Citations

Bacteriophage (phage) therapy has emerged as a promising solution to combat the growing crisis of multidrug-resistant (MDR) infections. There are several international centers actively engaged in implementation of phage therapy, and recent case series have reported encouraging success rates in patients receiving personalized, compassionate phage therapy for difficult-to-treat infections. Nonetheless, substantial hurdles remain in the way of more widespread adoption and more consistent success. This Review offers a comprehensive overview of current phage therapy technologies and therapeutic approaches. We first delineate the common steps in phage therapy development, from phage bank establishment to clinical administration, and examine the spectrum of therapeutic approaches, from personalized to fixed phage cocktails. Using the framework of a conventional drug development pipeline, we then identify critical knowledge gaps in areas such as cocktail design, formulation, pharmacology, and clinical trial design. We conclude that, while phage therapy holds promise, a structured drug development pipeline and sustained government support are crucial for widespread adoption of phage therapy for MDR infections.

Abstract The cortex generates diverse neural dynamics, ranging from broadband fluctuations to narrowband oscillations at specific frequencies. Here, we investigated whether broadband and oscillatory dynamics play different roles in the encoding and transmission of visual information. We used information-theoretical measures to dissociate neural signals sharing common information (i.e., redundancy) from signals encoding complementary information (i.e., synergy). We analyzed electrocorticography (ECoG) and local field potentials (LFP) in the visual cortex of human and non-human primates (macaque) to investigate the extent to which broadband signals (BB) and narrowband gamma (NBG) oscillations conveyed synergistic or redundant information about images. In both species, the information conveyed by BB signals was highly synergistic within and between visual areas. By contrast, the information carried by NBG was primarily redundant within and between the same visual areas. Finally, the information conveyed by BB signals emerged early after stimulus onset, while NBG sustained information at later time points. These results suggest a potential dual role of BB and NBG cortical dynamics in visual processing, with broadband dynamics supporting nonlinear pattern recognition and oscillations facilitating information maintenance across the cortex.

Abstract INTRODUCTION Cognition is reduced at low and high glucose, reflecting cognitive vulnerability to glucose (CVG) fluctuations. The impact of glucose fluctuations on the aging brain remains unclear. We examined whether CVG is associated with plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration. METHODS Participants included N = 114 adults with type 1 diabetes assessed for processing speed and sustained attention using ecological momentary assessment (EMA) combined with continuous glucose monitoring (CGM). We characterized associations between CVG and amyloid beta (Aβ) 42/40, phosphorylated tau (p‐tau) 181 and 217, neurofilament light chain, and glial fibrillary acidic protein. RESULTS CVG was associated with all plasma biomarkers, except Aβ 42/40. CVG for sustained attention exhibited strong associations with p‐tau biomarkers that persisted across covariate specifications. DISCUSSION CVG may be a useful digital phenotype of AD. It remains unclear whether CVG contributes to versus arises from neurodegeneration. We consider possible mechanisms linking cognitive vulnerability and long‐term glucose variability to the development of neuropathology. Highlights Cognitive vulnerability to glucose (CVG) may be a useful digital phenotype of neurodegeneration. We used cognitive ecological momentary assessment and continuous glucose monitoring to investigate CVG's associations with plasma biomarkers. Associations of CVG for sustained attention and phosphorylated tau 181 remained significant across covariates. We discuss possible mechanisms relating glucose variability, cognition, and neurodegeneration.

Abstract Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.

