OSF Saint Francis Medical Center

BACKGROUND: Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. PARTICIPANTS AND METHODS: The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. RESULTS: Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I-III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. CONCLUSIONS: cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.

BACKGROUND AND PURPOSE: Acute vestibular syndrome (AVS) is often due to vestibular neuritis but can result from vertebrobasilar strokes. Misdiagnosis of posterior fossa infarcts in emergency care settings is frequent. Bedside oculomotor findings may reliably identify stroke in AVS, but prospective studies have been lacking. METHODS: The authors conducted a prospective, cross-sectional study at an academic hospital. Consecutive patients with AVS (vertigo, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with >or=1 stroke risk factor underwent structured examination, including horizontal head impulse test of vestibulo-ocular reflex function, observation of nystagmus in different gaze positions, and prism cross-cover test of ocular alignment. All underwent neuroimaging and admission (generally <72 hours after symptom onset). Strokes were diagnosed by MRI or CT. Peripheral lesions were diagnosed by normal MRI and clinical follow-up. RESULTS: One hundred one high-risk patients with AVS included 25 peripheral and 76 central lesions (69 ischemic strokes, 4 hemorrhages, 3 other). The presence of normal horizontal head impulse test, direction-changing nystagmus in eccentric gaze, or skew deviation (vertical ocular misalignment) was 100% sensitive and 96% specific for stroke. Skew was present in 17% and associated with brainstem lesions (4% peripheral, 4% pure cerebellar, 30% brainstem involvement; chi(2), P=0.003). Skew correctly predicted lateral pontine stroke in 2 of 3 cases in which an abnormal horizontal head impulse test erroneously suggested peripheral localization. Initial MRI diffusion-weighted imaging was falsely negative in 12% (all <48 hours after symptom onset). CONCLUSIONS: Skew predicts brainstem involvement in AVS and can identify stroke when an abnormal horizontal head impulse test falsely suggests a peripheral lesion. A 3-step bedside oculomotor examination (HINTS: Head-Impulse-Nystagmus-Test-of-Skew) appears more sensitive for stroke than early MRI in AVS.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). CONCLUSIONS: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

BACKGROUND AND PURPOSE: To develop recommendations for the establishment of comprehensive stroke centers capable of delivering the full spectrum of care to seriously ill patients with stroke and cerebrovascular disease. Recommendations were developed by members of the Brain Attack Coalition (BAC), which is a multidisciplinary group of members from major professional organizations involved with the care of patients with stroke and cerebrovascular disease. SUMMARY OF REVIEW: A comprehensive literature search was conducted from 1966 through December 2004 using Medline and Pub Med. Articles with information about clinical trials, meta-analyses, care guidelines, scientific guidelines, and other relevant clinical and research reports were examined and graded using established evidence-based medicine approaches for therapeutic and diagnostic modalities. Evidence was also obtained from a questionnaire survey sent to leaders in cerebrovascular disease. Members of BAC reviewed literature related to their field and graded the scientific evidence on the various diagnostic and treatment modalities for stroke. Input was obtained from the organizations represented by BAC. BAC met on several occasions to review each specific recommendation and reach a consensus about its importance in light of other medical, logistical, and financial factors. CONCLUSIONS: There are a number of key areas supported by evidence-based medicine that are important for a comprehensive stroke center and its ability to deliver the wide variety of specialized care needed by patients with serious cerebrovascular disease. These areas include: (1) health care personnel with specific expertise in a number of disciplines, including neurosurgery and vascular neurology; (2) advanced neuroimaging capabilities such as MRI and various types of cerebral angiography; (3) surgical and endovascular techniques, including clipping and coiling of intracranial aneurysms, carotid endarterectomy, and intra-arterial thrombolytic therapy; and (4) other specific infrastructure and programmatic elements such as an intensive care unit and a stroke registry. Integration of these elements into a coordinated hospital-based program or system is likely to improve outcomes of patients with strokes and complex cerebrovascular disease who require the services of a comprehensive stroke center.

BACKGROUND: Pneumonia is an important complication of ischemic stroke and increases mortality 3-fold. Five guidelines recommend a dysphagia screen before oral intake. What constitutes an adequate dysphagia screen and which patients should receive it remain unclear. METHODS: Fifteen acute care institutions prospectively collected data on all admitted patients with acute ischemic stroke. Sites were required to collect data on demographics and 4 quality indicators. Optional data included stroke severity and complications. We measured adherence to a screen for dysphagia, the type of screen, and development of in-hospital pneumonia. RESULTS: Between December 2001 and January 2003, 2532 cases were collected. In-hospital complications were recorded on 2329 (92%) of cases. Stroke severity was captured on 1361 (54%). Adherence to a dysphagia screen was 61%. Six sites had a formal dysphagia screen, and their adherence rate was 78% compared with 57% at sites with no formal screen. The pneumonia rate at sites with a formal dysphagia screen was 2.4% versus 5.4% (P=0.0016) at sites with no formal screen. There was no difference in median stroke severity (5 versus 4; P=0.84) between the sites with and without a formal screen. A formal dysphagia screen prevented pneumonia even after adjusting for stroke severity. CONCLUSIONS: A formal dysphagia screen is associated with a higher adherence rate to dysphagia screens and a significantly decreased risk of pneumonia. A formal screening protocol should be offered to all stroke patients, regardless of stroke severity.

