Massachusetts General Hospital

Background For children with HIV on antiretroviral therapy (ART), transitioning to dolutegravir-containing regimens is recommended. The aim of this study was to assess whether introducing viral load testing to inform new nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) for children with HIV and viraemia alongside dolutegravir-based ART is beneficial and of good economic value. Methods We used the Cost-Effectiveness of Preventing AIDS Complications-Pediatric model to project clinical and cost implications of three strategies among a simulated cohort of South African children aged 8 years with HIV receiving abacavir–lamivudine–efavirenz: (1) continue current ART (no dolutegravir; abacavir–lamivudine–efavirenz); (2) transition all children with HIV to dolutegravir, keeping current NRTIs (dolutegravir; abacavir–lamivudine–dolutegravir); or (3) transition to dolutegravir based on viral load testing (viral load plus dolutegravir), keeping current NRTIs if virologically suppressed (abacavir–lamivudine–dolutegravir, 70% of cohort) or switching abacavir to zidovudine (zidovudine) if viraemic (zidovudine–lamivudine–dolutegravir, 30%). We assumed 50% of children who had viraemia after abacavir–lamivudine exposure had NRTI resistance; with resistance, we assumed zidovudine–lamivudine–dolutegravir was more effective than abacavir–lamivudine–dolutegravir. We designated a strategy as preferred if it was most effective and least costly or had an incremental cost-effectiveness ratio less than half the South African 2020 gross domestic product per capita. Findings Under base-case assumptions, the viral load plus dolutegravir strategy would be the most effective (projected undiscounted life expectancy of 39·72 life-years) and least costly strategy (US$24 600 per person); the no dolutegravir strategy was the least effective (34·49 life-years) and most expensive ($26 480 per person). In sensitivity analyses, the 24-week virological suppression probability and subsequent monthly virological failure risks (ie, late failure) were most influential on cost-effectiveness. Only with a high late-failure risk for zidovudine–lamivudine–dolutegravir (ie, ≥0·3% per month in the base case or >0·5% per month if abacavir also confers low virological suppression probability in the presence of NRTI resistance [65%]) would the dolutegravir strategy become preferred above the viral load plus dolutegravir strategy. Interpretation For programmes transitioning to dolutegravir-based regimens, our model predicted that doing so would be more effective and less costly than continuing current ART regimens, regardless of NRTI choice. Whether viral load testing for children with HIV is necessary to inform NRTI choice depends substantially on the comparative outcomes of abacavir and zidovudine after switching to dolutegravir-containing ART. Funding The Eunice Kennedy Shriver Institute for Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the Massachusetts General Hospital Executive Committee on Research, the Massachusetts General Hospital, and the Medical Research Council.

Purpose Smoking is causally related to alcohol use disorder. Although polycyclic aromatic hydrocarbons (PAHs) are major neurotoxic pollutants in tobacco smoke, evidence is lacking on the role of PAHs in the relationship between smoking and alcohol use disorder. This study investigated the types of PAHs associated with smoking and whether exposure to those PAHs mediated the effect of smoking on alcohol use disorder. Materials and Methods A total of 968 male firefighters were analyzed. Smoking history and cumulative pack-years were obtained using self-reported questionnaires. Alcohol use disorder was defined using the Alcohol Use Disorder Identification Test. PAH exposure was assessed by urinary metabolites. Regression analyses were performed between exposure (smoking), outcome (alcohol use disorder), and mediator (PAH metabolites) variables. A mediation analysis was performed to test the indirect effect of PAH metabolites on the association between smoking and alcohol use disorder. All analyses were repeated for 770 participants who were followed up after 2 years, while alcohol use disorder was redefined from follow-up data ensuring the temporal sequence of the variables. Results Both 2-naphthol [β=0.78, 95% confidence interval (CI): 0.59–0.98] and 2-hydroxyfluorene (β=0.69, 95% CI: 0.56–0.82) were associated with smoking history. Furthermore, 2-naphthol and 2-hydroxyfluorene mediated the associations of smoking history (proportion mediated: 14.2%, 23.6% respectively) or cumulative pack-years (proportion mediated: 14.4%, 25.4% respectively) with alcohol use disorder. The results were consistent in longitudinal settings. Conclusion Exposure to PAHs mediated the association between tobacco smoking and alcohol use disorder. PAH exposure from tobacco may increase the risk of addictive disorders.

