Safety and Immunogenicity of an mRNA-Based RSV Vaccine Including a 12-Month Booster in a Phase I Clinical Trial in Healthy Older Adults.

BACKGROUND: An mRNA-based RSV vaccine, mRNA-1345, is under clinical investigation to address RSV disease burden in older adults. METHODS: This phase 1, randomized, observer-blind, placebo-controlled, dose-ranging study evaluated safety, reactogenicity, and immunogenicity of mRNA-1345 in adults 65-79 years (NCT04528719). Participants were randomized to receive 1-dose of mRNA-1345 (12.5, 25, 50, 100, or 200-µg) or placebo and matched mRNA-1345 booster or placebo at 12-months. RESULTS: Overall, 298 participants received the first injection; 247 received the 12-month booster injection. mRNA-1345 was generally well-tolerated after both injections, with the most frequently reported solicited adverse reactions being injection-site pain, fatigue, headache, arthralgia, and myalgia. Reactogenicity was higher after the booster injection than the first injection but similar severity, time-to-onset, and duration. A single mRNA-1345 injection boosted RSV-A and RSV-B neutralizing antibody titers (nAb) and prefusion-F-binding antibody (preF-bAb) concentrations at 1-month (geometric mean-fold rises: RSV-A, 10.2-16.5; RSV-B, 5.3-12.5; preF-bAb, 7.2-12.1). RSV antibody levels remained above baseline through 12-months, indicating immune persistence. A 12-month booster injection also increased RSV-A and RSV-B nAb titers and preF-bAb concentrations; titers post-booster injection were numerically lower compared to titers after the first-dose, with overlapping 95% CIs. CONCLUSIONS: mRNA-1345 was well-tolerated and immunogenic following a single injection and a 12-month booster. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04528719.

Three-month antibody persistence of a bivalent Omicron-containing booster vaccine against COVID-19.

We previously presented day 29 interim safety and immunogenicity results from a phase 2/3 study (NCT04927065) comparing the Omicron-BA.1-containing bivalent vaccine mRNA-1273.214 (50-µg) to the 50-µg mRNA-1273 booster in adults who previously received the mRNA-1273 primary series (100-µg) and mRNA-1273 first booster (50-µg) dose. Primary endpoints were safety, non-inferiority of the neutralizing antibody (nAb) and seroresponse against Omicron BA.1, superiority of the nAb response against Omicron-BA.1, and non-inferiority of the nAb response against ancestral SARS-CoV-2 for second boosters of mRNA-1273.214 versus mRNA-1273 at days 29 and 91. The key secondary endpoint was the seroresponse difference of mRNA-1273.214 versus mRNA-1273 against ancestral SARS-CoV-2 at days 29 and day 91. Participants were sequentially enrolled and dosed with 50-µg of mRNA-1273 (n = 376) or mRNA-1273.214 (n = 437) as second booster doses. Here we present day 91 post-booster results. In participants with no pre-booster, severe acute respiratory syndrome coronavirus 2-infection (SARS-CoV-2), mRNA-1273.214 elicited Omicron-BA.1-nAb titers (95% confidence interval [CI]) that were significantly higher (964.4 [834.4-1114.7]) than those of mRNA-1273 (624.2 [533.1-730.9]) and similar to those of mRNA-1273 against ancestral SARS-CoV-2 at day 91. mRNA-1273.214 also induced higher binding antibody responses against Omicron BA.1 and alpha, gamma and delta variants than mRNA-1273. Safety profiles were similar for both vaccines. The Omicron-BA.1 bivalent vaccine improved antibody responses compared to mRNA-1273 through 90 days post-booster.

A Bivalent Omicron-Containing Booster Vaccine against Covid-19.