BACKGROUND: This randomized controlled trial evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES), for femoropopliteal artery lesions. Outcomes compare primary DES versus percutaneous transluminal angioplasty (PTA), overall DES (primary and provisional) versus standard care (PTA and provisional Zilver bare metal stent [BMS]), and provisional DES versus provisional BMS. METHODS AND RESULTS: Patients with symptomatic femoropopliteal artery disease were randomly assigned to DES (n=236) or PTA (n=238). Approximately 91% had claudication; 9% had critical limb ischemia. Patients experiencing acute PTA failure underwent secondary randomization to provisional BMS (n=59) or DES (n=61). The 1-year primary end points of event-free survival and patency showed superiority of primary DES in comparison with PTA; these results were sustained through 5 years. Clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% versus 59.3%, P<0.01), patency (66.4% versus 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% versus 67.6%, P<0.01) for the overall DES group were superior to standard care in nonrandomized comparisons. Similarly, clinical benefit (81.8% versus 63.8%, P=0.02), patency (72.4% versus 53.0%, P=0.03), and freedom from target lesion revascularization (84.9% versus 71.6%, P=0.06) with provisional DES were improved over provisional BMS. These results represent >40% relative risk reduction for restenosis and target lesion revascularization through 5 years for the overall DES in comparison with standard care and for provisional DES in comparison with provisional BMS. CONCLUSIONS: The 5-year results from this large study provide long-term information previously unavailable regarding endovascular treatment of femoropopliteal artery disease. The Zilver PTX DES provided sustained safety and clinical durability in comparison with standard endovascular treatments. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120406.

OBJECTIVE: To test the diagnostic accuracy of the horizontal head impulse test (h-HIT) of vestibulo-ocular reflex (VOR) function in distinguishing acute peripheral vestibulopathy (APV) from stroke. Most patients with acute vertigo, nausea/vomiting, and unsteady gait have benign APV (vestibular neuritis or labyrinthitis) as a cause. However, some harbor life-threatening brainstem or cerebellar strokes that mimic APV. A positive h-HIT (abnormal VOR) is said to predict APV. METHODS: Cross-sectional study at an urban, academic hospital over 6 years. Consecutive acute vestibular syndrome patients at high risk for stroke underwent structured examination (including h-HIT), neuroimaging, and admission. Stroke was confirmed by neuroimaging (MRI or CT). APV was diagnosed by normal MRI and appropriate clinical evolution in follow-up. RESULTS: Forty-three subjects enrolled. One had an equivocal h-HIT. Patients with APV had a positive h-HIT (n = 8/8, 100%). Most patients with stroke had a negative h-HIT (n = 31/34, 91%). However, contrary to conventional wisdom, three patients with stroke (9%) demonstrated a positive h-HIT (1 vestibulocerebellar, 1 pontocerebellar, 1 pontocerebello-labyrinthine stroke). CONCLUSIONS: Patients with lateral pontine and cerebellar strokes can have a positive horizontal head impulse test (h-HIT), so the sign's presence cannot be solely relied upon to identify a benign pathology. Additional clinical features (e.g., directionality of nystagmus, severity of truncal instability, nature of hearing loss) must be considered in patients with acute vestibular syndrome with a positive h-HIT before a central localization can be confidently excluded. Nonetheless, the h-HIT remains a useful bedside test-in acute vestibular syndrome patients, a negative h-HIT (i.e., normal VOR) strongly suggests a central lesion with a pseudo-labyrinthine presentation.

PURPOSE: To determine improvement in breast cancer detection by using supplemental three-dimensional (3D) automated breast (AB) ultrasonography (US) with screening mammography versus screening mammography alone in asymptomatic women with dense breasts. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant study. The SomoInsight Study was an observational, multicenter study conducted between 2009 and 2011. A total of 15 318 women (mean age, 53.3 years ± 10 [standard deviation]; range, 25-94 years) presenting for screening mammography alone with heterogeneously (50%-75%) or extremely (>75%) dense breasts were included, regardless of further risk characterization, and were followed up for 1 year. Participants underwent screening mammography alone followed by an AB US examination; results were interpreted sequentially. McNemar test was used to assess differences in cancer detection. RESULTS: Breast cancer was diagnosed at screening in 112 women: 82 with screening mammography and an additional 30 with AB US. Addition of AB US to screening mammography yielded an additional 1.9 detected cancers per 1000 women screened (95% confidence interval [CI]: 1.2, 2.7; P < .001). Of cancers detected with screening mammography, 62.2% (51 of 82) were invasive versus 93.3% (28 of 30) of additional cancers detected with AB US (P = .001). Of the 82 cancers detected with either screening mammography alone or the combined read, 17 were detected with screening mammography alone. Of these, 64.7% (11 of 17) were ductal carcinoma in situ versus 6.7% (two of 30) of cancers detected with AB US alone. Sensitivity for the combined read increased by 26.7% (95% CI: 18.3%, 35.1%); the increase in the recall rate per 1000 women screened was 284.9 (95% CI: 278.0, 292.2; P < .001). CONCLUSION: Addition of AB US to screening mammography in a generalizable cohort of women with dense breasts increased the cancer detection yield of clinically important cancers, but it also increased the number of false-positive results.

