Antibiotic Development: Lessons from the Past and Future Opportunities.

The challenge of antimicrobial resistance is broadly appreciated by the clinical and scientific communities. To assess progress in the development of medical countermeasures to combat bacterial infections, we deployed information gleaned from clinical trials conducted from 2000 to 2021. Whereas private sector interest in cancer grew dramatically over this period, activity to combat bacterial infections remained stagnant. The comparative ambivalence to antimicrobial resistance is reflected in the number of investigative drugs under clinical investigation, their stage of development and most troublingly, a declining number of organizations that are actively involved in the development of new products to treat bacterial infections. This drop reflects the exits of many companies that had previously developed antibacterial agents.

2023 in review: FDA approvals of new medicines.

An analysis of all new entities approved by both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) identified the approval of 69 new entities in the year 2023, 50 % more than in the previous year. Oncology drugs tied with congenital and infectious diseases drugs for the most approvals. Although orphan and priority approvals continued at a high pace, the rate of fast-track approvals continued to decline. The rate of industry consolidation also picked up again after decreasing slightly in 2022.

Contralateral Gluteal Compartment Syndrome After Prolonged Use of a Fracture Table in a Scissoring Position: A Case Report.

CASE: A 62-year-old Caucasian man presented with a comminuted subtrochanteric fracture after a low-energy fall. Physical examination postoperatively revealed a firm hard gluteal compartment in the contralateral buttocks. The patient underwent a fasciotomy, using the Kocher-Langenbeck approach, to release the gluteus maximus and lateral thigh fascia. At the most recent 6-month follow-up, gluteal function was intact with no long-term sequelae from compartment syndrome. CONCLUSION: Prolonged positioning on a fracture table can result in gluteal compartment syndrome of the contralateral extremity.

A Teenager With Dysphagia, Mild Dyspnea, and an Indolent Mass.

A 15-year-old male presented with dysphagia to solid foods, and dyspnea when laying on the right side that had progressed during 8 months. What is your diagnosis?

2022 in review: FDA approvals of new medicines.

An accounting of all new entities approved by both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) identified the approval of 44 new entities in the year 2022. Oncology-based drugs continued to be the most popular indication for these medicines. Likewise, orphan indications encompassed more than half of new drug approvals. The number of new entities approved in 2022 declined from its peak after 5 years of more than 50 annual approvals. Likewise, the rate of consolidations slowed somewhat, among both new entries in the realm of clinical-stage developers and more established organizations.

Inter-individual variability during neurodevelopment: an investigation of linear and nonlinear resting-state EEG features in an age-homogenous group of infants.

Electroencephalography measures are of interest in developmental neuroscience as potentially reliable clinical markers of brain function. Features extracted from electroencephalography are most often averaged across individuals in a population with a particular condition and compared statistically to the mean of a typically developing group, or a group with a different condition, to define whether a feature is representative of the populations as a whole. However, there can be large variability within a population, and electroencephalography features often change dramatically with age, making comparisons difficult. Combined with often low numbers of trials and low signal-to-noise ratios in pediatric populations, establishing biomarkers can be difficult in practice. One approach is to identify electroencephalography features that are less variable between individuals and are relatively stable in a healthy population during development. To identify such features in resting-state electroencephalography, which can be readily measured in many populations, we introduce an innovative application of statistical measures of variance for the analysis of resting-state electroencephalography data. Using these statistical measures, we quantified electroencephalography features commonly used to measure brain development-including power, connectivity, phase-amplitude coupling, entropy, and fractal dimension-according to their intersubject variability. Results from 51 6-month-old infants revealed that the complexity measures, including fractal dimension and entropy, followed by connectivity were the least variable features across participants. This stability was found to be greatest in the right parietotemporal region for both complexity feature, but no significant region of interest was found for connectivity feature. This study deepens our understanding of physiological patterns of electroencephalography data in developing brains, provides an example of how statistical measures can be used to analyze variability in resting-state electroencephalography in a homogeneous group of healthy infants, contributes to the establishment of robust electroencephalography biomarkers of neurodevelopment through the application of variance analyses, and reveals that nonlinear measures may be most relevant biomarkers of neurodevelopment.

