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The service sector and what is termed “service spend” (i.e., the actual amount spent on services) continues to drive the economy, yet the outsourcing of service activity receives little formal attention from management. This situation produces inefficiencies and missed opportunities to maximize value and, as such, creates dissatisfaction and ultimately failure within the bounds of the outsourcing relationship. With relational transparency, defined and communicated expectations, and a heightened sense of management involvement taken together as a baseline, firms engaging in service outsourcing may begin to see the promised fortunes that have heretofore been elusive.

In this article, a qualitative business mini-case study concerning issues surrounding warehouse management systems and supply chain management techniques are implemented at two very different Pittsburgh-area companies. The increasing importance of supply chains as it relates to selection and management of real-time data to improve its overall efficiency and proactiveness are briefly highlighted through the literature. This chapter showcases some of these techniques developing into integrated management tools. It is hoped as business firms enter into deeper manufacturer/supplier relationships. These relationships will change from being skeptical and hostile to being mutually cooperative and dependent on one another.

These NCCN Guidelines for Distress Management discuss the identification and treatment of psychosocial problems in patients with cancer. All patients experience some level of distress associated with a cancer diagnosis and the effects of the disease and its treatment regardless of the stage of disease. Clinically significant levels of distress occur in a subset of patients, and identification and treatment of distress are of utmost importance. The NCCN Distress Management Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights describe updates to the NCCN Distress Thermometer (DT) and Problem List, and to the treatment algorithms for patients with trauma- and stressor-related disorders.

Understanding the history of microcystins (MCs) pollution in large lakes can help inform future lake management. We collected sediment cores from Lake Taihu to: investigate the long-term record of MCs (MC-LR, MC-YR, and MC-RR), explore the main environmental drivers of MCs, and assess their public health and ecological risks. Results showed that MCs content in all cores increased over time. The core from north Taihu had the highest MC concentrations, with an average total MCs (sum of MC-LR, MC-YR, and MC-RR = TMCs) content of (74.31±328.55) ng/g. The core from eastern Taihu showed the lowest average TMCs content of (2.91±3.95) ng/g. PCA showed that sediment MCs at the three sites were positively correlated with sediment chlorophyll-a. MC-LR and MC-YR in northern and western Taihu negatively correlated with both the sediment total organic carbon/sediment total nitrogen ratio (STOC/STN) and water nitrate (NO

Data-driven most powerful tests are statistical hypothesis decision-making tools that deliver the greatest power against a fixed null hypothesis among all corresponding data-based tests of a given size. When the underlying data distributions are known, the likelihood ratio principle can be applied to conduct most powerful tests. Reversing this notion, we consider the following questions. (a) Assuming a test statistic, say T, is given, how can we transform T to improve the power of the test? (b) Can T be used to generate the most powerful test? (c) How does one compare test statistics with respect to an attribute of the desired most powerful decision-making procedure? To examine these questions, we propose one-to-one mapping of the term 'Most Powerful' to the distribution properties of a given test statistic via matching characterization. This form of characterization has practical applicability and aligns well with the general principle of sufficiency. Findings indicate that to improve a given test, we can employ relevant ancillary statistics that do not have changes in their distributions with respect to tested hypotheses. As an example, the present method is illustrated by modifying the usual t-test under nonparametric settings. Numerical studies based on generated data and a real-data set confirm that the proposed approach can be useful in practice., Comment: Accepted

Palliative care is intended to relieve caregivers of physical, psychological, and even spiritual elements of care. One of the most prevalent issues facing this form of care is a lack of healthcare resources and structures to deal with an aging population. This aging population is placing a strain on the healthcare system, prompting a need for a shift in system management. A potential answer to this issue may be the Multi-Agent System (MAS). This category of computerized networking system was created by programmers to gather relevant health information on a patient and allow for the system to act with other agents to decide the best course for disease management. It can also allow for a multidisciplinary healthcare team to make more informed plans of actions for their patients by providing accurate and up-to-date information resulting from a greater synergetic mesh. MASs could fulfill the demands of a rising chronic illness population and deliver high-quality care, indicating a major paradigm shift within the US. In this review, we will evaluate the aging population and contributing factors, palliative care and the need for the multi-agent system, and clinical considerations involving examples from healthcare systems both on and beyond US shores.