OBJECTIVES: A prospective, multinational randomized controlled trial (RCT) and a complementary single-arm study evaluated the 2-year safety and effectiveness of a paclitaxel-coated drug-eluting stent (DES) in patients with superficial femoral artery lesions. The RCT compared the DES with percutaneous transluminal angioplasty (PTA) and provisional bare-metal stent (BMS) placement. BACKGROUND: Local drug delivery for superficial femoral artery lesions has been investigated with the intent of limiting restenosis similarly to DES for the coronary arteries. One-year outcomes of DES in the superficial femoral artery are promising, but longer-term benefits have not been established. METHODS: In the RCT, patients were randomly assigned to primary DES implantation (n = 236) or PTA (n = 238). Acute PTA failure occurred in 120 patients, who underwent secondary randomization to DES (n = 61) or BMS (n = 59) placement. The single-arm study enrolled 787 patients with DES treatment. RESULTS: Compared with the control group, the primary DES group demonstrated significantly superior 2-year event-free survival (86.6% vs. 77.9%, p = 0.02) and primary patency (74.8% vs. 26.5%, p < 0.01). In addition, the provisional DES group exhibited superior 2-year primary patency compared with the provisional BMS group (83.4% vs. 64.1%, p < 0.01) and achieved higher sustained clinical benefit (83.9% vs. 68.4%, p = 0.05). Two-year freedom from target lesion revascularization with primary DES placement was 80.5% in the single-arm study and 86.6% in the RCT. CONCLUSIONS: Two-year outcomes with the paclitaxel-eluting stent support its sustained safety and effectiveness in patients with femoropopliteal artery disease, including the long-term superiority of the DES to PTA and to provisional BMS placement. (Evaluation of the Zilver PTX Drug-Eluting Stent in the Above-the-Knee Femoropopliteal Artery; NCT00120406; Zilver(®) PTX™ Global Registry; NCT01094678).

OBJECT: Hypothermia is by far the most potent neuroprotectant. Nevertheless, timely and safe delivery of hypothermia remains a clinical challenge. To maximize neuroprotection yet minimize systemic complications, ultra-early delivery of selective cerebral hypothermia by Emergency Medical Service (EMS) personnel in the field would be advantageous. The authors (W.E. and H.W.) have developed a cooling helmet by using National Aeronautics and Space Administration spinoff technology. In this study its effectiveness in lowering brain temperature in patients with severe stroke or head injury is examined. METHODS: Patients were randomly assigned to groups receiving either the cooling helmet or no cooling, and brain temperatures (0.8 cm below the cortical surface) were continuously monitored for a mean of 48 to 72 hours with a Neurotrend sensor and then compared with the patients' core temperatures. There were eight patients in the study group and six in the control group. The mean change in temperature (brain-body temperature) calculated from 277 data hours in the study group was -1.6 degrees C compared with a mean change in temperature of +0.22 degrees C calculated from 309 data hours in the control group. This was statistically significant (p < 0.0001). On average, 1.84 degrees C of brain temperature reduction (range 0.9-2.4 degrees C) was observed within 1 hour of helmet application. It took a mean of 3.4 hours (range 2-6 hours) to achieve a brain temperature lower than 34 degrees C and 6.67 hours (range 1-12 hours) before systemic hypothermia (< 36 degrees C) occurred. Use of the helmet resulted in no significant complications. There was, however, one episode of asymptomatic bradycardia (heart rate < 40) that responded to a 0.5 degrees C body temperature increase. CONCLUSIONS: This helmet delivers initial rapid and selective brain cooling and maintains a significant temperature gradient between the core and brain temperatures throughout the hypothermic period to provide sufficient regional hypothermia yet minimize systemic complications. It results in delayed systemic hypothermia, creating a safe window for possible ultra-early delivery of regional hypothermia by EMS personnel in the field.