There are no words to describe adequately the agony and profound grief when a physician suffers the loss of their child, spouse, sibling, parent, or relative. Although physicians are trained to cope with death in their professional lives, they need to learn to deal with loss in their personal lives, similar to all individuals. In this chapter, the authors describe how they were able to manage the complex emotions from loss and, from that process, become better physicians. This is a subcollection from the book, Becoming a Better Physician, which contains stories from doctors and doctors-to-be about the obstacles they faced, how they responded, and how the experience affected their lives, work, or perspectives to make them better physicians.

Physicians are also patients and may encounter difficulty being on the other side of the doctor–patient relationship. This relationship is especially important for doctors who have chronic or serious illnesses. Assuming the role of patient rather than provider requires a significant change in mindset for a physician. However, the lessons learned by a physician from their own illness can make them a more compassionate, communicative, and humble provider of care. This is a subcollection from the book, Becoming a Better Physician, which contains stories from doctors and doctors-to-be about obstacles they faced, how they responded, and how the experience affected their lives, work, or perspectives to make them better physicians.

Caring and compassion are fundamental features of a doctor’s work. In giving care to others, doctors give a part of themselves; at the same time, they gain and develop other parts of their identity. These personal essays, written by doctors and trainees, are about different challenges they have experienced in caring about and caring for patients, family members, and themselves. This is a subcollection from the book, Becoming a Better Physician, which contains stories from doctors and doctors-to-be about obstacles they faced, how they responded, and how the experience affected their lives, work, or perspectives to make them better physicians.

The identity of a doctor is informed by the identity of the person. Life encounters, experiences, and struggles contribute to the personal growth and wisdom of doctors, shaping their perspectives, attitudes, and understanding of themselves. These personal essays, written by doctors and trainees, are about different challenges they have faced in their life journey, including bias and racism, immigration, cultural identity, emotional stressors, fatigue and burnout, work–life balance, and more. This is a subcollection from the book, Becoming a Better Physician, which contains stories from doctors and doctors-to-be about obstacles they faced, how they responded, and how the experience affected their lives, work, or perspectives to make them better physicians.

Training to become a physician is a long, arduous, and anxiety-provoking process. There will be times of emotional upheaval, profound apprehension, and questions of professionalism. However, there will also be opportunities to gain deep knowledge and to develop long-standing friendships and relationships. This chapter highlights how physicians were able to cope with these challenges as they progressed through medical school and residency. This is a subcollection from the book, Becoming a Better Physician, which contains stories from doctors and doctors-to-be about the obstacles they faced, how they responded, and how the experience affected their lives, work, or perspectives to make them better physicians.

Doctoring is as much a career as a calling. From residency to retirement, the development of this career is an active process, and the constant effort to grow professionally can be arduous. These personal essays, written by doctors, are about different career challenges they have encountered in domains such as advocacy and activism, communication, work-life balance, gender inequity, cultural competence, moral injury, job loss, and more. This is a subcollection from the book Becoming a Better Physician, which contains stories from doctors and doctors-to-be about obstacles they faced, how they responded, and how the experience affected their lives, work, or perspectives to make them better physicians.

Background A national database is used to evaluate pediatric burn survivor outcomes, but the generalizability to the United States pediatric burn injury population is unclear, as only 60% of enrollees are U.S. residents. An increased understanding of population similarities and differences between residents of the United States and residents of Mexico treated in the United States within this database will help determine its ability to extrapolate. Objective Assess the generalizability of a national burn database to the U.S. pediatric burn injury population. Design This retrospective cohort study analyzed pediatric enrollees in a burn database. Data were stratified into children who were residents of the United States or Mexico at time of injury and grouped by age into <5 years, 5–10 years, and >10 years. Setting Not applicable. Participants A total of 2043 children enrolled in the database from 1998 to 2020. Interventions Not applicable. Main Outcomes Measured Determination of similarities and differences between gender, injury etiology, total body surface area injured, length of stay, and place of injury between the two groups. Results Both groups showed an increased incidence of burn injury among males as they aged. In U.S. residents, the most frequent etiology in patients <5 years was scald (292 [53.6%]), followed by fire/flame (157 [28.8%]). In residents of Mexico, fire/flame burns were more frequent in all ages and electric burns were more common among children >5 years. In both groups, outdoor injuries became more common as children aged. Children from Mexico had larger burns and longer lengths of hospital stay than children from the United States across all ages. Conclusion Differences between U.S. and Mexico groups were likely attributable to children with more severe burns being transferred to the United States for care, whereas those with low‐severity burns were treated locally. This suggests that children from Mexico in the database were not representative of the pediatric burn injury population of the United States or Mexico more broadly and caution should be used before generalizations are made using this database.