This article presents a theory of organizational purpose that is normatively neutral and, hence, can be deployed to study firms without prejudging their role in society. The argument employs two philosophical concepts: intentionality and speech acts. The first is used to conceptualize the corporate mind, which is a set of long-lived beliefs about the world-as-it-is and intentions about the world-as-it-will-be that drives organizational activity. Corporate minds allow for complex and valuable forms of social cooperation and, hence, the article argues that the purpose of any organization is to sustain a corporate mind. Five core attributes enable organizations to fulfil this purpose: those are authorization, property rights, the ability to contract, the capacity to deliberate, and conversability. Conversability allows organizations to perform speech acts: that is, to make statements about the corporate mind that are referred to in this article as meta-contractual avowals. The article provides a value-neutral account of corporate governance as the set of devices that ensures the consistency of an organization’s corporate mind, meta-contractual avowals, and authorized actions. This theory sheds light upon the structure of purpose discourse and the relationship between different theories of the firm.

Electroencephalogram (EEG) discontinuity can occur at high concentrations of anesthetic drugs, reflecting suppression of electrocortical activity. This EEG pattern has been reported in children and reflects a deep state of anesthesia. Isoelectric events on the EEG, a more extreme degree of voltage suppression, have been shown to be associated with worse long-term neurologic outcomes in neonates undergoing cardiac surgery. However, the clinical significance of EEG discontinuities during pediatric anesthesia for noncardiac surgery is not yet known and merits further research. In this study, we assessed the incidence of EEG discontinuity during anesthesia induction in neurologically normal infants and the clinical factors associated with its development. We hypothesized that EEG discontinuity would be associated with sevoflurane-induced alpha (8-12 Hz) power during the period of anesthesia induction in infants.We prospectively recorded 26 channels of EEG during anesthesia induction in an observational cohort of 54 infants (median age, 7.6 months; interquartile range [IQR] [4.9-9.8 months]). We identified EEG discontinuity, defined as voltage amplitude25 microvolts for2 seconds, and assessed its association with sevoflurane-induced alpha power using spectral analysis and multivariable logistic regression adjusting for clinically important variables.EEG discontinuity was observed in 20 of 54 subjects (37%), with a total of 25 discrete events. Sevoflurane-induced alpha power in the posterior regions of the head (eg, parietal or occipital regions) was significantly lower in the EEG discontinuity group (midline parietal channel on the electroencephalogram, International 10-20 System [Pz]; 8.3 vs 11.2 decibels [dBs]; P = .004), and this association remained after multivariable adjustment (adjusted odds ratio [aOR] = 0.51 per dB increase in alpha power [95% CI, 0.30-0.89]; P = .02). There were no differences in the baseline (unanesthetized) EEG between groups in alpha power or power in any other frequency band.We demonstrate that EEG discontinuity is common during anesthesia induction and is related to the level of sevoflurane-induced posterior alpha power, a putative marker of cortical-thalamic circuit development in the first year of life. This association persisted even after adjusting for age and propofol coadministration. The fact that this difference was only observed during anesthesia and not in the baseline EEG suggests that otherwise hidden brain circuit properties are unmasked by general anesthesia. These neurophysiologic markers observed during anesthesia may be useful in identifying patients who may have a greater chance of developing discontinuity.

Although older adults are often concerned about instances of forgetting, forgetting can be a useful feature of our memory system. Specifically, strategically forgetting less important information can benefit memory for goal-relevant information (i.e., responsible remembering and responsible forgetting). In two experiments, we presented younger and older adults with a list of words (either unrelated words or items to bring on a camping trip) with a cue indicating whether participants ("You") or their "Friend" was responsible for remembering each item. Results revealed that both younger and older adults engaged in responsible remembering and forgetting by better remembering items they were responsible for remembering, indicating a strategic utilization of their limited memory capacity. Additionally, regardless of age and the cue indicating who was responsible for remembering each item, participants used importance to guide the encoding and retrieval of information. Thus, people may be able to engage strategic cognitive mechanisms to maximize memory utility for important, goal-relevant information, and responsible forgetting can enhance memory utility in both younger and older adults by using importance to drive memory and reduce consequences for forgetting.

