A hybrid Shewhart chart for visualizing and learning from epidemic data.

OBJECTIVE: As the globe endures the coronavirus disease 2019 (COVID-19) pandemic, we developed a hybrid Shewhart chart to visualize and learn from day-to-day variation in a variety of epidemic measures over time. CONTEXT: Countries and localities have reported daily data representing the progression of COVID-19 conditions and measures, with trajectories mapping along the classic epidemiological curve. Settings have experienced different patterns over time within the epidemic: pre-exponential growth, exponential growth, plateau or descent and/ or low counts after descent. Decision-makers need a reliable method for rapidly detecting transitions in epidemic measures, informing curtailment strategies and learning from actions taken. METHODS: We designed a hybrid Shewhart chart describing four 'epochs' ((i) pre-exponential growth, (ii) exponential growth, (iii) plateau or descent and (iv) stability after descent) of the COVID-19 epidemic that emerged by incorporating a C-chart and I-chart with a log-regression slope. We developed and tested the hybrid chart using international data at the country, regional and local levels with measures including cases, hospitalizations and deaths with guidance from local subject-matter experts. RESULTS: The hybrid chart effectively and rapidly signaled the occurrence of each of the four epochs. In the UK, a signal that COVID-19 deaths moved into exponential growth occurred on 17 September, 44 days prior to the announcement of a large-scale lockdown. In California, USA, signals detecting increases in COVID-19 cases at the county level were detected in December 2020 prior to statewide stay-at-home orders, with declines detected in the weeks following. In Ireland, in December 2020, the hybrid chart detected increases in COVID-19 cases, followed by hospitalizations, intensive care unit admissions and deaths. Following national restrictions in late December, a similar sequence of reductions in the measures was detected in January and February 2021. CONCLUSIONS: The Shewhart hybrid chart is a valuable tool for rapidly generating learning from data in close to real time. When used by subject-matter experts, the chart can guide actionable policy and local decision-making earlier than when action is likely to be taken without it.

Efficacy and safety following bosutinib dose reduction in patients with Philadelphia chromosome‒positive leukemias.

The recommended starting dose of bosutinib is 500 mg/day for chronic-phase (CP) or accelerated-/blast-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy. However, some patients may require dose reductions to manage the occurrences of adverse events (AEs). Bosutinib efficacy and safety were evaluated following dose reductions in a phase I/II study of Ph+ patients with CP CML resistant/intolerant to imatinib or imatinib plus dasatinib and/or nilotinib, and those with accelerated-/blast-phase CML or acute lymphoblastic leukemia after at least imatinib treatment. In all, 570 patients with ≥4 years' follow-up were included in this analysis. Among 144 patients who dose-reduced to bosutinib 400 mg/day (without reduction to 300 mg/day), 22 (15 %) had complete cytogenetic response (CCyR) before and after reduction, 40 (28 %) initially achieved CCyR after reduction, and 4 (3 %) only had CCyR before reduction. Among 95 patients who dose-reduced to bosutinib 300 mg/day, 23 (24 %) had CCyR before and after reduction, 13 (14 %) initially achieved CCyR after reduction, and 3 (3 %) only had CCyR before reduction. Results were similar to matched controls who remained on 500 mg/day, indicating dose reductions had not substantially affected efficacy. The incidence of treatment-emergent AEs was lower after dose reductions, particularly for gastrointestinal events. The incidence of hematologic toxicities generally was similar before and after dose reduction. The management of AEs with bosutinib through dose reduction can lead to improved/maintained efficacy and better tolerability; still, approximately half of patients on treatment at year 4 maintained a dose of ≥500 mg/day. ClinicalTrials.gov: NCT00261846.

Mass Spectrometry Techniques: Principles and Practices for Quantitative Proteomics.