Drug product shortages can adversely affect drug therapy, compromise or delay medical procedures, and result in medication errors.1,2 Health care professionals are increasingly concerned about the clinical effect that shortages have on patients and the tremendous resources required to address shortages.3,–5 Adverse patient outcomes related to drug product shortages1,2,6,–9 have prompted aggressive management strategies by health care providers and gained the attention of the Joint Commission,10 the government,11,12 and the media.13,14 Drug product shortages adversely affect health-system finances by increasing the cost of delivering patient care, largely through higher drug acquisition and personnel costs.6 In addition, shortages create a high level of frustration for everyone involved, including purchasing agents, pharmacists, nurses, physicians, and patients.7 Managing drug product shortages is particularly complex for practitioners in hospitals and health systems (hereinafter, “health systems”), because these facilities routinely treat patients with acute or emergent conditions, use a significant number of medically necessary or single-source products, and use high-cost new drug technologies. These health care providers are challenged during drug product shortages to ensure the provision of seamless, safe, and therapeutically equivalent drug therapy, preferably at comparable costs. The pharmacy department must take a leadership role in efforts to develop and implement appropriate strategies and processes for informing practitioners of shortages and ensuring the safe and effective use of therapeutic alternatives. Strategic planning is required for managing drug product shortages, just as it is for disasters such as major weather events and mass-casualty incidents. Because a thorough understanding of why drug product shortages occur is essential for their successful management, these guidelines begin with a description of factors that contribute to or exacerbate shortages. The guidelines then describe a three-phase approach to contingency planning for management of drug product shortages and include strategies for prevention. Given the differences and complexities in health-system organizational arrangements and practice settings, some aspects of these guidelines may not be applicable in all settings. Pharmacy managers should use their professional judgment in assessing and adapting these guidelines to meet their needs. For the purpose of these guidelines, a drug product shortage is defined as a supply issue that affects how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent. Shortages can be the result of one or a combination of factors throughout the supply chain. The supply chain includes sources of raw materials, manufacturers, regulators, wholesalers or distributors, prime vendors, group purchasing organizations, and end-user health care systems. The factors that follow contribute to disruptions in the availability of drug products. Disruptions in the supply of raw or bulk materials are especially problematic when the primary or sole source experiences production difficulties or discontinues production, affecting multiple manufacturers. An estimated 80% of the raw materials used in pharmaceuticals comes from outside the United States.4 Availability problems can arise when armed conflict or political upheaval disrupts trade, animal diseases contaminate tissue from which raw materials are extracted, climatic and other environmental conditions depress the growth of plants used to produce raw materials, or raw materials are degraded or contaminated during harvesting, storage, or transport. Drug product shortages can also occur when the primary or sole manufacturer of a drug product halts or delays production in response to a Food and Drug Administration (FDA) enforcement action concerning noncompliance with current good manufacturing practices (cGMPs). Contributing factors may include antiquated manufacturing equipment, a shift of resources from maintenance of equipment and facilities to research and development, loss of manufacturer personnel experienced in production and compliance issues as a result of company mergers or retirements, cGMP-related problems with subcontractors who supply products to multiple pharmaceutical manufacturers, and limited FDA resources for timely inspections of manufacturing sites.4 Resolution of these issues is often a lengthy process and may include inspections to ascertain cGMP compliance, issuance of an injunction against the manufacturer, or seizure of products. In some instances, a manufacturer’s decision to close a specific manufacturing facility results in unintended drug product shortages. Such was the case when the sole source for hyaluronidase production closed, leaving no supplier.5 FDA enforcement actions are intended to protect the public from potentially unsafe drug products. These actions are evaluated by FDA’s Center for Drug Evaluation and Research (CDER) drug shortage coordinator to determine if the action might create a shortage of a medically necessary drug product.12 (FDA’s definition of a medically necessary product is discussed in the “Government intervention” section below.) In the event that a significant corrective action involves a medically necessary product, FDA will help the manufacturer return to compliance, consider qualifying additional manufacturing sites, or, in extreme circumstances, permit importation of the product from a foreign manufacturing source once the required quality controls are met. Voluntary recalls, generally related to manufacturing problems, can cause shortages, especially when a sole manufacturer’s drug product dominates the market supply. Voluntary recalls are generally temporary and occur as a result of a minor lapse in manufacturing procedures that would not be subject to FDA legal action. Recalls usually affect specific lots and are conducted either because of a lack of assurance that the recalled product is safe or for reasons not related to safety, such as technical deficiencies in the drug’s labeling. An ethical dilemma could arise when it is predictable that complying with the voluntary recall may cause a drug product shortage in a given health system. Changes in a product’s formulation or manufacturer may also delay product availability. One example is the transition from albuterol metered-dose inhalers (MDIs) containing chlorofluorocarbons to MDIs containing hydro-fluoroalkanes in 2006. Manufacturers’ business decisions are based on a variety of factors, including availability of generic products, market size, patent expiration, drug-approval status, regulatory compliance requirements, and anticipated clinical demand. Occasionally, manufacturers temporarily or permanently reduce production quantities of certain drug products as they shift production efforts or reallocate resources to other products. A manufacturer’s reasoned, sound business decision to discontinue production of a drug product because of insufficient financial return or a high cost to correct manufacturing issues can cause an unanticipated, serious shortage, especially in the instance of a sole-source or medically necessary product.15 For example, a shortage of diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed was precipitated when one of the manufacturers, claiming low revenues, discontinued its product in 2000.5 Manufacturers are not required to notify FDA of a drug discontinuation unless the product is a sole-source or medically necessary product.16 For medically necessary drugs, FDA can encourage other manufacturers to produce the product or request that the manufacturer not suspend production until an alternative source is available. However, FDA does not have the authority to require a company to make any product, even if it is medically necessary. Even with advance notice, some agents, such as vaccines or antibiotics, are complex to manufacture, and shortages may result even if other manufacturers are willing and able to produce the product. Similarly, business decisions on the part of wholesale distributors and end-user health systems may contribute to drug product shortages. Manufacturer mergers often result in decisions to narrow the focus of product lines or move a production line to a new facility, resulting in the discontinuation or delayed availability of drug products. Mergers between two companies that manufacture similar product lines typically result in single-source products. As the number of manufacturers of a product decreases, resiliency in the supply chain also decreases, making product supplies more vulnerable. Many vaccines in the United States are single-source products, in part because of discontinuations and consolidations. Most hospitals and health systems obtain the majority of their drug products through wholesale distributors. Restricted distribution methods that bypass the normal supply chain can also create shortages. As the result of either market approval requirements or postmarketing surveillance, manufacturers limit the availability of specific drug products. Only selected suppliers and end users who comply with manufacturer agreements can obtain the product. A manufacturer can also place restrictions on available limited supplies, requiring health systems to order directly from the manufacturer or through a specialty distributor to receive an allocation. Communication and transportation efficiencies throughout the supply chain have allowed inventory reductions at all levels. Most manufacturers, distribution centers, and health systems use “just-in-time” inventory management to reduce the cost of inventory on hand and optimize cash flow. This strategy is recognized as sound business management for all stakeholders, but an unexpected shortage at any point in the supply chain can significantly affect the end user and patient. Some manufacturers and distributors use inventory management strategies that minimize end-of-quarter or end-of-year product inventories or limit shipments based on yearly quotas. Poor ordering practices, stockpiling before price increases, hoarding caused by rumors of an impending shortage, and unexpected delivery delays may affect inventory levels in individual health systems. Hospitals in rural areas face additional inventory challenges caused by distant distribution centers and the inability to easily borrow an item from a nearby hospital. Drug product shortages may also occur when all hospitals in an area disproportionately use the same wholesaler. Some shortages are wholesaler dependent, as shortages of drugs can occur when contracts with suppliers are delayed. Occasionally, the demand for a drug product unexpectedly increases or exceeds production capacity. This may occur when a new indication is approved for an existing drug product, when usage patterns change in response to new therapeutic guidelines, when a substantial disease outbreak occurs, or when unpredictable factors influence demand. Shortages may be prolonged when the raw materials are limited or manufacturing processes are complex or dependent on a long lead time. For example, when the Centers for Disease Control and Prevention (CDC) recommended annual influenza vaccination for children age 6–59 months in 2006, only one product had FDA-approved labeling for use in children 6–23 months old.17,18 The increased frequency of drug product shortages has precipitated the development of nontraditional distributors, also known as open-market, gray-market, or alternative distributors. These specialty, licensed distributors or brokers obtain products in short supply for the purpose of reselling them to end users who are unable to obtain them through their normal suppliers. These distributors aggressively market the availability of these products to hospitals, specialty health systems, home care agencies, and physician practices, generally at substantially higher prices. Typically, these distributors have a limited quantity of product, often only enough for one or two patients. Many do not offer a return or refund on a product if it expires or is not used. Especially worrisome is the inability to ascertain the product’s pedigree or ensure the reliability of the product’s source, which could be outside the United States, and proper handling and storage throughout the chain of custody. The extent to which the activities of such nontraditional distributors contribute to drug product shortages is unknown. Compounding pharmacies have also pursued the production of drugs that are in short supply. Caution is warranted because preparations from these pharmacies may not meet applicable state or federal standards (e.g., United States Pharmacopeia chapter 797 or FDA labeling requirements). The sources of raw materials used by compounding pharmacies have been questioned, and apparent lapses in quality control have resulted in serious patient injury, including death.13 Natural disasters can have a profound effect on the availability of drug products. Damage to manufacturing facilities, particularly those that are the sole source of a drug product or category of products, is likely to cause long-term shortages. Damage to manufacturing facilities in Puerto Rico in 1998 from hurricane George caused shortages of several drug products. Fires, hurricanes, tornadoes, and floods are examples of natural disasters that may temporarily compromise drug product supplies. In some instances, these shortages may be exacerbated by an escalated need for certain classes of drug products to care for victims of the disaster. In 2005, areas affected by and affected by an increased need for and the inability to obtain The of a shortage a of events drug and therapeutic Drug include the shortage and its anticipated the availability of supplies from alternative and alternative supplies the of compounding the product, and and about alternative and the cost of all The of process may an of the effect on patient care and development of a strategy for the to all professionals and to affected patients when In an would be a for providers in advance of impending drug product would them to address and all aspects and of the In of pharmacists, when with the of a drug product, on which to decisions about patient for the product. of the supply especially manufacturers and distributors, have been in and to health systems. The in is exacerbated by the and in the supply chain. The pharmacy department must take a leadership role in managing shortages by and appropriate strategies and processes for the safe and effective use of therapeutic alternatives. Health systems should develop a contingency planning strategy to for the of a prolonged drug product it often is not to when shortages will the process for with them can be defined in The health should a point to implement and process and an organizational approach to and The should determine and for during of the process (e.g., pharmacy and medical can be and and a of the current and the effect of the shortage on the health system. An effective the for the shortage and an end and supply are The of all activities that can be before the of the shortage are on the health when a order or other is is often before patients on the drug product and alternative should be drug products have limited therapeutic can have significant patient care and cost Health systems need to the effect of those on their should also include the development of methods for and The contingency involves and for which is limited because of financial or the health For example, products are available only in and at a high cost when no therapeutic are available or when shortages are control availability is not health systems must for a product’s The purchasing is often the who a shortage and may be the for managing drug product shortages. This must be of in the health supply chain that may a shortage (e.g., one to manufacturers have no more the purchasing is not a or must with a a shortage is the point or or should an to its A the and an of the current inventory and usage patterns can be used to determine the of the can product manufacturers, distributors, and other sources to determine the for the shortage and its This may be available on the Drug Center to the can a shortage of when the product will be available help determine the health to the shortage and its and long-term management the end result is the the to and the of effect to the for the shortage and in the supply chain problems raw materials to manufacturer, manufacturer to or wholesaler to health system. A lack of raw materials may affect several manufacturers of the drug product. A manufacturer’s problems may affect only its product. on distributors are dependent on their inventory levels. a shortage is the pharmacy should the inventory on hand and the it will inventory includes all supplies of the drug product the health including the care medication storage and distribution and on available quantities and the pharmacy should how long the health can a can be from and issue by distributors, the purchasing and the pharmacy and medication storage and can in usage the system. of all alternative drug products should be to of current use and are should be when assessing how long the available inventory of the shortage drug product and alternative products will A all factors to the shortage (e.g., current medical alternative sources or to determine the effect on patient care and costs. Shortages affect safe medication practices throughout the medication distribution and process a health system. alternative or must consider in their procedures for and distribution and the effect on compliance, and product The extent to which a health will be affected by a given shortage on the health and level of and its an shortage is the health should take to for known and problems in patient care and costs. The in the is to therapeutic to the drug product. A process for and therapeutic for the health should be The health should make decisions about alternative in with and pharmacy and obtain approval of the appropriate medical should be to ensure supplies to meet new demand. In supplies of the alternative may be affected by the current about the drug product shortage, alternative temporary therapeutic guidelines, and should be to clinical by the effective available the health system. Communication of is essential for ensuring patient and medication caused by differences between drug and other systems and systems must be with Pharmacy department for prescribers with medication and with should be about the alternative decisions and is necessary to and pharmacy or The when the of arrangements with other a or system. supplies of a potentially product and about alternative should be the This is limited for rural hospitals and for area hospitals by a wholesaler. a limited supply of a drug available and for specific patient are a health may the drug for specific patient (e.g., medical may on patient on and if available for the drug in may be in to appropriate drug Such are particularly in with long-term shortages such as with limit product use for patients or in the health should be by a Communication is essential to ensure that supplies are available to of guidelines for must be to in the of medication with management and or may be when supplies are For example, during the influenza vaccine shortage of health systems not have product to follow recommended guidelines and use of the product to specific patient management is a during a to do stockpiling in advance of a shortage can can exacerbate the shortage and supplies from other health systems with patients in Health systems should from which two can cause shortages when health systems the supply chain and manufacturing and inventory is and may not be by normal usage if shortages do not occur as purchasing in response to a shortage has on the likely cause of the shortage and it might occur in the supply chain. may arise that but do not end This when the supply from raw to product, several the long that a shortages, manufacturers and distributors often a product on the of An order generally has no effect on increasing an allocation. Health systems must guidelines for with in which a product is available only from a compounding source or nontraditional source or when a drug is not available at One of a shortage is by patients who that they have care or drug events as a result of alternative therapy, or nontraditional drug product This is likely with for which no are available. Even management and legal may have in of the they should be when all for either the drug product or have been health must determine its on purchasing drugs from the or compounding pharmacies and on compounding These decisions should be before the and of a specific shortage and its effect on patient should be drug product sources (e.g., have limited supplies, and the quality of these products may be as the of the medication may be unknown. Compounding pharmacies may also patient several have been with Health systems may to products if they can meet the necessary raw materials may be in some In the event that the drug product is available only from manufacturers or through nontraditional distributors, the increased of these sources should be alternative may also costs. The financial should be through with a request and for contingency caused by drug product shortages (e.g., in product, or compounding or must be to and to with all affected about the of a shortage is Some health systems may a specific department to may that a strategy organizational and or should be when a drug product shortage will delay or compromise care, especially when patients have been on the drug product and when may not be as effective (e.g., or The Joint that prescribers potentially affected by drug product shortages be Communication with the professional or patient organizations, and can of the shortage and its or FDA about a drug product shortage can these attention to the shortage may encourage production by other manufacturers, efforts to develop alternative and on the safe and effective use of alternatives. FDA is for with drug product shortages to the extent of its are several of The extent of FDA’s activities on a shortage FDA will to or shortages of medically necessary products. A product is to be medically necessary or a medical if it used to treat or a serious disease or medical and is no other available source of that product or alternative drug that is by medical to be an to the patient and cost to the and manufacturer are insufficient reasons for a product as a medical A of medical involves a of the issue with the product the medical FDA has that a shortage of a medically necessary product the will its actions may include with pharmaceutical manufacturers to encourage additional technical to manufacturers cGMP or of drug product or cGMP-related FDA may take these actions the cause of the shortage involves business decisions to manufacturing the product, voluntary recalls, FDA enforcement or other on the availability of medically necessary drug products is on and the availability of and vaccine products by FDA’s Center for Evaluation and Research is on FDA and health care professionals and to product shortages. of drug product shortages can be by Drug Shortages and on vaccine and product shortages FDA’s shortage will obtain about availability and will with drug product shortage Drug product supply issues are more they result from manufacturing difficulties or natural disasters that affect production, reductions in the supply of raw materials, voluntary recalls, manufacturer business FDA enforcement actions to ensure public safety, or stockpiling that to shortages. it is to for shortage, proper planning can minimize on patient care and health-system and problems from The to will be in the of to and with and for in the management of drug product shortages.

