at the beginning and end of one academic year in college. A subgroup returned for follow-up at the end of 2 years.ResultsAmong 97 students, 33% had IgG antibodies to Fel d 1 but no evidence of sensitization, 25% had positive skin test results and/or serum IgE antibodies, and 42% had negative skin test results and no detectable serum antibodies. Among the non–cat sensitized students with IgG antibodies, the titers decreased during 8 months (P = .002). Titers of IgG4 to Fel d 1 also decreased (P < .001). Among the sensitized students, no change in IgE antibodies to cat occurred in 8 months (P = .20), whereas Fel d 1 specific IgG antibodies decreased (P < .001). Thus, ratios of IgG to IgE decreased highly significantly (P = .007). Among the students with negative skin test results who returned for follow-up (n = 56), none developed positive skin test results or serum IgE antibodies.ConclusionUnder conditions of marked decrease in exposure, no participants developed new-onset sensitization. Among the individuals sensitized at study entry, there were major decreases in the ratio of IgG to IgE.     

Association between cognitive function and asthma in adults

BackgroundCognitive deficits are associated with asthma globally; however, the association between cognitive function and asthma has not been fully elucidated.ObjectiveTo assess the relationship between asthma and cognitive function.MethodsA total of 202 patients with asthma aged older than 18 years were analyzed retrospectively from August 2019 to February 2020. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) test. We compared the associations of clinical parameters with cognitive function (MoCA, ≥23 vs <23) and lung function (forced expiratory volume in 1 second [FEV1], ≥70% vs <70%).ResultsOf the total participants, 89 (44.1%) indicated cognitive impairment, of whom23.1% were aged less than 65 years and 72.9% were aged 65 years or older. MoCA scores were significantly different according to age (24.91 ± 3.89 for ages <65 years vs 19.11 ± 5.11 for ages ≥65 years, P < .001) and lung function (23.29 ± 5.17 for FEV1 ≥70% vs 21.23 ± 5.21 for FEV1 <70%, P = .006), but not according to asthma control (22.35 ± 5.38 for nonsevere asthma vs 22.88 ± 4.91 for severe asthma, P = .55). Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.014-1.13; P = .01), educational status (OR, 6.068; CI, 2.175-16.927; P = .001), and asthma duration (OR, 1.007; CI, 1.001-1.013; P = .02) were significantly associated with cognitive impairment.ConclusionCognitive impairment was largely observed in adults (44.1%) with asthma and was more prevalent in older adults than in younger adults. Longer asthma duration and lower lung function were more associated with cognitive dysfunction.     

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

PurposeGermline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.MethodsWe collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.ResultsEstimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.ConclusionThese results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.     

The frequency and characteristics of epinephrine use during in-flight allergic events

BackgroundAllergic reactions account for 2% to 4% of medical events in-flight and 5.5% of all medical events in passengers 18 years and under.ObjectiveTo evaluate the incidence of in-flight allergic events including availability, use of epinephrine, and final patient outcome.MethodsWe conducted a retrospective study of the ground-based medical service (GBMS) database from January 2017 to December 2019 for all allergic events and epinephrine utilization.ResultsA total of 140,579 in-flight medical events (IFMEs) were initially retrieved from the period between January, 2017 and December, 2019, of which 4230 (3.0%) unique cases were identified as allergic events. Epinephrine administration was recommended in 398 passengers by GBMS. Of those, 328 (82.4%) ultimately received at least 1 dose of epinephrine. In multivariate analysis, there was a significant difference in the involvement of volunteers (odds ratio [OR], 3.19; P value < .001; 95% confidence interval [CI], 2.43-4.16), availability of autoinjectors (OR, 2; P value < .001; 95% CI, 1.55-2.58), flight diversion (OR, 11.21; P value < .001; 95% CI, 3.60-34.89), and hospital transport (OR, 6.58; P value < .001; 95% CI, 4.62-9.38) between the 2 groups. Passengers older than 12 years of age were at a higher risk for epinephrine administration. In the secondary analysis of 51 airlines that consistently use GBMS for all IFMEs, the incidence of allergic events was found to be 0.91 cases per million passengers. The incidence of severe in-flight allergic emergencies requiring epinephrine administration was 0.08 cases per million passengers or 12.5 million passengers for 1 event.ConclusionIFME requiring epinephrine administration is rare with an incidence rate of 1 event in 12.5 million passengers. The risk for epinephrine administration is higher in passengers more than 12 years of age and is associated with significantly higher flight diversion, hospital transport, and involvement of medical volunteers.     