Telemedicine, telehealth, and E-health all offer significant benefits for pain management and healthcare services by fostering the physician–patient relationship in otherwise challenging circumstances. A critical component of these artificial-intelligence-based health systems is the “agent-based system”, which is rapidly evolving as a means of resolving complicated or straightforward problems. Multi-Agent Systems (MAS) are well-established modeling and problem-solving modalities that model and solve real-world problems. MAS’s core concept is to foster communication and cooperation among agents, which are broadly considered intelligent autonomous factors, to address diverse challenges. MAS are used in various telecommunications applications, including the internet, robotics, healthcare, and medicine. Furthermore, MAS and information technology are utilized to enhance patient-centered palliative care. While telemedicine, E-health, and MAS all play critical roles in managing chronic pain, the published research on their use in treating chronic pain is currently limited. This paper discusses why telemedicine, E-health, and MAS are the most critical novel technologies for providing healthcare and managing chronic pain. This review also provides context for identifying the advantages and disadvantages of each application’s features, which may serve as a useful tool for researchers.

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802—a highly potent DENV inhibitor that blocks the NS3–NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.

Background: Exogenous melatonin is commonly used to treat insomnia, other sleep problems, and numerous medical illnesses, including Alzheimer’s disease, autism spectrum disorder, and mild cognitive impairment in adults and children. There is evolving information regarding issues with the use of chronic melatonin. Methods: The present investigation was a narrative review. Results: Melatonin usage has risen dramatically in recent years. Many countries only allow melatonin prescriptions. In the United States (U.S.), it is classified as a dietary supplement accessible over the counter and can be derived from animals, microorganisms, or, most commonly, made synthetically. No regulatory agency oversees its manufacturing or sale in the U.S. melatonin concentration of marketed preparations varies widely between product labels and manufacturers. Melatonin’s ability to induce sleep is detectable. However, it is modest for most people. Sleep length appears to be less important in sustained-release preparations. The optimal dosage is unknown, and routinely used amounts vary substantially. Melatonin’s short-term negative effects are minimal, resolve at medicine cessation, and do not usually prevent usage overall. Much research on long-term melatonin administration has found no difference between exogenous melatonin and placebo in terms of long-term negative effects. Conclusion: Melatonin at low to moderate dosages (approximately 5–6 mg daily or less) appears safe. Long-term usage appears to benefit certain patient populations, such as those with autism spectrum disorder. Studies investigating potential benefits in reducing cognitive decline and increased longevity are ongoing. However, it is widely agreed that the long-term effects of taking exogenous melatonin have been insufficiently studied and warrant additional investigation.

While driving under the influence of drugs, drivers are more likely to be involved in and cause more accidents than drivers who do not drive under the influence. Ketamine is derived from phencyclidine and acts as a noncompetitive antagonist and allosteric modulator of N-methyl-D-aspartate receptors. Ketamine has been used to treat a variety of psychiatric disorders, with the most notable being treatment-resistant depression. With the rise of at-home ketamine treatment companies, the safety of unsupervised administration remains under evaluation. A study with ketamine and a ketamine-like medication, rapasitnel, showed that those who were given ketamine experienced more sleepiness and had decreased self-reported motivation and confidence in their driving abilities. Moreover, there seem to be significant differences in the acute versus persistent effects of ketamine, as well as the anesthetic versus subanesthetic doses, both in terms of effects and outcomes. These divergent effects complicate the clinical uses of ketamine, specifically involving driving, drowsiness, and cognitive abilities. This review aims to describe not only the various clinical uses of ketamine but also the potentially detrimental effects of driving under the influence, which should be understood to help with counseling the patients who use these substances, both for their well-being and to protect public safety.

