Clinical pharmacology strategies to accelerate the development of polatuzumab vedotin and summary of key findings.

The favorable benefit-risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody-drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.

Target-decoy false discovery rate estimation using Crema.

Assigning statistical confidence estimates to discoveries produced by a tandem mass spectrometry proteomics experiment is critical to enabling principled interpretation of the results and assessing the cost/benefit ratio of experimental follow-up. The most common technique for computing such estimates is to use target-decoy competition (TDC), in which observed spectra are searched against a database of real (target) peptides and a database of shuffled or reversed (decoy) peptides. TDC procedures for estimating the false discovery rate (FDR) at a given score threshold have been developed for application at the level of spectra, peptides, or proteins. Although these techniques are relatively straightforward to implement, it is common in the literature to skip over the implementation details or even to make mistakes in how the TDC procedures are applied in practice. Here we present Crema, an open-source Python tool that implements several TDC methods of spectrum-, peptide- and protein-level FDR estimation. Crema is compatible with a variety of existing database search tools and provides a straightforward way to obtain robust FDR estimates.

Computational and Systems Biology Advances to Enable Bioagent Agnostic Signatures.

Enumerated threat agent lists have long driven biodefense priorities. The global SARS-CoV-2 pandemic demonstrated the limitations of searching for known threat agents as compared to a more agnostic approach. Recent technological advances are enabling agent-agnostic biodefense, especially through the integration of multi-modal observations of host-pathogen interactions directed by a human immunological model. Although well-developed technical assays exist for many aspects of human-pathogen interaction, the analytic methods and pipelines to combine and holistically interpret the results of such assays are immature and require further investments to exploit new technologies. In this manuscript, we discuss potential immunologically based bioagent-agnostic approaches and the computational tool gaps the community should prioritize filling.

A Continuously Worn Dual Temperature Sensor System for Accurate Monitoring of Core Body Temperature from the Ear Canal.

The objective of this work was to develop a temperature sensor system that accurately measures core body temperature from an ear-worn device. Two digital temperature sensors were embedded in a hearing aid shell along the thermal gradient of the ear canal to form a linear heat balance relationship. This relationship was used to determine best fit parameters for estimating body temperature. The predicted body temperatures resulted in intersubject limits of agreement (LOA) of ±0.49 °C over a range of physiologic and ambient temperatures without calibration. The newly developed hearing aid-based temperature sensor system can estimate core body temperature at an accuracy level equal to or better than many devices currently on the market. An accurate, continuously worn, temperature monitoring and tracking device may help provide early detection of illnesses, which could prove especially beneficial during pandemics and in the elderly demographic of hearing aid wearers.

Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice.

Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1's osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).

The Inclusion of Chiropractic Care in the Healthy China Initiative 2030.

The Healthy China Initiative 2030 represents a major shift in China's healthcare policies for health promotion and disease prevention. Chiropractic care, with its focus on musculoskeletal health and nonpharmacological treatment, can contribute to the goals of this initiative. However, its potential contribution is hampered by the lack of official recognition and regulation in mainland China, which restricts its general awareness and integration into healthcare systems, and potentially leads to untreated musculoskeletal disorders. This research proposes the inclusion of chiropractic care in the Healthy China Initiative 2030 framework. It provides an overview of the goals of this initiative and the current state of chiropractic care in China. The alignment of chiropractic principles and practices with the aims of the Healthy China Initiative 2030 is also discussed. Policy recommendations for integrating chiropractic care into the healthcare system are proposed, which include the establishment of education standards, licensing protocols, and collaborative research initiatives. Potential challenges, including regulatory barriers, a lack of awareness, and research limitations are highlighted. We also present potential strategies to leverage opportunities for promoting chiropractic care, such as the rising demand for musculoskeletal care. This research provides the first focused discussion on the integration of chiropractic care into China's evolving preventive healthcare landscape under the Healthy China Initiative 2030.