Quadriceps muscle compensatory activations are delayed following anterior cruciate ligament reconstruction using hamstring tendon graft

BackgroundCompensatory and anticipatory quadriceps activation (CQA and AQA) in response to postural perturbations are essential for functional stability of the knee. This study aimed at investigating CQA and AQA before and after anterior cruciate ligament reconstruction (ACLR) using hamstrings graft.MethodsTwelve participants with ACLR and 12 healthy controls were exposed to 10 either unpredictable or predictable perturbations of the knee before ACLR (T1), two months (T2) and six months (T3) after surgery. Latencies of CQA and AQA in vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM) were measured.ResultsLatency of CQA was delayed in ACLR compared to controls at T1 for VL (105 ± 25 vs. 57 ± 9 ms; P < .001), RF (102 ± 23 vs. 56 ± 9 ms; P < .001) and VM (107 ± 24 vs. 66 ± 16 ms; P < .001), at T2 for VL (68 ± 14 vs. 55 ± 10 ms; P < .01) and at T3 for VL (105 ± 22 vs. 58 ± 7 ms; P < .001), RF (102 ± 22 vs. 58 ± 12 ms; P < .001) and VM (106 ± 20 vs. 63 ± 8 ms; P < .001). AQA occurred earlier in ACLR than in controls at T1 for VL (− 82 ± 64 vs. − 14 ± 11 ms; P < .05) and VM (− 105 ± 68 vs. -9 ± 12 ms; P < .05).ConclusionCQA are delayed following ACLR with hamstring graft and should be addressd by post-surgical rehabilitation.     

Current medical management of hereditary angioedema: Follow-up survey of US physicians

BackgroundPhysician surveys on hereditary angioedema (HAE) management in 2010 and 2013 revealed important trends in HAE care.ObjectiveTo evaluate current HAE management and the impact of new treatment options on physician practice patterns over time.MethodsDuring June and July 2019, 5382 physicians were contacted by means of postal mail to complete a 47-question survey; 177 responded (3%).ResultsAcross the 3 surveys, the home replaced the emergency department as the most typically reported setting for HAE attack treatment (54.3% vs 11.6% in 2010 and 32.5% in 2013; P < .001). Physicians reported C1 esterase inhibitor (C1-INH) as the most typically prescribed long-term prophylactic treatment (LTP) (60.0% vs 20.4% in 2010 and 56.7% in 2013; P < .001). Subcutaneous LTP medications were most typically prescribed over intravenous (C1-INH, 41.4%; subcutaneous lanadelumab, 21%; intravenous C1-INH, 18.6%). Danazol, the most frequently prescribed LTP treatment, dropped to 6.4% (55.8% in 2010 and 23.4% in 2013; P < .001). The strongest nonefficacy factor influencing clinician treatment choice changed over time, with cost and (or) insurance coverage increasing to 43.7% (from 24.4% in 2010 and 40.5% in 2013; P = .001), whereas the concern over adverse effects dropped to 16.2% (from 55.8% in 2010 and 29.5% in 2013; P < .001). Physician-reported patient satisfaction remains high, with only 1.5% of physicians indicating patients are not satisfied with treatment.ConclusionThe US physician survey data reflect improvements in the HAE management in recent years. Therapeutic advances in HAE have led to reported higher rates of home treatment of HAE attacks, reduced concern for adverse treatment effects, and high levels of patient satisfaction.