Background Hepatic steatosis (HS) and 10‐year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 7.5% are associated with increased risk for cardiovascular events. Aim To assess underlying coronary artery disease (CAD) and major adverse cardiovascular event (MACE) among those with and without HS at different ASCVD risk. Methods We evaluated stable chest pain patients receiving coronary computed tomography (CT) in the PROMISE trial. HS and CAD endpoints were defined on coronary CT. MACE was defined as unstable angina, non‐fatal myocardial infarction, and all‐cause death. Multivariable Cox regression, adjusting for CAD characteristics, assessed the association of HS with MACE for ASCVD < 7.5%. Results One thousand two hundred and four of 3702 (32.5%) patients were at ASCVD < 7.5% and 20.3% (244/1204) of them had HS. Individuals with HS were younger (54.3 ± 5.2 vs. 55.8 ± 5.2; p < 0.001), more often males (40.2% [98/244] vs. 27.1% [260/960]; p < 0.001), had more risk factors/person (2.06 ± 0.89 vs. 1.93 ± 0.91; p = 0.047). CAD characteristics were similar between HS vs. non‐HS patients at ASCVD < 7.5% and ASCVD ≥ 7.5% (all p > 0.05). Patients with HS had greater MACE rate compared to non‐HS patients (ASCVD < 7.5%: 3.75%[9/244] vs. 1.5% [14/960]; p = 0.027 and ASCVD ≥ 7.5%: 4.7% [33/696] vs. 3.1% [56/1802]; p = 0.043). In patients without HS, MACE rate was higher in the ASCVD ≥ 7.5% vs. < 7.5% (3.1% [56/1802] vs. 1.5% [14/960]; p = 0.011). In patients with HS, MACE rates were not significantly different between ASCVD ≥ 7.5% vs. < 7.5% (4.7% [33/696] vs. 3.7% [9/244]; p = 0.484). In ASCVD < 7.5%, HS predicted MACE (aHR:2.34, 95%CI:1.01–5.43; p = 0.048), independent of CAD characteristics. Conclusions Individuals with HS at ASCVD < 7.5% risk had similar CAD characteristics as patients without HS at < 7.5% ASCVD risk, yet experienced comparable MACE rates as those at ASCVD ≥ 7.5%.

Traumatic brain injury (TBI) is considered to initiate cerebrovascular pathology, involving in the development of multiple forms of neurodegeneration. However, it is unknown the relationships between imaging marker of cerebrovascular injury (white matter hyperintensity, WMH), its load on white matter tract and disrupted brain dynamics with cognitive function in mild TBI (mTBI). MRI data and neuropsychological assessments were collected from 85 mTBI patients and 52 healthy controls. Between‐group difference was conducted for the tract‐specific WMH volumes, white matter integrity, and dynamic brain connectivity (i.e., fractional occupancies [%], dwell times [seconds], and state transitions). Regression analysis was used to examine associations between white matter damage, brain dynamics, and cognitive function. Increased WMH volumes induced by mTBI within the thalamic radiation and corpus callosum were highest among all tract fibers, and related with altered fractional anisotropy (FA) within the same tracts. Clustering identified two brain states, segregated state characterized by the sparse inter‐independent component connections, and default mode network (DMN)‐centered integrated state with strongly internetwork connections between DMN and other networks. In mTBI, higher WMH loads contributed to the longer dwell time and larger fractional occupancies in DMN‐centered integrated state. Every 1 mL increase in WMH volume within the left thalamic radiation was associated with a 47% increase fractional occupancies, and contributed to 65.6 s delay in completion of cognitive processing speed test. Our study provided the first evidence for the structural determinants (i.e., small vessel lesions) that mediate the spatiotemporal brain dynamics to cognitive impairments in mTBI.