BACKGROUND AND PURPOSE: Since the FDA approved tissue plasminogen activator (tPA) in 1996 for acute ischemic stroke, few data have been obtained during the postmarketing phase, and applicability in rural hospitals does not exist. We attempt to examine the safety and outcome of intravenous tPA for acute ischemic stroke in the OSF Stroke Network. METHODS: Fifty-seven consecutive patients treated with tPA were examined from June 1996 through December 1998. Admission and discharge National Institute of Health Stroke Scales (NIHSS), modified Rankin Scales (MRS), and discharge disposition, as well as intracerebral hemorrhage and mortality rates, were compared. RESULTS: Of 20 network hospitals, 12 had the experience of administering tPA. No statistically significant differences in the variables recorded were observed for patients treated at the community hospitals versus those who received tPA at the tertiary medical center. In 35% of patients, tPA was initiated by an emergency room or primary care physician in consultation with an OSF neurologist. At discharge, 47% of the patients had minimal or no disability (MRS, 0 to 1), 44% had an NIHSS score of 0 or 1, 54% went home, 25% were transferred to in-patient rehabilitation, 12% went to a nursing or skilled-care facility, and 9% died. Intracerebral hemorrhage rate was 9%; 5% were symptomatic. CONCLUSIONS: tPA can be administered safely with good outcome at community and rural hospitals. The OSF Stroke Network can serve as a model to assist small community hospitals to set up stroke programs and deliver up-to-date, acute stroke therapies.