In the current omics-age of research, major developments have been made in technologies that attempt to survey the entire repertoire of genes, transcripts, proteins, and metabolites present within a cell. While genomics has led to a dramatic increase in our understanding of such things as disease morphology and how organisms respond to medications, it is critical to obtain information at the proteome level since proteins carry out most of the functions within the cell. The primary tool for obtaining proteome-wide information on proteins within the cell is mass spectrometry (MS). While it has historically been associated with the protein identification, developments over the past couple of decades have made MS a robust technology for protein quantitation as well. Identifying quantitative changes in proteomes is complicated by its dynamic nature and the inability of any technique to guarantee complete coverage of every protein within a proteome sample. Fortunately, the combined development of sample preparation and MS methods have made it capable of quantitatively comparing many thousands of proteins obtained from cells and organisms.

Synesthesia, hallucination, and autism.

Synesthesia literally means a "union of the senses" whereby two or more of the five senses that are normally experienced separately are involuntarily and automatically joined together in experience (1, 2, 3). For example, some synesthetes experience a color when they hear a sound, although many instances of synesthesia also occur entirely within the visual sense. In this paper, I first mainly engage critically with Sollberger's view that there is reason to think that at least some synesthetic experiences can be viewed as truly veridical perceptions, and not as illusions or hallucinations (4). Among other things, I explore the possibility that many forms of synesthesia can be understood as experiencing what I will call "second-order secondary properties," that is, experiences of properties of objects induced by the secondary qualities of those objects. In doing so, I shed some light on why synesthesia is typically one-directional and its relation to some psychopathologies such as autism.

Understanding variation in reported covid-19 deaths with a novel Shewhart chart application.

OBJECTIVE: Motivated by the coronavirus disease 2019 (covid-19) pandemic, we developed a novel Shewhart chart to visualize and learn from variation in reported deaths in an epidemic. CONTEXT: Without a method to understand if a day-to-day variation in outcomes may be attributed to meaningful signals of change-rather than variability we would expect-care providers, improvement leaders, policy-makers, and the public will struggle to recognize if epidemic conditions are improving. METHODS: We developed a novel hybrid C-chart and I-chart to detect within a geographic area the start and end of exponential growth in reported deaths. Reported deaths were the unit of analysis owing to erratic reporting of cases from variability in local testing strategies. We used simulation and case studies to assess chart performance and define technical parameters. This approach also applies to other critical measures related to a pandemic when high-quality data are available. CONCLUSIONS: The hybrid chart detected the start of exponential growth and identified early signals that the growth phase was ending. During a pandemic, timely reliable signals that an epidemic is waxing or waning may have mortal implications. This novel chart offers a practical tool, accessible to system leaders and frontline teams, to visualize and learn from daily reported deaths during an epidemic. Without Shewhart charts and, more broadly, a theory of variation in our epidemiological arsenal, we lack a scientific method for a real-time assessment of local conditions. Shewhart charts should become a standard method for learning from data in the context of a pandemic or epidemic.

A predictive survival model for patients with head and neck squamous cell carcinoma treated with immune check point inhibitors.

BACKGROUND: ICIs have expanded treatment options for HNSCC. A minority of the patients respond to these expensive treatments. PATIENTS AND METHODS: This is a single institutional retrospective review on 121 unresectable or metastatic HNSCC patients treated with ICIs. We predicted that inflammatory markers available through routine blood work, in addition to clinical characteristics may divide patients into groups more or less likely to respond to these agents. Here we develop and internally validate our nomogram to predict survival in patients treated with ICIs.

CNS small vessel disease: A clinical review.

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.

Matching-adjusted indirect comparison of bosutinib, dasatinib and nilotinib effect on survival and major cytogenetic response in treatment of second-line chronic phase chronic myeloid leukemia.