Background: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. Methods: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1–5; prednisone 60 mg/m2 orally on days 1–15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006–000995-33) and is completed. Findings: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1–69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3–89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8–92·5), for which the 95% CI included the 90% target rate. The most common grade 3–4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. Interpretation: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. Funding: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

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Therapeutic effect of tamoxifen (Tam) against ER+ breast cancer (BC) is known to be mediated by its binding to estrogen receptor-alpha (ERά/ESR1) and inhibiting estrogen signaling leading to altered gene expression. Besides this canonical mode of function, our pre-clinical studies had revealed a novel mechanism wherein ESR1 directly binds wild type p53 (wt TP53) resulting in repression of its tumor suppressor functions, and Tam blocks this inactivation of TP53. Although patients with Luminal Tumors expressing wt TP53 are known to be more responsive to tamoxifen therapy, the underlying mechanism in tumors has remained unknown. To test the hypothesis that abrogation of the ESR1-mediated functional inactivation of TP53 is one of the major mechanisms that underlie the early effects of Tam therapy, we conducted a window of opportunity clinical trial in newly diagnosed luminal breast cancer patients undergoing surgical therapy. Methods: 59 women with ER+ invasive BC were randomized to 20mg Tam daily for 28 days prior to surgery or standard of care (SOC). TP53 status was confirmed by massively parallel sequencing. ER+ wt TP53 tumors were included in the study. IHC was performed on FFPE tissue from tumors to compare expression of ESR1 and TP53 along with their selected downstream targets. ESR1–TP53 interaction in situ was determined by Proximity Ligation Assay (PLA).17β-estradiol and Tam metabolites were measured in the plasma, tumor, and surrounding normal tissue using LC-MS/MS. Global transcriptome analysis in tumors was conducted by RNA-seq. Proteome expression in resected tumors was analyzed by reverse phase protein array (RPPA) with 216 proteins. Findings: Importantly, IHC on tumor tissues showed that the levels of ESR1 and TP53 were not altered in response to Tam therapy, whereas ESR1–TP53 interaction was considerably disrupted by Tam (in situ PLA data). Differential gene expression (DGE) analysis using DESeq2 R package followed by GSEA pathway analysis showed that 307 genes were differentially expressed (p< 0.05) (log FC>1.5) in tumors from Tam-treated versus untreated patients in response to Tam therapy. Pathways representing TP53 signaling, stem cells, and low-grade luminal breast cancer were upregulated in the Tam treated group while those representing adipogenesis, invasive breast cancer, estradiol response, ras signaling, and E2F targets were downregulated. “Master Regulators” identified by iRegulon included several p53 targets. Integration of RNA-seq and RPPA data revealed that DEGs fall into three categories: (i) regulated by TP53, (ii) regulated by ESR1, and (iii) regulated by both TP53 and ESR1. Together, the data demonstrated that in addition to its conventional effects mediated by its binding to ESR1 and inhibiting estrogen signaling leading to altered gene expression, Tam disrupted the ESR1–TP53 interaction leading to functional reactivation of TP53 and reprogramming of gene expression. Conclusions: Our data 1) support ESR1–TP53 crosstalk in tumors as a novel mechanism underlying endocrine therapy response of luminal BC patients, and 2) highlight the importance of factoring TP53 into therapeutic strategies for ER+ BC patients, and 3) have implications in stratifying ER+ BC patients to those who will or will not be responsive to Tam therapy. Citation Format: Gokul M. Das, Swati A. Kulkarni, Chetan Oturkar, Spencer Rosario, Stephen B. Edge, Jianmin Wang, Wendy M. Swetzig, Alan D. Hutson, Benny Kaipparettu, Adrienne Groman, Araba Adjei, Andrew K. Goey, Carl D. Morrison, Shicha Kumar. PD10-05 Neoadjuvant tamoxifen therapy reactivates tumor suppressor protein p53 in luminal breast cancer patients: Results from a window-of-opportunity clinical trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD10-05.