OBJECTIVE The global need for neurosurgical care is significant and often unmet. Building partnerships between high-income countries (HICs) and lower-middle-income countries (LMICs) can help bridge the gap. Six features of sustainable global surgical partnerships have been identified; however, their application in neurosurgery has not been studied. The authors analyzed how the 6 pillars of sustainability are applied to neurosurgical partnerships established by the Neurosurgery Outreach Foundation (NOF) with hospitals in LMICs in Asia. METHODS NOF is an all-volunteer, nonprofit US foundation with the mission to advance neurosurgical care in underserved communities through education, service, and support. The authors examined the NOF programs and identified the characteristics associated with the 6 pillars of sustainability, which are community engagement, multidisciplinary collaboration, education and training, outcome measurement, multisource funding, and bilateral authorship. The authors discuss how these pillars contribute to the establishment of sustainable partnerships. RESULTS From 2010 to 2024, NOF has established partnerships at 4 sites: Cebu, Manila, and Davao, the Philippines; and Ulaanbaatar, Mongolia. Partnerships were established with tertiary or quaternary government hospitals to develop neurosurgical programs tailored to the needs of each site and remained sustained and active. Educational surgical missions were in-person outreach activities conducted annually or biennially and were supplemented with online or remote collaboration. The 5 pillars of sustainable partnerships present at all sites include community engagement, multidisciplinary collaboration, education and training, outcome measurement, and multisource funding. The sixth pillar, bilateral authorship, was present at University of the Philippines–Philippine General Hospital in Manila. CONCLUSIONS Using the 6 pillars of sustainable global partnerships, neurosurgical partnerships can be developed and maintained by all-volunteer nonprofit organizations such as NOF. Incorporating these pillars during the planning and executing of global neurosurgical partnerships are essential for long-term success.

OBJECTIVE The aim of this study was to examine female authorship in research from collaborations between high-income countries (HICs) and lower-middle-income and low-income countries (LMICs/LICs) across two time periods: 2018–2020 and 2021–2023. METHODS A bibliometric analysis of neurosurgical research articles from the Scopus database, published between 2018 and 2023, was performed to investigate collaboration trends between HICs and LMICs/LICs. Only neurosurgical publications were included, and female authors were identified based on names traditionally associated with female gender identity, verified through online searches and tools such as Genderize.io. Articles with more than 25 authors, commentaries, letters, and news items were excluded to ensure a focus on original research. The selected articles spanned various neurosurgical specialties and were restricted to English-language journals with an impact factor greater than 1. The country affiliations of first, corresponding, and last authors were categorized using the 2018 World Bank classification to understand collaboration patterns across income levels. RESULTS The analysis revealed a steady increase in neurosurgical publications from 2018 to 2023, with a notable rise in the second triennium (2021–2023). Authors from HICs consistently held the majority of first, corresponding, and last authorship positions. Concerning first authorship, authors with affiliations from HICs increased from 66% in the first triennium to 75% in the second. Similarly, corresponding authors from HICs increased from 75% to 82% over the same period. Male authors dominated all key authorship roles, with 127 male-led first authorships compared with 46 female-led first authorships in the second triennium. This male predominance persisted in corresponding and last author roles as well. CONCLUSIONS Global neurosurgical research is growing but significant gender disparities persist, especially in LMICs/LICs, with female researchers underrepresented in key authorship roles, requiring targeted efforts to address systemic barriers and promote gender equity in academic leadership.

OBJECTIVE Unmet global neurosurgical needs pose a significant challenge, as do unequal opportunities for neurosurgical education and training across the globe. Mission:BRAIN is a nonprofit organization working to provide neurosurgical expertise and resources to both patients and healthcare providers in underserved areas. It operates globally, with local chapters involving primarily medical students. Its presence in Europe has expanded in the last few years with initiatives that contribute to shaping an international approach to global neurosurgery challenges. The authors aim to investigate the impact of student-led organizations, such as Mission:BRAIN, on global neurosurgery, with a focus on low-income countries and low- to middle-income countries, while also assessing the changes observed within the European group during its initial 2 years. METHODS Quantitative and qualitative analyses were employed to investigate changes in the number of chapters, members, and events. The perceived impact was evaluated using a Likert scale survey administered to European members. RESULTS Between 2022 and 2023, the number of European chapters increased by 150% (n = 10) and memberships doubled. Of the 102 survey respondents, 56.9% were female and 42.2% were male. Similarly, the number of events grew by 240%, with a significant increase in educational events (325%, p = 0.007). Participation in events increased by 10.13%, reflecting growing interest and engagement. For most members (72.6%), the activities in the European region have increased global awareness of the importance of neurosurgical care in underserved areas; for 45.1% of them, outreach events have effectively communicated the importance of neurosurgical care to nonmedical audiences. For 67.6% of the members, European chapters have contributed to fostering collaboration and knowledge sharing among medical students and healthcare providers. Furthermore, 59% agreed that Mission:BRAIN initiatives have contributed to addressing disparities in neurosurgical care and education. CONCLUSIONS Mission:BRAIN’s growth in Europe showcases the pivotal role of medical students. The impact of the organization’s activities demonstrates the students’ potential to contribute to the overarching effort of bridging worldwide gaps in healthcare and education and calls for their active participation and recognition.