Metastatic renal cell carcinoma to the thyroid with cervicothoracic venous tumor thrombosis.

INTRODUCTION: Metastatic renal cell carcinoma (RCC) represents 25%-42% of metastatic thyroid malignancies. Propensity for RCC to demonstrate intravascular extension to the inferior vena cava is well documented. We present an analogous phenomenon of intravascular extension to the internal jugular vein (IJV) from thyroid gland metastasis. METHODS: A 69-year-old male presented with metastatic RCC of the right thyroid lobe. Imaging demonstrated tumor thrombosis of the ipsilateral IJV, extending inferiorly to the junction of the brachiocephalic, subclavian, and internal jugular veins within the mediastinum. RESULTS: Surgical excision required control of both the IJV in the neck and mediastinal venous great vessels via sternotomy, prior to subtotal thyroidectomy and venotomy for en bloc resection. CONCLUSION: This case report describes metastatic RCC to the thyroid gland with cervicothoracic venous tumor thrombosis successfully treated with subtotal thyroidectomy, sternotomy for venotomy and tumor thrombectomy, and preservation of IJV conduit.

Systemic corticosteroids for orbital complications of pediatric rhinosinusitis: A systematic review.

OBJECTIVES: Determine if systemic corticosteroids administration is associated with reduced length of stay, surgical intervention, and abscess formation in pediatric patients with orbital complications of rhinosinusitis. METHODS: Systematic review and meta-analysis were performed utilizing the PubMed and MEDLINE databases to identify articles published between January 1990 and April 2020. Retrospective cohort study of the same patient population over the same time period at our institution. RESULTS: Eight studies, 477 individuals, met criteria for inclusion in the systematic review. 144 patients (30.2%) received systemic corticosteroids, while 333 patients (69.8%) did not. Meta-analyses of frequency of surgical intervention and subperiosteal abscess showed no difference between those who did and did not receive systemic steroids ([OR = 1.06; 95% CI: 0.46 to 2.48] and [OR = 1.08; 95% CI: 0.43 to 2.76], respectively). 6 articles evaluated hospital length of stay (LOS). 3 of these reported enough data to perform meta-analysis, which showed patients with orbital complications who received systemic corticosteroids had shorter mean hospital LOS when compared with those who did not receive systemic steroids (SMD = -2.92, 95% CI: 5.65 to -0.19). CONCLUSION: While available literature was limited, systematic review and meta-analysis suggests systemic corticosteroids decrease length of stay for hospitalized pediatric patients with orbital complications of sinusitis. Further research is needed to more clearly define the role of systemic corticosteroids as an adjunctive treatment.

Langerhans Cell Histiocytosis of the Head and Neck: Experience at a Rural Tertiary Referral Center.

OBJECTIVES: Retrospectively analyze head and neck Langerhans Cell Histiocytosis at a rural tertiary referral center and compare results with previously published data. METHODS: Electronic health record review was performed from 2003 to 2019. Patients with biopsy proven LCH with primary head and neck involvement were included. Demographics, presentation, imaging characteristics, treatment modality, delay in diagnosis (DD, ≥60 days), and outcomes were analyzed and reported. RESULTS: Twenty-four patients were included. The most common presenting symptoms were otorrhea (n = 6) and scalp pain or swelling (n = 6). All patients had bony involvement. The most common site was facial or skull lesions (n = 20). Most skull lesions (75%) demonstrated CNS risk. Six patients were treated with primary surgery, 15 with primary chemotherapy, and 3 with surgery plus adjuvant chemotherapy. Nine patients experienced relapse of disease with median time to documented relapse of 11.4 months; all were treated with salvage chemotherapy to achieve complete remission (median follow-up: 72 months). Patients most likely to relapse were those with multisystem disease (5/7, 71.4%), temporal bone lesions (4/7, 57.1%), and DD (7/12, 58.3%). Of the 9 total patients who experienced relapse, 78% had a delay in diagnosis. CONCLUSIONS: LCH is a complex disease process in which diagnosis can be delayed if not considered in the differential. Within the head and neck, the skull, including isolated temporal bone involvement, is the most common site of involvement. Treatment modality does not appear to have an influence on relapse rates. Relapse was more likely to occur in the first year after treatment and close monitoring is required.