The increasing prevalence of stimulant use disorder (StUD) involving methamphetamine and cocaine has been a growing healthcare concern in the United States. Cocaine usage is associated with atherosclerosis, systolic and diastolic dysfunction, and arrhythmias. Furthermore, approximately one of every four MIs is cocaine-induced among patients aged 18 to 45. Methamphetamine use has been associated with nerve terminal damage in the dopaminergic system resulting in impaired motor function, cognitive decline, and co-morbid psychiatric disorders. Current treatment options for StUD are extremely limited, and there are currently no FDA-approved pharmacotherapies. Behavioral interventions are considered first-line treatment; however, in a recent meta-analysis comparing behavioral treatment options for cocaine, contingency management programs provided the only significant reduction in use. Current evidence points to the potential of various neuromodulation techniques as the next best modality in treating StUD. The most promising evidence thus far has been transcranial magnetic stimulation which several studies have shown to reduce risk factors associated with relapse. Another more invasive neuromodulation technique being studied is deep-brain stimulation, which has shown promising results in its ability to modulate reward circuits to treat addiction. Results showing the impact of transcranial magnetic stimulation (TMS) in the treatment of StUD are limited by the lack of studies conducted and the limited understanding of the neurological involvement driving addiction-based diseases such as StUD. Future studies should seek to provide data on consumption-reducing effects rather than craving evaluations.

Integrative and conjugative elements (ICEs) are mobile genetic elements that can transfer by conjugation to recipient cells. Some ICEs integrate into a unique site in the genome of their hosts. We studied quantitatively the process by which an ICE searches for its unique integration site in the Bacillus subtilis chromosome. We followed the motion of both ICEBs1 and the chromosomal integration site in real time within individual cells. ICEBs1 exhibited a wide spectrum of dynamical behaviors, ranging from rapid sub-diffusive displacements crisscrossing the cell, to kinetically trapped states. The chromosomal integration site moved sub-diffusively and exhibited pronounced dynamical asymmetry between longitudinal and transversal motions, highlighting the role of chromosomal structure and the heterogeneity of the bacterial interior in the search. The successful search for and subsequent recombination into the integration site is a key step in the acquisition of integrating mobile genetic elements. Our findings provide new insights into intracellular transport processes involving large DNA molecules.

Objective: This review aims to evaluate the effectiveness of the two most commonly used oxygen delivery methods for the treatment of thermal burn wound healing: hyperbaric oxygen therapy (HBOT) and topical oxygen therapy (TOT). Method: The PubMed database was searched for articles discussing the use of HBOT or TOT in the treatment of thermal burns. Results: The search yielded 43,406 articles, of which 28 (23 HBOT, 5 TOT) met the inclusion criteria. Both experimental and clinical studies have demonstrated conflicting results after treating thermal burns with HBOT or TOT. Overall, 14/23 studies demonstrated positive results for HBOT on the healing of burn wounds and associated complications, such as oedema and pain. Findings from these studies showed it can reduce morbidity and mortality in certain high-risk groups such as those with diabetes or extensive burns. Although the five studies (one human and four animal trials) reviewing TOT showed promising outcomes, this therapeutic modality has not been well investigated. Conclusion: Therapeutic use of HBOT in thermal burns has been popular in the past but its use remains controversial due to inconsistent results, serious side-effects, lack of convenience and high costs. The use of TOT in the management of burns needs further exploration by scientists and clinicians alike, in addition to the implementation of a standardised treatment protocol.