BACKGROUND: The safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster vaccine are not known. METHODS: In this ongoing, phase 2-3 study, we compared the 50-µg bivalent vaccine mRNA-1273.214 (25 µg each of ancestral Wuhan-Hu-1 and omicron B.1.1.529 [BA.1] spike messenger RNAs) with the previously authorized 50-µg mRNA-1273 booster. We administered mRNA-1273.214 or mRNA-1273 as a second booster in adults who had previously received a two-dose (100-µg) primary series and first booster (50-µg) dose of mRNA-1273 (≥3 months earlier). The primary objectives were to assess the safety, reactogenicity, and immunogenicity of mRNA-1273.214 at 28 days after the booster dose. RESULTS: Interim results are presented. Sequential groups of participants received 50 µg of mRNA-1273.214 (437 participants) or mRNA-1273 (377 participants) as a second booster dose. The median time between the first and second boosters was similar for mRNA-1273.214 (136 days) and mRNA-1273 (134 days). In participants with no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the geometric mean titers of neutralizing antibodies against the omicron BA.1 variant were 2372.4 (95% confidence interval [CI], 2070.6 to 2718.2) after receipt of the mRNA-1273.214 booster and 1473.5 (95% CI, 1270.8 to 1708.4) after receipt of the mRNA-1273 booster. In addition, 50-µg mRNA-1273.214 and 50-µg mRNA-1273 elicited geometric mean titers of 727.4 (95% CI, 632.8 to 836.1) and 492.1 (95% CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5 (BA.4/5), and the mRNA-1273.214 booster also elicited higher binding antibody responses against multiple other variants (alpha, beta, gamma, and delta) than the mRNA-1273 booster. Safety and reactogenicity were similar with the two booster vaccines. Vaccine effectiveness was not assessed in this study; in an exploratory analysis, SARS-CoV-2 infection occurred in 11 participants after the mRNA-1273.214 booster and in 9 participants after the mRNA-1273 booster. CONCLUSIONS: The bivalent omicron-containing vaccine mRNA-1273.214 elicited neutralizing antibody responses against omicron that were superior to those with mRNA-1273, without evident safety concerns. (Funded by Moderna; ClinicalTrials.gov number, NCT04927065.).

Incidental Finding of Gallbladder Torsion During Laparoscopic Cholecystectomy.

Laparoscopic cholecystectomy is a common general surgery procedure, with over a million laparoscopic cholecystectomies performed in the United States annually. A rare presentation, which may be encountered incidentally during surgery, is torsion of the gallbladder. Gallbladder torsion is encountered in 0.01% of all patients with acute cholecystitis. It should be considered in the differential diagnosis of elderly female patients presenting with symptoms of acute or chronic cholecystitis.  In this case report, we discuss the incidental finding of gallbladder torsion during laparoscopic cholecystectomy in an 82-year-old female admitted to the hospital with symptoms of cholecystitis. Preoperative CT imaging revealed a chronic, large hiatal hernia and a dilated gallbladder containing heterogeneous densities, possibly related to sludge. During the operation, a necrotic, torsed gallbladder and long cystic duct were found. A laparoscopic cholecystectomy was performed and the remainder of the patient's hospital course was uncomplicated. Intraoperatively, our patient was found to have torsion of the gallbladder. Preoperative lab values revealed mild hyponatremia, hypokalemia, and hypochloremia with normal liver enzymes, bilirubin, and alkaline phosphatase levels. This is consistent with documented cases, as typically the biliary tree is not obstructed. Additionally, preoperative imaging rarely reveals the diagnosis. Prompt detorsion and cholecystectomy should be performed to prevent gangrene and perforation. Gallbladder torsion can result in perforation if not quickly identified and treated. We recommend prompt laparoscopic detorsion and cholecystectomy to prevent perforation.

Resection of an Asymptomatic Lymphangioma in a 76-Year-Old Male.