Abstract The growing prevalence of obesity, a risk factor for disorders such as Alzheimer’s Disease (AD), raises concerns about the effects on cognitive health. AD currently impacts 6.9 million Americans aged 65 and older and is characterized by the presence of amyloid beta (Aβ) plaques, neurofibrillary tau tangles, and neuroinflammation, all of which contribute to cognitive impairment. Insulin resistance, common in both obesity and AD, disrupts brain glucose metabolism and accelerates neurodegeneration. Understanding the factors that link these conditions could lead to new strategies for combating disease. Notably, the B-like vitamin choline is necessary for fat metabolism and has been shown to help reduce obesity incidence. However, ∼90% of Americans are deficient, and decreases in this nutrient have been associated with cognitive decline. Here, we examined circulating choline levels, inflammation, and metabolic dysfunction in human participants with obesity (BMI > 30) compared to normal BMIs (18.5–24.9), as well as in 3xTg-AD mice, an AD model, fed a choline-deficient diet throughout adulthood. Our results revealed that obese participants exhibited significantly lower circulating choline levels compared to those with a healthy BMI. Lower choline levels correlated with higher %Body fat and increased markers of insulin resistance. Elevated inflammatory cytokines in obese participants were also seen in 3xTg-AD mice on a choline-deficient diet, which exhibited significant weight gain and metabolic dysfunction. AD-like pathology was also exacerbated in choline deficient 3xTg-AD mice. These findings underscore the relationship between low choline levels, obesity, insulin resistance, and cognitive decline risk. Adequate choline intake may mitigate the risk of obesity, potentially preventing cognitive decline and associated diseases. Highlights Obesity is linked to increased insulin resistance (IR) and systemic inflammation, both of which are recognized risk factors for Alzheimer’s disease (AD). Women exhibit lower circulating choline levels compared to men, and obese individuals display significantly lower choline levels than those with a healthy BMI. Lower circulating choline levels are linked to a higher body fat percentage, increased markers of IR and liver dysfunction, as well as heightened systemic inflammation. 3xTg-AD mice on a choline-deficient diet experience considerable weight gain, metabolic dysfunction, heightened systemic inflammation, and AD-like pathology, resembling the conditions observed in obese human participants.

Background Patients undergoing medical procedures benefit from preprocedural education. Objective To evaluate a multisensory virtual reality preoperative educational program for patients undergoing elective cardiovascular surgical procedures with postoperative recovery in the intensive care unit (ICU) and assess its impact on patients’ outcomes and experience. Methods Patients scheduled for elective cardiovascular surgical procedures with expected recovery in the ICU were enrolled. A multidisciplinary team designed the virtual reality simulation. Educational objectives focused on patient safety, family presence, ICU machinery and activities, reorientation, and communication with the care team. Historical control patients (n = 94) underwent medical record review and were contacted to complete surveys. Virtual reality simulation patients (n = 44) underwent medical record review, viewed the simulation at a preoperative appointment, and completed surveys. The study included patients admitted from June 4, 2019, to May 12, 2022. Results Durations of postoperative sedation and mechanical ventilation were lower in patients receiving virtual reality simulation. Most patients in the virtual reality simulation group (92%) said the simulation alleviated their anxiety and helped them understand what to expect in the ICU. The simulation improved their feeling of safety and decreased their fear of the unknown. Delirium incidence was not different in the 2 groups. Conclusions Preprocedural education via virtual reality simulation can improve the experience and outcomes of patients undergoing elective cardiothoracic surgery with recovery in the ICU.