Chronic rhinosinusitis with nasal polyps (CRSwNP) carries a high disease burden, and many studies have been done investigating the efficacy of various medical and surgical therapies. However, outcome metrics have varied across these studies, making it difficult to compare therapeutic efficacy on a large scale. In this article, we discuss various outcome metrics used across prior studies as well as the relationship between these measures.Outcome metrics in CRSwNP studies include both clinically assessed and patient-reported outcome measures (PROMs). The former includes olfaction testing, scoring systems based on imaging and endoscopic evaluation, and histopathological and immunohistochemical evaluation of sinus tissue, and the latter includes quality-of-life instruments, symptom severity scales, and disease-control instruments. Recent studies evaluating the efficacy of new biologics have used a combination of both types of metrics.Both clinical metrics and patient-reported outcomes provide utility in evaluating disease severity and control in patients with CRSwNP, although there are nuances when comparing therapies in this population as patients with CRSwNP are heterogeneous and may have symptoms across several domains. However, PROMs in conjunction with clinical metrics provide useful information to assess patient symptoms and response to interventions.

Glucagon stimulates hepatic glucose production through its direct effects on the liver but may indirectly inhibit this process by acting on the brain. This was tested by delivering glucagon via the cerebral circulatory system. Central nervous system glucagon action reduced liver gluconeogenic flux, but glycogenolysis increased, resulting in no net change in hepatic glucose production. Surprisingly, brain glucagon also appeared to suppress lipolysis (plasma free fatty acid and glycerol levels were reduced).

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a mutation in the C1 esterase inhibitor gene. HAE affects 1/50,000 people worldwide. Three main types of HAE exist: type I, type II, and type III. Type I is characterized by a deficiency in C1-INH. C1-INH is important in the coagulation complement, contact systems, and fibrinolysis. Most HAE cases are type I. Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH. Formally known as type III HAE is typically an estrogen-dependent or hereditary angioedema with normal C1-INH activity. Current guidelines now recommend subdividing hereditary angioedema with normal C1 esterase inhibitor gene (HAE-nl-C1-INH formerly known as HAE type III) based on underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene mutation (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), mutation in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1). The clinical presentation of HAE varies between patients, but it usually presents with nonpitting angioedema and occasionally abdominal pain. Young children are typically asymptomatic. Those affected by HAE usually present with symptoms in their early 20s. Symptoms can arise as a result of stress, infection, or trauma. Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin. C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected. Acute treatment of HAE can include IV infusions of C1-INH, receptor antagonists, and kallikrein inhibitors. Short- and long-term prophylaxis can also be administered to patients with HAE. First-line therapies for long-term prophylaxis also include IV infusion of C1-INH. This review aims to thoroughly understand HAE, its clinical presentation, and how to treat it.

PURPOSE Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136 ). METHODS Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte–associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review. RESULTS A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti–PD-1 plus anti–CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count). CONCLUSION Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti–PD-1 plus anti–CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.

Craniovertebral junction (CVJ) cysts, including retro-odontoid pseudotumors, are challenging pathologies to treat and manage effectively. Surgical intervention is indicated when these lesions result in progressive myelopathy, intractable pain, or instability.To present a case series of older patients who underwent successful resection retro-odontoid lesions using transdural approach.A single-center, retrospective observation study of older patients who underwent transdural resection of CVJ cysts at a single institution was performed. Summary demographic information, clinical presentation, perioperative and intraoperative imaging, and Nurick scores were collected and analyzed.Eight patients were included (mean age [±SD] 75.88 ± 9.09 years). All patients presented with retro-odontoid lesions resulting in severe cervical stenosis, cord compression, and myelopathy. The mean duration of surgery was 226 ± 83.7 minutes. The average intraoperative blood loss was 181.2 cc. The average hospital stay was 4.5 days ± 1.3 (range, 3-7 days). The average follow-up time was 12.5 ± 9.5 months. No intraoperative complications were encountered. The Nurick classification score for myelopathy improved at the final postoperative examination (2.38 ± 1.06 vs 1 ± 1.07). Three patients demonstrated a pre-existing deformity prompting an instrumented fusion. Both computed tomography and MRI evidence of complete regression of retro-odontoid cyst were noted in all patients on the final follow-up.Posterior cervical transdural approach for ventral lesions at the CVJ is a safe and effective means of treating older patients with progressive myelopathy. This technique provides immediate spinal cord decompression while limiting neurological complications commonly associated with open or endoscopic anterior transpharyngeal approaches.