Lymphangiomas are benign congenital malformation comprised of the lymphatic system. They typically present in the head, neck, and axillary regions of children with <1% being described in the small bowel mesentery. We report a case of a 76-year-old man who presented with incidental large (9x6 cm) multiloculated cystic mass in the right upper quadrant (RUQ) on a CT scan performed for nephrolithiasis. He was asymptomatic at the presentation. We performed a diagnostic laparoscopy which was converted to an open procedure due to the mesenteric mass extending deeply toward the mesenteric root. The depth of invasion required small bowel resection with primary side-to-side anastomosis. Pathology confirmed a lymphangioma of the small bowel mesentery with histopathological analysis and cytology negative for malignant cells. Lymphangiomas are benign masses, however, their complete resection, including the resection of the involved organs is necessary. Incomplete resection or drainage is no longer used in management due to high rates of recurrence. Mesenteric lymphangiomas, while typically benign congenital malformations, can progress and impact surrounding structures via mass effect. Definitive treatment of lymphangiomas, even when asymptomatic, should be complete resection.

Analysis of the Changing Economics of US Hospital Transcatheter Aortic Valve Replacement Programs.

New technologies in medicine, even if they are promising medically, are often expensive and logistically difficult to implement at the hospital level. Transcatheter aortic valve replacement (TAVR) is a model technology that is revolutionary in treating aortic stenosis, but has been plagued with significant challenges with financial sustainability. In this article, a margin analysis at the hospital level was performed using literature data. A TAVR industry analysis was performed using Porter's Five Forces framework. The data indicate that TAVR is more expensive than surgical aortic valve replacement, although the cost of TAVR is declining with the use of an optimized minimalist protocol. The overall industry is growing as its clinical indications expand, and it will likely undergo significant reduction of costs when new valves enter the US market. As such, TAVR is a growing industry, with financial sustainability currently dependent on operational efficiency. A concluding list of specific program interventions is provided to help TAVR programs improve operational efficiency and clinical outcomes, as well as help decide whether to create, expand, or redirect funding for TAVR programs. Importantly, the frameworks used to analyze this rapidly evolving technology can be applied to other new technologies to determine financial sustainability.

Transcatheter Aortic Valve Replacement Programs: Clinical Outcomes and Developments.

Transcatheter aortic valve replacement is a relatively recent revolutionary treatment that has now become a standard procedure for treating severe aortic stenosis. In this article, the authors review the clinical history of transcatheter aortic valve replacement, summarize the major clinical trials, and describe the evolution of the technique over time. In doing so, the authors hope to provide a clear and concise review of the history and clinical evidence behind transcatheter aortic valve replacement.

Fibroadenoma containing lobular carcinoma in situ, an unusual finding in a normally benign mass.

This is the case of a 27-year-old female who underwent breast lumpectomy for fibroadenoma of the left breast. Pathologic evaluation of the specimen revealed lobular carcinoma in situ (LCIS) entirely confined to a large fibroadenoma without LCIS in the surrounding breast tissue.

Online Physician Reviews Do Not Reflect Patient Satisfaction Survey Responses.

Online physician reviews have become increasingly prevalent and are a common means by which patients explore medical options online. Currently, there are no data comparing physicians with negative online reviews and those without negative reviews. We sought to compare industry-vetted patient satisfaction surveys (PSSs), such as Press Ganey (PG) PSSs, between those physicians with negative online reviews and those without negative reviews. Overall, there were 113 unique individuals with negative online reviews from September 1, 2014, to December 31, 2014, with 8 being nonphysicians. We matched 113 physicians in similar departments/divisions. We obtained PG PSS scores of both groups and compared the mean scores of the 2 groups. Press Ganey PSS scores were available for 98 physicians with negative online reviews compared with 82 matched physicians without negative online reviews. The mean raw PG PSS scores were not different between the 2 groups (4.05; 95% CI, 3.99-4.11 vs 4.04; 95% CI, 3.97-4.11; P=.92). We also noted no difference in mean scores on questions related to physician-patient communication and interaction skills between those with poor online reviews and those without (4.38; 95% CI, 4.32-4.43 vs 4.41; 95% CI, 4.35-4.47; P=.42). However, there was a significantly lower non-physician-specific mean in those with negative online reviews (3.91; 95% CI, 3.84-3.97) vs those without negative online reviews (4.01; 95% CI, 3.95-4.09) (P=.02). Here, we provide data indicating that online physician reviews do not correlate to formal institutional PG PSS. Furthermore, physicians with negative online reviews have lower scores on non-physician-specific variables included in the PG PSSs, emphasizing that these discrepancies can negatively affect overall patient experience, online physician reviews, and physician reputation. It is prudent that an improved mechanism for online ratings be implemented to better inform patients about a physician's online reputation.