BACKGROUND AND PURPOSE: Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial (HeADDFIRST) was a randomized pilot study to obtain information necessary to design a Phase III trial to evaluate the benefit of surgical decompression for brain swelling from large supratentorial cerebral hemispheric infarction. METHODS: All patients with stroke were screened for eligibility (age 18-75 years, National Institutes of Health Stroke Scale≥18 with Item 1a<2 [responsive to minor stimulation], and CT demonstrating unilateral, complete middle cerebral artery territory infarction by specific imaging criteria). All enrolled patients were treated using a standardized medical treatment protocol. Those with both≥4 mm of pineal shift and deterioration in level of arousal or ≥7.5 mm of anteroseptal shift within 96 hours of stroke onset were randomized to continued medical treatment only or medical treatment plus surgery. Death at 21 days was the primary outcome measure. RESULTS: Among 4909 screened patients, only 66 (1.3%) patients were eligible for HeADDFIRST. Forty patients were enrolled, and 26 patients developed the requisite brain swelling for randomization. All who failed to meet randomization criteria were alive at 21 days. Mortality at 21 and 180 days was 40% (4/10) in the medical treatment only and 21% (3/14) and 36% (5/14) in the medical treatment plus surgery arms, respectively. CONCLUSIONS: HeADDFIRST randomization criteria effectively distinguished low from high risk of death from large supratentorial cerebral hemispheric infarction. Lower mortality in the medical treatment only group than in other published trials suggests a possible benefit to standardizing medical management. These results can inform the interpretation of recently completed European trials concerning patient selection and medical management. CLINICAL TRIAL REGISTRATION: This trial was not registered because enrollment began before July 1, 2005.