East Meets West: Perspectives on the Development of Chiropractic Education and Profession Under Hong Kong's "One Country, Two Systems" Policy.

In Hong Kong, chiropractic care developed under the national policy of "one country, two systems," whereby Hong Kong retained its own economic and political systems while remaining part of mainland China. This environment allowed Western education standards and practices to be adopted while integrating local cultural beliefs. In this respect, chiropractic healthcare emerged as an early model of culturally synergistic East meets West care. However, despite Hong Kong's large population and interest in natural health options, the field faces several challenges, including competition with other professions, costs of education, and political uncertainty. Collaborating across professions, demonstrating value through outcomes, and adapting to cultural contexts may facilitate the integration of chiropractic care into Hong Kong's healthcare system. Moreover, positioning chiropractic care within Hong Kong's integrative East meets West healthcare movement may help sustain the practice regardless of political shifts. Through strategic partnerships and the maintenance of high standards balanced by cultural sensitivity, the chiropractic field in Hong Kong exemplifies the global spread of healthcare professions. Overall, chiropractic care in Hong Kong has had to navigate complex sociocultural and political circumstances and evolve into an integrated approach, reflecting the region's pluralistic society. The study first discussed the development of the chiropractic profession in Hong Kong under the "one country, two systems" policy. It then examined the opportunities and challenges faced by the profession and concluded by delving into the future prospects of chiropractic in the region.

Prevention-Focused Care: The Potential Role of Chiropractors in Hong Kong's Primary Healthcare Transformation.

Hong Kong's healthcare system is moving toward preventive and primary care to address the complicated demands of the aging population. Chiropractic professionals are in an advantageous position to support a prevention-focused strategy by identifying musculoskeletal problems early, reducing risks, and promoting healthy lifestyles. This article examines how the involvement of chiropractors in public health programs could improve population health in Hong Kong and boost primary care. The inclusion of chiropractors in district health centers and other initiatives would offer safer and more cost-effective choices for treating functional problems and chronic pain. Chiropractors should be involved in policymakers' attempts to create a sustainable healthcare system that meets Hong Kong's long-term healthcare requirements.

Recognizing Hong Kong Chiropractors' Sick Leave Authority: Valuing a Conservative Approach to Workers' Compensation.

Although registered under Hong Kong's legislative framework, chiropractors are not able to certify sick leave, restricting the effectiveness of their services for patients with musculoskeletal issues requiring time away from work. This paper explores the evolution of chiropractic regulation in Hong Kong, the growth of the profession, and the tardy recognition of chiropractors' power to issue sick leave certificates. The chiropractic profession and its patients have long lobbied for this authority, but the government has been slow to respond. This document presents a comprehensive analysis of the benefits and restrictions of allowing chiropractors prescriptive authority for sick leave and requests that this change in policy be considered. Developing responsible criteria for chiropractors to prescribe sick leave within their scope of practice could legitimize chiropractic's position in the population's health and interdisciplinary pain care while lowering the burden on injured workers.

Optimizing Primary Healthcare in Hong Kong: Strategies for the Successful Integration of Radiology Services.

The primary healthcare system in Hong Kong plays a crucial role in addressing the healthcare needs of its population. However, the integration of radiology services into primary care settings has not been fully realized, and there is significant potential for improvement. Incorporating radiology services into primary healthcare can enhance patient care, promote cost-effectiveness, and increase the overall efficiency of the healthcare system by enabling earlier diagnosis and intervention for various health conditions. To successfully integrate radiology services, key strategies include the establishment of public-private partnerships, the adoption of teleradiology and telemedicine services, the development of comprehensive regulatory and policy frameworks, and the exploration of innovative financial models and incentives. By embracing these strategies, Hong Kong can optimize its primary healthcare system and ensure more equitable, effective care for its population.

Unlocking Athletic Potential: The Integration of Chiropractic Care into the Sports Industry and Its Impact on the Performance and Health of Athletes and Economic Growth in China and Hong Kong.