Knowledge management in the era of digital medicine: A programmatic approach to optimize patient care in an academic medical center.

INTRODUCTION: The pace of medical discovery is accelerating to the point where caregivers can no longer keep up with the latest diagnosis or treatment recommendations. At the same time, sophisticated and complex electronic medical records and clinical systems are generating increasing volumes of patient data, making it difficult to find the important information required for patient care. To address these challenges, Mayo Clinic established a knowledge management program to curate, store, and disseminate clinical knowledge. METHODS: The authors describe AskMayoExpert, a point-of-care knowledge delivery system, and discuss the process by which the clinical knowledge is captured, vetted by clinicians, annotated, and stored in a knowledge content management system. The content generated for AskMayoExpert is considered to be core clinical content and serves as the basis for knowledge diffusion to clinicians through order sets and clinical decision support rules, as well as to patients and consumers through patient education materials and internet content. The authors evaluate alternative approaches for better integration of knowledge into the clinical workflow through development of computer-interpretable care process models. RESULTS: Each of the modeling approaches evaluated has shown promise. However, because each of them addresses the problem from a different perspective, there have been challenges in coming to a common model. Given the current state of guideline modeling and the need for a near-term solution, Mayo Clinic will likely focus on breaking down care process models into components and on standardization of those components, deferring, for now, the orchestration. CONCLUSION: A point-of-care knowledge resource developed to support an individualized approach to patient care has grown into a formal knowledge management program. Translation of the textual knowledge into machine executable knowledge will allow integration of the knowledge with specific patient data and truly serve as a colleague and mentor for the physicians taking care of the patient.

IVIG Versus PLEX in the Treatment of Worsening Myasthenia Gravis: What is the Evidence?: A Critically Appraised Topic.

BACKGROUND: Immune therapies such as intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) are first line in the treatment of worsening myasthenia gravis. Although PLEX is favored in myasthenic crisis, IVIG is increasingly used in exacerbations due to cost and ease of administration. OBJECTIVES: To review and critically assess current evidence on the effects of IVIG and PLEX on functional outcomes in patients with worsening myasthenia gravis. METHODS: A structured critical appraisal was conducted on the objective topic. This included a creation of a structured question based on a clinical scenario, comprehensive literature search, selection of evidence for review, and critical appraisal of selected evidence. Evidence was summarized and commentary provided. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of neuromuscular neurology. RESULTS: A single-blinded, randomized-controlled trial that compared IVIG and PLEX in 84 patients with worsening myasthenia gravis was selected for review. Primary outcome measure was functional status at 14 days after treatment, as assessed by the Quantitative Myasthenia Gravis Score. Change in Quantitative Myasthenia Gravis Score at day 14 for all subjects was 4.0, without statistically significant differences between IVIG and PLEX groups. CONCLUSIONS: IVIG and PLEX are equally effective in worsening myasthenia gravis. Treatment decisions may depend on several variables, including presence of respiratory distress, medical comorbidities, access to medication, and cost. PLEX will likely remain the treatment of choice in true myasthenic crisis.

The significance of intraoperative electromyographic "lateral spread" in predicting outcome of microvascular decompression for hemifacial spasm.