Immunoconjugates and bispecific antibodies: Trends in therapeutic success and commercial focus.

Monoclonal antibodies (mAbs) have revolutionized the selective targeting of disease, as well as changing the character of the pharmaceutical industry. Although most attention has focused on conventional antibodies, immunoconjugates and bispecific antibodies (bsAbs) are beginning to show greater potential. Herein, we identify trends in the development and approval of antibody derivatives, as well as the organizations developing these products. Whereas industry development of immunoconjugates has grown steadily over four decades, momentum behind bispecific agents has seemingly expanded only recently. Together, our findings suggest that antibody derivatives provide interesting, albeit still speculative, opportunities for targeted interventions.

Monoclonal antibodies: Trends in therapeutic success and commercial focus.

Monoclonal antibody products have risen from obscurity in the 1990s to a position that increasingly dominates both revenue generation and patient impact. This success has occurred largely over the past two decades, and we have identified factors associated with the remarkable advances that have contributed to the discovery, development and approval of monoclonal antibodies. Although consolidation has increased in recent years, the net number of monoclonal antibody developers continues to grow, bucking the general trend in the biopharmaceutical industry.

Green building standards and the United Nations' Sustainable Development Goals.

Sustainable practices in the building industry are strongly influenced by published green and sustainable building and real-estate standards (GSBRES). Therefore, it is crucial to assess how these standards contribute to achieving the United Nations' Sustainable Development Goals (SDGs). This paper evaluates the extent to which GSBRESs align with the 2030 Agenda for Sustainable Development, lending a particular focus to the call for transformative change implicit in the SDGs. To this end, we develop a methodology that combines qualitative and quantitative analysis to assess the overlap between the content of three GSBRESs (LEED for design, BOMA BEST for operation, and GRESB for investment) and the SDGs. Despite the overlaps between the attributes of the GSBRESs and the general topics of the SDGs, we find that less than 20% of GSBRES attributes address the specific targets of the 2030 Agenda. Most importantly, the qualitative analysis shows that less than 10% of the standards' scores is attributed to transformative change. We conclude that claims that the GSBRESs are effective in advancing the SDGs are overstated and, without further empirical evidence, caution that they increase the risk of sustainable development greenwashing. We recommend that the standards be repositioned to adopt transformation-focused indicators related to a project's long-term impacts.

2021 in review: FDA approvals of new medicines.

The year 2021 witnessed a remarkable number of US Food and Drug Administration (FDA) approvals and registered clinical trials. In total, 60 new molecular entities (NMEs) were approved by the FDA, the highest level achieved in the post-Prescription Drug User Fee (PDUFA) era and tied with 2018. Of these NMEs, 49 used the incentives of the Orphan Drug Act or were approved under Priority, Fast-Track, Accelerated, and/or Breakthrough designations. Looking further, the number of registered clinical trials was off its 2020 record peak but well within the 5-year running average. Nonetheless, these remarkable outcomes were tempered by the fact that the rate of industry consolidation and turnover continued apace, reducing the number of organizations involved in the clinical development of new medicines and raising questions about long-term sustainability.

2020 in review: FDA approvals of new medicines.

Amid a global pandemic, the US Food and Drug Administration (FDA) remained relatively active, approving 55novel molecular entities (NMEs) in 2020, the third highest annual rate recorded. Orphan approvals also surged, capturing 60% of NMEs introduced during 2020, as did the number of NMEs approved using a priority review. The pandemic did appear to impact one recent trend, and in a paradoxically encouraging way. Escalating rates of consolidation slowed in 2020, with only 102 companies lost, down by two-thirds over the rate in 2019. This leaves 2000 extant clinical-stage pharmaceutical companies. When limiting this analysis to companies contributing to the research and development (R&D) of an approved drug, eight were lost, leaving 144 extant.

Gray-Scale Inversion on High Resolution Computed Tomography of the Temporal Bone: An Observational Study.