This study explores the significant role chiropractic care can play in the sports industry, with a focus on countries like China and Hong Kong. As a vital component of sports medicine, chiropractic care can enhance athletic performance, health, and competitiveness by addressing biomechanical imbalances and optimizing neuromuscular function. The potential impact of chiropractic care on the sports industry includes attracting international events and investments, leading to increased economic opportunities, and the overall growth of the industry. Key strategies for promoting chiropractic care in the sports industry encompass developing a robust chiropractic care infrastructure, raising public awareness through targeted campaigns, and implementing supportive policies by governments and sports organizations. The integration of chiropractic care within sports medicine not only benefits individual athletes but also contributes to the broader development and success of the sports industry as a whole.

The evolution of mechanism of accommodation and a novel hypothesis.

Myopia and presbyopia are two major optometry problems facing the whole society. The mechanism of accommodation is strongly related to the treatments of myopia and presbyopia. However, the key mechanism of accommodation has puzzled us for over 400 years and is still not clear at present, leading to the stagnation of prevention and treatment of myopia and presbyopia. With the continued development of experimental technologies and equipment, the approaches to elucidate accommodation's intricacies have become more methodological and sophisticated. Fortunately, some significant progress has been made. This article is to review the evolution of the mechanism of accommodation. Helmholtz proposed a classical theory of "zonules relax during accommodation." In contrast, Schachar put forward a theory of "zonules taut during accommodation." Those hypotheses are relatively complete, but either do not fully explain everything about the accommodation mechanism or lack sufficient experimental and clinical evidence to support them. Then, some contentious issues are discussed in detail to find the truth. Finally, we proposed our hypothesis about accommodation based on the anatomy of the accommodative apparatus.

Cervicogenic Dizziness After Self-Manipulation of the Cervical Spine.

Patients with pre-existing cervical pathologies who experience dizziness and related neck pain are referred to as having cervicogenic dizziness. We describe a case of a 49-year-old female who presented with acute onset of vertigo and imbalance following self-manipulation of the cervical spine. Examination revealed a restricted cervical range of motion, muscle hypertonicity, and positive neurological signs. Radiographs demonstrated loss of normal cervical lordosis. The patient was diagnosed with cervicogenic dizziness and prescribed chiropractic treatments that included spinal manipulation, soft tissue release, and rehabilitative exercises. After four weeks of care, her symptoms had improved. At the six-month follow-up, the patient remained asymptomatic with a full cervical range of motion. This case highlights the risks associated with neck manipulation and the effectiveness of chiropractic treatment for cervicogenic dizziness. Patients should be counseled to seek evaluation and treatment from appropriate medical professionals for neck issues or dizziness/imbalance.

Bilateral Cellulitis Presented As Lower-Extremity Pain Reported in a Chiropractic Clinic: A Case Report.

Bilateral lower-extremity cellulitis is a rare but serious condition that can lead to long-term health complications if left untreated. Herein, we report a case of a 71-year-old obese male with a two-month history of lower-extremity pain and ankle swelling. Magnetic resonance imaging (MRI) revealed the presence of bilateral lower-extremity cellulitis, which was confirmed through blood culture by the patient's family doctor. The patient's initial presentation of musculoskeletal pain, limited mobility, and other features coupled with MRI findings served as indications for timely referral to the patient's family doctor for further evaluation and management. Chiropractors should be aware of the warning signs of infection and the importance of advanced imaging for diagnosing such cases. Early detection and prompt referral to a family doctor for care can help prevent long-term health complications associated with lower-extremity cellulitis.

Chiropractic Care in a Patient With Hereditary Spastic Paraplegia and Chronic Pain.

Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disorder, which is challenging to diagnose and is known to be associated with more than 73 genes. Neurodegenerative disorders are characterized by progressive spasticity and weakness of the lower limbs. Here, we report the case of a 13-year-old girl with a history of HSP who presented to a chiropractic clinic with chronic low back pain and rehabilitation for lower extremity weakness. She had been receiving non-steroidal anti-inflammatory drugs and baclofen for spasticity. Full-spine radiography revealed borderline acetabular dysplasia in the right hip. After nine months of chiropractic therapy, the patient reported reduced lower extremity spasticity and pain as well as improved strength and functionality. As non-invasive therapies have minimal side effects, chiropractic therapy can be used alongside or in combination with other treatments as an additional option for the long-term management of HSP.

A Severe Disc Herniation Mimics Spinal Tumor.

Lumbar disc herniation (LDH) is prevalent among adults aged 25-55 years who spend a considerable proportion of their time sitting or standing with heavy workloads. We report the case of a 33-year-old male waiter with severe LDH, causing compression of the nerve roots and spinal cord with neurological dysfunction, who presented to a chiropractic clinic. Magnetic resonance imaging (MRI) revealed a radiological differential diagnosis comprising LDH and an epidural mass lesion. To rule out serious pathology, a second MRI with contrast was ordered, which confirmed the diagnosis of severe LDH. Diagnosing large LDH may be challenging, and severe disc herniation often mimics spinal tumors. This study offers insights into the differential diagnosis of LDH and spinal tumors, as well as the design of a treatment strategy for severe LDH in the chiropractic clinic.

Delayed Skin Allergy to Glucosamine Chondroitin Supplement.

Glucosamine chondroitin is a popular dietary supplement used for joint health and osteoarthritis pain and is one of the dietary supplements commonly recommended by chiropractors. Herein, we present the case of a 36-year-old woman who developed a skin rash with delayed onset after taking glucosamine and chondroitin pills for lumbar degenerative joint disease. Within 3 hours of taking the supplement, she developed an itchy rash on her torso and legs. Over the next few hours, the rash spread over her entire body, and facial swelling developed. Given the timing of the symptoms after the administration of glucosamine chondroitin, an allergic reaction was suspected. The supplement was withdrawn and the allergic reactions were treated with antihistamines and steroids for several days. This case report demonstrates the need to recognize delayed allergic reactions as a potential side effect of widely used supplements, such as glucosamine chondroitin, which can produce hypersensitivity reactions in sensitive individuals.

A Central Slip Injury in a Professional Basketball Player.

Hand injuries are extremely prevalent in sports such as ball sports. Delayed diagnosis or improperly managed injuries have the potential to prolong the athlete's return to the competition and permanently damage their abilities. We report the case of a 35-year-old male professional basketball player who presented to a chiropractor with pain and swelling of the right fifth finger two days after a basketball game. The injury occurred when a player passed the basketball and the ball hit his fifth finger "head-on". Examination revealed enlargement of the middle joint of the right fifth finger and a boutonniere deformity. He was diagnosed with a central slip injury using magnetic resonance imaging (MRI). Since there are no standard treatment guidelines for central slip injuries, multi-model chiropractic therapy was applied to the injury and adjacent sites. The patient returned to the game by the end of the third week and fully recovered within six weeks. Chiropractors must understand how to best guide athletes' clinical management of these injuries, given the inherent need for immediate and complete recovery.

The Crux Toolkit for Analysis of Bottom-Up Tandem Mass Spectrometry Proteomics Data.

The Crux tandem mass spectrometry data analysis toolkit provides a collection of algorithms for analyzing bottom-up proteomics tandem mass spectrometry data. Many publications have described various individual components of Crux, but a comprehensive summary has not been published since 2014. The goal of this work is to summarize the functionality of Crux, focusing on developments since 2014. We begin with empirical results demonstrating our recently implemented speedups to the Tide search engine. Other new features include a new score function in Tide, two new confidence estimation procedures, as well as three new tools: Param-medic for estimating search parameters directly from mass spectrometry data, Kojak for searching cross-linked mass spectra, and DIAmeter for searching data independent acquisition data against a sequence database.