Objective: In clinical trials of second-line therapies for chronic phase chronic myeloid leukemia (CP-CML), to date, only single-arm trials have been conducted for the available tyrosine kinase inhibitor treatments (bosutinib, dasatinib and nilotinib). These trials included heterogeneous patient populations in terms of disease and baseline characteristics. These hamper the use of standard network meta-analyses for indirect treatment comparison of relative efficacy. In this situation, a matching-adjusted indirect comparison (MAIC) in second-line CP-CML was performed. The aim was to compare the relative efficacies of bosutinib, dasatinib and nilotinib in second-line CP-CML patients.Methods: The MAIC was preceded by a systematic literature review that ensured inclusion of the underlying data for the analyses. The outcomes were measured in terms of overall survival (OS), progression-free survival (PFS) and major cytogenetic response (MCyR). The treatments were quantitatively compared based on Cox proportional hazard ratio (HR) regressions, on restricted mean survival (RMST, when the proportionality assumption showed evidence of violation) and on odds ratios (for response measures).Results: Comparing with dasatinib, bosutinib resulted in HRs for PFS and OS of 0.63 (0.44-0.90, p < .05) and 0.82 (0.54-1.26, p = .37) respectively, and resulted in an OR for MCyR of 0.78 (0.53-1.16). Although the proportionality of hazards assumption was violated for PFS, the RMST analyses confirmed the findings of the Cox regression. When compared with nilotinib, bosutinib showed a significant HR of 0.54 (0.38-0.76, p < .01) in favor of bosutinib for PFS, a non-significant HR of 0.72 (0.46-1.13, p = .16) for OS and a non-significant OR of 0.98 (0.71-1.35) for MCyR.Conclusions: Bosutinib had a significantly greater PFS than both dasatinib and nilotinib. For OS, the findings were numerically in favor of bosutinib, but not statistically significant. For MCyR, the findings were numerically in favor of dasatinib and nilotinib, but not statistically significant.

A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma.

Purpose Vorinostat is a potent HDAC inhibitor that sensitizes head and neck squamous cell carcinoma (HNSCC) to cytotoxic therapy while sparing normal epithelium. The primary objective of this Phase I study was to determine the maximally tolerated dose (MTD) and safety of Vorinostat in combination with standard chemoradiation therapy treatment in HNSCC. Patients and Methods Eligible patients had pathologically confirmed Stage III, IVa, IVb HNSCC, that was unresectable or borderline resectable involving the larynx, hypopharynx, nasopharynx, and oropharynx. Vorinostat was administered at the assigned dosage level (100-400 mg, three times weekly) in a standard 3 + 3 dose escalation design. Vorinostat therapy began 1 week prior to initiation of standard, concurrent chemoradiation therapy and continued during the entire course of therapy. Results Twenty six patients met eligibility criteria and completed the entire protocol. The primary tumor sites included tonsil (12), base of tongue (9), posterior pharyngeal wall (1), larynx (4) and hypopharynx (3). Of the 26 patients, 17 were HPV-positive and 9 were HPV-negative. The MTD of Vorinostat was 300 mg administered every other day. Anemia (n = 23/26) and leukopenia (n = 20/26) were the most commonly identified toxicities. The most common Grade3/4 events included leukopenia (n = 11) and lymphopenia (n = 17). No patient had Grade IV mucositis, dermatitis or xerostomia. The median follow time was 33.8 months (range 1.6-82.9 months). Twenty four of 26 (96.2%) patients had a complete response to therapy. Conclusion Vorinostat in combination with concurrent chemoradiation therapy is a safe and highly effective treatment regimen in HNSCC. There was a high rate of complete response to therapy with toxicity rates comparable, if not favorable to existing therapies. Further investigation in Phase II and III trials is strongly recommended.

Rapid detection of Listeria monocytogenes rhombencephalitis in an immunocompetent patient by multiplexed PCR.

A 46-year-old previously healthy man presented with 1 week of headache, nausea, vomiting and dizziness. He was found to have cranial nerve deficits, his cerebrospinal fluid (CSF) demonstrated a lymphocytic pleocytosis and brain MRI suggested rhombencephalitis. Although Gram stains and cultures of his CSF did not identify a pathogen, Listeria monocytogenes DNA was detected by the FilmArray Meningitis/Encephalitis panel within 2 hours of performing a lumbar puncture. He was treated with ampicillin and gentamicin and had a near-complete recovery. This case highlights the importance of recognising L. monocytogenes infection as a cause of acute cranial nerve impairment with MRI findings suggestive of brainstem encephalitis. It also highlights the frequently atypical CSF profile and low yield of culture in L. monocytogenes rhombencephalitis and the value of multiplex PCR testing of CSF to rapidly identify this pathogen and permit targeted therapy.