OBJECTIVES: This is a qualitative study to explore the utility of gray-scale inversion or the "invert" function of high-resolution computed tomography (HRCT) scans in the diagnosis of temporal bone anatomy and pathology. METHODS: This is a case series describing an innovative application of an existing image processing tool to visualize temporal bone anatomy and pathology. Illustrative patients at a tertiary referral center with otologic symptoms and findings leading to HRCT scans of the temporal bone were included. Diagnostic HRCT scans were evaluated utilizing the gray-scale inversion function (invert function). RESULTS: Nine illustrative cases which demonstrate conditions such as persistent stapedial artery, membranous stapes footplate, total ossicular prosthesis migration into the vestibule, third window syndrome such as superior semicircular canal dehiscence (SSCD) and cochlea-facial nerve dehiscence, otosclerosis, and ossicular chain discontinuity are included. The enhanced visualization was confirmed surgically in 3 cases, and 1 had physiological confirmation using cervical vestibular evoked myogenic potentials (cVEMP). CONCLUSIONS: Gray-scale inversion can be used to improve visualization of temporal bone anatomy and pathologic changes when diagnoses are in doubt. The invert function is a useful adjunct in the armamentarium of both radiologists and otologists when evaluating HRCT of the temporal bone.

Sources of innovation for new medicines: questions of sustainability.

The biopharmaceutical industry has undergone remarkable changes over the past half century, driven largely by a need to offset the ever-rising costs of developing new medicines. In this report, we aggregated information about the creation and fate of all clinical-stage biopharmaceutical companies, assessing trends over time. These results reveal that the rate of new company formation has been declining at the same time that industry consolidation has been accelerating at an unprecedented rate. Consequently, the number of companies involved in biopharmaceutical research and development has declined by one-third over the past decade, while those able to achieve at least one FDA approval has dropped by more than half. These findings raise important questions about the sustainability of an industry that is vital for both public and economic health.

Expanding roles for academic entrepreneurship in drug discovery.

An assessment of inventors of US Food and Drug Administration (FDA)-approved medicines reveals a growing role for academic entrepreneurship in general and National Institutes of Health (NIH)-supported investigators in particular. For all small-molecule therapeutics approved between 2001 and 2019 (383 in total), 8.3% listed an academic inventor in the Orange Book. Remarkably, an additional 23.8% listed an inventor from a company founded by an NIH-funded academic inventor. Over time, the relative inventive contributions from academia has progressively increased, including nearly one-third of medicines approved since 2017. These findings suggest a surging role for academic inventors and founders, perhaps in combination with a faltering of traditional private sector dominance of drug discovery.

2019 in review: FDA approvals of new medicines.

The US Food and Drug Administration (FDA) green-lighted the marketing of 53 therapeutic agents in 2019. This rate of approvals was consistent with the 5-year running average. Nonetheless, a few changes are worth noting. The rate of medicines first approved using an orphan drug designation declined from 56% in 2018 to 41% in 2019, which mirrored a comparable decline in the use of priority review. A second notable feature was an uptick in industry consolidation. Twenty-five companies were lost, primarily because of mergers, leaving only 146 extant companies that have contributed to the research or development of an innovative FDA-approved medicine.

Rising Academic Contributions to Drug Development: Evidence of Vigor or Trauma?

We analyzed therapeutic areas most commonly targeted by academia since 2001, finding a domination of certain oncology and infectious diseases. These findings raise important questions about whether this trend reflects an expanded opportunity arising from academic research or a troubling sign of an industry struggling with the challenges of innovation.

Transcanal incision and drainage of a parapharyngeal abscess in a pediatric patient: A novel technique.

The disease of parapharyngeal abscess is well known to the otolaryngologist and is commonly managed via transoral, transcervical, or combined incision and drainage. We report a novel approach to an abscess that was drained through the external auditory canal (EAC). An otherwise healthy 2-year-old female presented with a 4-day history of fevers, decreased oral intake, neck stiffness, and voice changes. CT neck with contrast revealed a deep abscess in the left neck extending from the peritonsillar space into the parapharyngeal space in close proximity to the anterior aspect of the EAC. Because the EAC was the closest surface to the abscess collection, we elected to attempt drainage through this route. Successful incision and drainage was performed via transcanal approach. She received intravenous antibiotics and steroids post-operatively and surgical packing was removed. She was discharged home on post-operative day 5 afebrile and tolerating a regular diet and continued to do well at most recent outpatient follow-up.