OBJECTIVES: During microvascular decompression (MVD) of the facial nerve for hemifacial spasm (HFS), an abnormal muscle response can be recorded upon stimulation of the facial nerve, also known as the lateral spread response. This response may vanish after MVD and has been associated with a successful outcome. The purpose of this study was to determine if resolution of lateral spread correlated with the elimination of HFS in a single surgeon's experience. Design and SETTING: (1) Retrospective analysis of 38 patients undergoing MVD with intraoperative electromyography for HFS. (2) Meta-analysis of studies from the literature. MAIN OUTCOME MEASURE: Presence or absence of HFS and any complications. RESULTS: Lateral spread response was seen in 36 patients; 20 patients had full resolution. Of these, 15 patients became HFS free, and 5 five patients still had some degree of HFS. Sixteen patients had a persistent lateral spread response despite a technically successful MVD; 11 of these became spasm free, and 5 still suffered from some degree of facial twitching. Analyzing 16 studies reporting a total of 1301 patients, a significant correlation (p < 0.0001) between response cessation and resolution of HFS was found. CONCLUSION: The role of monitoring lateral spread response as a predictor for clinical outcome is limited.

Childhood onset of stiff-man syndrome.

IMPORTANCE: Reports of pediatric-onset stiff-man syndrome (SMS) are rare. This may be an underrecognized disorder in child neurology practice. OBJECTIVE: To describe patients with disorders in the SMS spectrum beginning in childhood. DESIGN, SETTING, AND PARTICIPANTS: This study was a medical record review and serological evaluation conducted at child and adult neurology clinics at the Mayo Clinic, Rochester, Minnesota. Systematic review of the literature was conducted of patients who presented from 1984-2012 with onset of symptomatic SMS occurring at age 18 years or younger. MAIN OUTCOMES AND MEASURES: Response to symptomatic and immunotherapies, patient and physician reported, including modified Rankin scale. RESULTS: We identified 8 patients with childhood-onset SMS, representing 5% of patients with SMS evaluated at Mayo Clinic during a period of 29 years (4 were girls). The median age at symptom onset was 11 years (range, 1-14 years). The diagnosis in 3 patients was not established until adulthood (median symptom duration at diagnosis, 14 years; range, 0-46 years). The phenotypes encountered were: classic SMS (n = 5, involving the low back and lower extremities), variant SMS (n = 2, limited to 1 limb [with dystonic posture] or back), and progressive encephalomyelitis with rigidity and myoclonus (n = 1). Initial misdiagnoses included functional movement disorder (n = 2), generalized dystonia and parkinsonism (n = 1), and hereditary spastic paraparesis (n = 1). Six patients had 1 or more coexisting autoimmune disorders: type 1 diabetes mellitus (n = 4), thyroid disease (n = 2), and vitiligo (n = 2). Serologic study results revealed glutamic acid decarboxylase 65-IgG in all cases (median value, 754 nmol/L; range, 0.06-3847 nmol/L; normal value, ≤ 0.02 nmol/L) and glycine receptor antibody in 3 cases. Improvements were noted with symptomatic therapy (diazepam, 6 of 6 patients treated, and oral baclofen, 3 of 3 treated) and immunotherapy (intravenous immune globulin, 3 of 4 treated and plasmapheresis, 3 of 4 treated). The 3 patients with glycine receptor antibody all improved with immunotherapy. At last follow-up, 4 patients had mild or no symptoms, but 4 had moderate or severe residual symptoms and required maintenance symptomatic therapy (n = 5) and immunotherapy (n = 4). Ten of 12 pediatric SMS cases identified by literature review had a severe whole-body phenotype resembling progressive encephalomyelitis with rigidity and myoclonus. CONCLUSIONS AND RELEVANCE: Childhood-onset SMS is a rare but underrecognized and treatable disorder. Serological and electrophysiological testing aid diagnosis.

The business case for health-care quality improvement.

The business case for health-care quality improvement is presented. We contend that investment in process improvement is aligned with patients' interests, the organization's reputation, and the engagement of their workforce. Four groups benefit directly from quality improvement: patients, providers, insurers, and employers. There is ample opportunity, even in today's predominantly pay-for-volume (that is, evolving toward value-based purchasing) insurance system, for providers to deliver care that is in the best interest of the patient while improving their financial performance.

Sinusitis and chronic cough in children.