Hepatitis B virus (HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more than 600000 annual deaths due to cirrhosis and hepatocellular carcinoma. An effective vaccine exists and preventative initiatives center around universal vaccination especially in those at highest risk. Effective vaccination algorithms have led to a significant decline in the development of new infections and its devastating consequences. The vaccine is administered intramuscularly in three doses, with 95% showing long lasting serologic immunity. An additional fourth dose or a repeated higher dose three course regimen is given to those that fail to show immunity. Despite these additional regimens, some remain vulnerable to hepatitis B and are deemed non-responders. Individuals with chronic disease states such as kidney disease, liver disease, diabetes mellitus, as well as those with a genetic predisposition, and those on immunomodulation therapy, have the highest likelihood of non-response. Various strategies have been developed to elicit an immune response in these individuals. These include increased vaccination dose, intradermal administration, alternative adjuvants, alternative routes of administration, co-administration with other vaccines, and other novel therapies. These alternative strategies can show improved response and lasting immunity. In summary, HBV vaccination is a major advance of modern medicine and all individuals at risk should be sought and vaccinated with subsequent adequate titers demonstrated.

To increase cardiopulmonary arrest survival, the American Heart Association developed basic and advanced cardiac life support (ACLS) courses that expose participants to realistic learning situations. This experimental study compared results of two ACLS classes on measures of knowledge (content exam) and resuscitation skills (performance exam). Both the control and experimental groups consisted of physicians, nurses, emergency medical technicians, respiratory therapists, and advanced health care providers. The control group used low-fidelity simulation (LFS); the experimental group was exposed to enhanced realism via high-fidelity simulation (HFS). The findings showed a positive correlation between enhanced practice and learning but no significant correlation between posttest and skills test scores for the LFS and HFS groups. The HFS group did score higher on both cognitive and behavioral tests, but the difference was not statistically significant. Participants from both groups indicated satisfaction with their forms of simulation experience and course design. In addition, participants' self-confidence to care for a victim of cardiopulmonary arrest was increased after completing their course; profession and work experience had no effect on responses. The largest difference noted was in verbal responses to course satisfaction. The experimental group stated that learning using HFS was enjoyable and adamantly recommended that ACLS should only be taught using HFS. Further study is required to assess if practicing beyond the course enhances short- and long-term retention of ACLS techniques.

PURPOSE: To explore regional variation of the macular microvasculature in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), also to detect the association between retinal macular microvascular parameters and the progress of preclinical AD. METHODS: Prospective study of healthy controls, patients with MCI and patients with AD by using Optical coherence tomography angiography (OCT-A). We quantified foveal avascular zone (FAZ) areas, densities of the superficial retinal capillary plexuses (SRCP) and deep retinal capillary plexuses (DRCP). The SRCP and DRCP were divided into inner (3 mm) and external (6 mm) annular rings, each containing four quadrants (SI, II, TI, NI, SE, IE, TE and NE). The data were analysed statistically by using SPSS 22 software. RESULTS: Totally, 60 subjects including 21 HC (33 eyes), 21 patients with MCI (32 eyes) and 18 AD patients (28 eyes) were recruited. The microvascular densities of DRCP at all quadrants of the parafovea and perifovea were significantly lower in AD patients compared to HC group (p < 0.05). Compared to the HCs, MCI patients showed significant microvascular loss in most sectors of the parafovea and the SE sector of the DRCP (p < 0.05), but not in the parafovea (p = 0.829) or perifovea (p = 0.824) of the SRCP. No significant difference was found in microvascular density of SRCP among the groups, except at SI between the AD and HC groups (p = 0.048). CONCLUSION: Our findings demonstrated the macular microvascular attenuation in MCI and AD patients. Both AD and MCI patients showed retinal microvascular density loss, which is more significant in the deep retinal capillary plexuses. Optical coherence tomography angiography (OCT-A) can be used to identify early microvascular abnormalities in AD and MCI. Quantified microvascular density in the DRCP might serve as potential biomarkers of early sign of AD then contribute to forestall the progression of preclinical AD.