Adult Intestinal Botulism: A Rare Presentation in an Immunocompromised Patient With Short Bowel Syndrome.

The cholinergic heat-labile neurotoxin produced by Clostridium species is primarily responsible for the clinical manifestations of botulism. The classic phenotypic presentation of botulism consists of subacute descending flaccid paralysis with intact sensory function. Traditionally, it is classified into 3 main forms (foodborne, wound-related, and infantile) on the basis of primary site of toxin entry into the human nervous system. Toxemia is the common pathophysiology in all forms of botulism. Adult intestinal toxemia botulism is an extremely rare form of the disease with pathogenesis similar to that of infant-type botulism. Symptomatic adults usually have an anatomic abnormality in the gastrointestinal tract leading to changes in normal gut flora. The current case is an addition to the growing literature on this unusual clinical variant of botulism.

The Clinical Dilemma of Anticoagulation Use in Patients with Cerebral Amyloid Angiopathy and Atrial Fibrillation.

PURPOSE OF REVIEW: This review highlights current management of patients with concomitant cerebral amyloid angiopathy (CAA) and atrial fibrillation (AF). We review quantifying risk of ischemic and hemorrhagic stroke as well as treatments to minimize future risk. RECENT FINDINGS: Ischemic stroke risk in AF can be quantified by CHA2DS2-VASc and assessing left atrial echocardiographic characteristics. Patients deemed not low risk by CHA2DS2-VASC should be anticoagulated. CAA increases intracranial hemorrhage risk. CAA biomarkers include cortical microbleeds (CMBs), cortical superficial siderosis (cSS), convexal subarachnoid hemorrhage (cSAH), and lobar intracerebral hemorrhage (ICH). CAA with prior lobar ICH has an annual recurrence rate of 8.9%. CAA with cSAH carries an even higher annual lobar ICH risk of 19%. CMBs are associated with a dose-dependent risk of ICH, which rises with OACs. In patients with AF, antithrombotics should be avoided in CAA with predominant ICH, cSS, or cSAH features. Those with ≥ 2 CMB require in-depth risk-benefit analysis using a multidisciplinary approach.

Government As Innovation Catalyst: Lessons From The Early Center For Medicare And Medicaid Innovation Models.

Congress established the Center for Medicare and Medicaid Innovation (CMMI) to design, test, and spread innovative payment and service delivery models that either reduce spending without reducing the quality of care or improve the quality of care without increasing spending. CMMI sought to leverage these models to foster market innovation and accelerate the transformation of payment and care delivery to achieve the Triple Aim of better health, better care, and lower cost. This article provides a perspective on the design and execution of CMMI's five initial models, the resulting outcomes and lessons, and how their core concepts evolved within and spread beyond CMMI. This experience yields three key insights that could inform future efforts by CMMI and public and private payers, including model designs and policy decisions. These insights center on the need for iterative testing and learning guided by market feedback, more realistic time frames to demonstrate impact on cost and quality, and greater integration of models.

Integrating Social Needs Into Health Care: A Twenty-Year Case Study Of Adaptation And Diffusion.

The US health care system has recently begun to account for patients' unmet social needs in care delivery and payment reform. This article presents a twenty-year qualitative case study of five stages of diffusion-testing and learning, standardization, replication, shifting from doing to enabling, and catalyzing broad adoption-of a practical approach for integrating social needs into clinical care. This case study of Health Leads and its funders confirms the importance of focusing on a clear aim, investing in model testing and standardization to enable subsequent responsiveness to the market, and the willingness of innovators and their investors to cede control of a model to allow local adaption and accelerate broad adoption.

Repair of Circumflex Aortic Arch in an Adult.

We describe the diagnoses and repair of a symptomatic circumflex aortic arch in an adult.

Extracardiac Fontan Operation Through a Right Thoracotomy.

An extracardiac Fontan operation through a right thoracotomy incision is an alternative approach in children who have an ascending aorta that is in close proximity to the sternum, as in aortic atresia or transposed great vessels, and in those who have had prior mediastinitis.