BACKGROUND: Chronic cough in children is a common problem, and sinusitis is a common etiology. The diagnosis of sinusitis is often clinical, but confirmation is thought to require a CT scan due to the difficulty of interpreting a Water's view sinus X-ray. OBJECTIVES: The purposes of the study were (1) to examine the frequency of an abnormal sinus X-ray in children with a chronic cough of more than 4 weeks duration; (2) to compare the interpretation of the sinus film between allergy/pulmonary clinicians and radiologists; and (3) to correlate symptoms with X-ray results. METHODS: A chart review of 2- to 18-year-old patients with coughing exceeding 4 weeks was performed. Data was collected for patients who had received a Water's view sinus film as part of their evaluation. Exam, X-ray results, and clinical outcomes were categorized and statistical analyses performed. RESULTS: A total of 86 patients were included. Clinicians found that 65% of the children had positive Water's view films, compared with the radiologist's reading of 62% (non significant). Significant associations between post-tussive emesis (P = 0.01) and purulence (P = 0.03) were noted with a positive film. Positive sinus X-ray was highly associated with all findings except wheeze when present together (P < 0.001). CONCLUSION: Sinus abnormalities on X-ray are associated with prolonged cough in 65% of children. The Water's view sinus film is a clinically useful screening tool for clinicians in the workup of chronic cough. Certain physical findings and clinical complaints, when present concurrently, correlate with the X-ray results.

Accuracy of electromyography needle placement in cadavers: non-guided vs. ultrasound guided.

INTRODUCTION: Accuracy of needle electromyography is typically ensured by use of anatomical landmarks and auditory feedback related to voluntary activation of the targeted muscle; however, in certain clinical situations, landmarks may not be palpable, auditory feedback may be limited or not present, and targeting a specific muscle may be more critical. In such settings, image guidance might significantly enhance accuracy. METHODS: Two electromyographers with different levels of experience examined 14 muscles in each of 4 fresh-frozen cadaver lower limbs. Each muscle was tested a total of eight times; four fine wires were inserted without ultrasound (US) guidance and four were inserted under US guidance. Overall accuracy as well as accuracy rates for the individual electromyographers were calculated. RESULTS: Non-guided needle placement was significantly less accurate than US-guided needle placement, particularly in the hands of less experienced electromyographers, supporting the use of real-time US guidance in certain challenging situations in the electromyography laboratory.

Evidence-based management of statin myopathy.

Statin-associated muscle symptoms are a relatively common condition that may affect 10% to 15% of statin users. Statin myopathy includes a wide spectrum of clinical conditions, ranging from mild myalgia to rhabdomyolysis. The etiology of myopathy is multifactorial. Recent studies suggest that statins may cause myopathy by depleting isoprenoids and interfering with intracellular calcium signaling. Certain patient and drug characteristics increase risk for statin myopathy, including higher statin doses, statin cytochrome metabolism, and polypharmacy. Genetic risk factors have been identified, including a single nucleotide polymorphism of SLCO1B1. Coenzyme Q10 and vitamin D have been used to prevent and treat statin myopathy; however, clinical trial evidence demonstrating their efficacy is limited. Statin-intolerant patients may be successfully treated with either low-dose statins, alternate-day dosing, or using twice-weekly dosing with longer half-life statins. An algorithm is presented to assist the clinician in managing myopathy in patients with dyslipidemia.

Effect of baseline plasma fatty acids on eicosapentaenoic acid levels in individuals supplemented with alpha-linolenic acid.

We previously reported a >50% increase in mean plasma eicosapentaenoic acid levels in a general medicine clinic population after supplementation with alpha-linolenic acid. In the current analysis, we evaluate the variability of changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid and evaluated the impact of baseline plasma fatty acids levels on changes in eicosapentaenoic acid levels in these individuals. Changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid ranged from a 55% decrease to a 967% increase. Baseline plasma fatty acids had no statistically significant effect on changes in eicosapentaenoic levels acid after alpha-linolenic acid supplementation. Changes in eicosapentaenoic acid levels varied considerably in a general internal medicine clinic population supplemented with alpha-linolenic acid. Factors that may impact changes in plasma eicosapentaenoic acid levels after alpha-linolenic acid supplementation warrant further study.