AIM: To detect pancreatic neuroendocrine tumors (PNETs) has been varied. This study is undertaken to evaluate the accuracy of endoscopic ultrasound (EUS) in detecting PNETs. METHODS: Only EUS studies confirmed by surgery or appropriate follow-up were selected. Articles were searched in Medline, Ovid journals, Medline nonindexed citations, and Cochrane Central Register of Controlled Trials and Database of Systematic Reviews. Pooling was conducted by both fixed and random effects model). RESULTS: Initial search identified 2610 reference articles, of these 140 relevant articles were selected and reviewed. Data was extracted from 13 studies (n = 456) which met the inclusion criteria. Pooled sensitivity of EUS in detecting a PNETs was 87.2% (95%CI: 82.2-91.2). EUS had a pooled specificity of 98.0% (95%CI: 94.3-99.6). The positive likelihood ratio of EUS was 11.1 (95%CI: 5.34-22.8) and negative likelihood ratio was 0.17 (95%CI: 0.13-0.24). The diagnostic odds ratio, the odds of having anatomic PNETs in positive as compared to negative EUS studies was 94.7 (95%CI: 37.9-236.1). Begg-Mazumdar bias indicator for publication bias gave a Kendall's tau value of 0.31 (P = 0.16), indication no publication bias. The P for χ² heterogeneity for all the pooled accuracy estimates was > 0.10. CONCLUSION: EUS has excellent sensitivity and specificity to detect PNETs. EUS should be strongly considered for evaluation of PNETs.

The purpose of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of brain perfusion SPECT studies using 99m Tc radiopharmaceuticals.

OBJECTIVE: The goal was to determine whether very low birth weight infants could tolerate higher rates of infusion of intravenous fat emulsion during the first week of life and maintain their serum triglyceride levels at <or=200 mg/dL. METHODS: This was a randomized, controlled trial of 110 infants who were classified as appropriate for gestational age and had birth weights between 750 g and 1500 g. The primary clinical outcome was serum triglyceride levels; secondary outcomes also were monitored. RESULTS: One hundred infants completed the study (experimental group: N = 48; control group: N = 52). Infants in the experimental group had significantly higher energy intake for the entire 7-day study period and achieved 90 kcal/kg per day (1 kcal = 4.184 kJ) significantly sooner (7.38 +/- 3.381 days vs 9.44 +/- 3.578 days). Triglyceride levels for infants in the experimental group remained significantly higher for the first 5 days of life. Fifteen percent of infants in the experimental group but only 4% of infants in the control group developed hypertriglyceridemia. Ten percent of infants in the control group but no infants in the experimental group required insulin therapy. Forty-two percent of infants in the experimental group and 17% of infants in the control group remained at >or=10th percentile for weight for age. Fourteen percent of infants in the control group but no infants in the experimental group developed necrotizing enterocolitis. Twenty-three percent of infants in the control group but only 6% of infants in the experimental group developed retinopathy of prematurity. There were no significant differences in other outcomes. CONCLUSIONS: Very low birth weight infants can tolerate higher rates of infusion of intravenous fat emulsion solutions during the first week of life without significant adverse events.

Background: Preliminary evidence indicates that prophylactic-dose thromboprophylaxis may be inadequate to control the increased risk of venous thromboembolism (VTE) in patients hospitalized for coronavirus disease 2019 (COVID-19) infection. Additionally, it remains unclear whether the D-dimer measurement is useful for VTE risk stratification among COVID-19 patients. This study aimed to offer benchmark data on the incidence of VTE and to examine the difference in D-dimer levels among anticoagulated COVID-19 patients with and without VTE incident. Methods: A comprehensive literature review of PubMed from inception to May 2020 was performed for original studies that reported the frequency of VTE and death among COVID-19 patients who received thromboprophylaxis on hospitalization. The endpoints included VTE (a composite of pulmonary embolism (PE) or deep vein thrombosis (DVT)), PE, DVT, and mortality. Results: A total of 11 cohort studies were included. Among hospitalized COVID-19 patients, 23.9% (95% confidence interval (CI), 16.2% to 33.7%; I2 = 93%) developed VTE despite anticoagulation. PE and DVT were detected in 11.6% (95% CI, 7.5% to 17.5%; I2 = 92%) and 11.9% (95% CI, 6.3% to 21.3%; I2 = 93%) of patients, respectively. Patients in the intensive care unit (ICU) had a higher risk for VTE (30.4% )95% CI, 19.6% to 43.9%)) than those in the ward (13.0% (95% CI, 5.9% to 26.3%)). The mortality was estimated at 21.3% (95% CI, 17.0% to 26.4%; I2 = 53%). COVID-19 patients who developed VTE had higher D-dimer levels than those who did not develop VTE (mean difference, 2.05 µg/mL; 95% CI, 0.30 to 3.80 µg/mL; P = 0.02). Conclusions: The heightened and heterogeneous risk of VTE in COVID-19 despite prophylactic anticoagulation calls into research on the pathogenesis of thromboembolic complications and strategy of thromboprophylaxis and risk stratification. Prominent elevation of D-dimer may be associated with VTE development and can be used to identify high-risk subsets.