Biophotons is the very weak light generated by cells. This light has been shown to change with different states of cell activity and/or cell health. Although their precise significance is still not clear, biophotons are thought to function as a means of cell-to-cell communication and cell repair. In this narrative review, we consider first, the current technology available that detects biophotons. These include (1) photomultipliers: these devices have advantages of giving real-time outputs, cover a relatively large detection area and have a low dark-noise per unit detection ability; their quantum efficiency is not great however and they do not have the ability to capture images; (2) image detectors: can capture images with an ultra-sensitive camera, together with count photons from living tissue; their process of acquiring an image can take a long time however, and their photon counts are less accurate than those obtained with photomultipliers and (3) histological methods: that relies on the reduction of silver (Ag) ⁺ to Ag that is thought to mark sites of photon activation and can be identified with a light microscope; there are however, some issues on how this reduction process affects the tissue and whether it can influence biophoton count. Next, we consider prospects for future methods that may determine both the functional significance of biophotons, together with how their detection can be used clinically. The development of better technology in the field of biophoton research can reveal a better understanding of how the brain functions under both normal and pathological conditions.

Understanding neuromodulatory effects of serotonin 2A receptor (5-HT 2A R) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT 2A R affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg). Receptor occupancy was assessed with [ ¹¹ C]MDL-100907 PET, and cerebral blood volume (CBV) changes were measured with phMRI. Mixed partial agonists psilocybin and lisuride evoked biphasic CBV responses, whereas the selective 25CN-NBOH produced monophasic CBV increases. Cortical occupancy for psilocybin plateaued at 60 µg/kg (32%), whereas a lower dose of lisuride (5 µg/kg) resulted in similar occupancy (31%). Administration of 25CN-NBOH resulted in lower occupancy (7%) but larger changes in CBV compared to psilocybin and lisuride. The associations between CBV and 5-HT 2A R occupancy appear linear for lisuride and 25CN-NBOH, but not for psilocybin. We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies.

Percutaneous balloon ganglyolysis (PBG) for trigeminal neuralgia (TN) is an inexpensive and minimally invasive treatment modality that is effective and safe. While there are reports of its efficacy, there is still a lack of evidence of which patients are at a higher risk of treatment failures and needing retreatment. We performed a retrospective study at a major academic institution from 2012 to 2023, including TN patients who underwent PBG procedures to evaluate predictors of retreatment. Patients without imaging available from the PBG were excluded. Fifty-two patients who underwent 83 procedures in total were included in the analysis. All patients had typical TN and were primarily female (59.6%), with a median age of 61.5 years. Immediately after PBG, 42.3% had pain resolution, and 57.7% had improved but persistent pain. 30.8% underwent retreatment with PBG in a median of 32 months. From multiple factors assessed, TN disease duration ≤ 6 months and trigeminal nerve enhancement on pre-operative MRI were identified as significant retreatment predictors on univariate analysis. However, after performing logistic regression, only TN disease duration ≤ 6 months remained significant OR 3.99 (95% CI 1.59–10.0; p = 0.003). This was further confirmed in a Kaplan-Meier survival analysis, which showed that patients with TN duration ≤ 6 months require retreatment earlier (22 vs. 41 months; p = 0.01). Retreatment after PBG occurs roughly in a third of patients, and TN disease duration of ≤ 6 months is an important predictor in this study. Further studies should be performed to confirm these findings, which may impact treatment considerations in the future. Supplementary Information The online version contains supplementary material available at 10.1007/s10143-024-03099-0.

Cervical cancer is a significant global health issue, ranking as the second most prevalent cancer among women of reproductive age. While prevention strategies like HPV vaccination and screening have made it highly preventable, these benefits are mostly seen in high-HDI nations. In contrast, LMICs lag behind, with Afghanistan facing a growing crisis due to war, poverty, and lack of awareness. The recent influx of Afghan evacuees to the U.S. poses a risk of introducing undiagnosed cases. Addressing this requires collaborative efforts to raise awareness, promote screening, and vaccination among Afghan women, leveraging culturally sensitive approaches and community partnerships to improve health outcomes.

In recent years, the ageing population has increasingly grown. This process carries a range of pathophysiological changes involving alterations in the skeletal muscle, vascular endothelium and brain function, becoming an important risk factor for developing cognitive disorders and cardiovascular diseases. With ageing, there is a decrease in muscle mass and muscle strength, and a relationship between muscle strength decrease and cognitive decline has been shown. Lower handgrip strength has been linked to memory impairment, lower global cognitive function, decreased attention and reduced visuospatial abilities in the elderly, but understanding of the underlying mechanisms that explain the link between altered skeletal muscle function and structure, endothelial dysfunction, and the role of endothelial dysfunction in the onset of cognitive disorders has been scarcely explored. This review aims to detail the cellular and molecular mechanisms by which the progressive changes associated with ageing can alter healthy skeletal muscle and endothelial function, creating an environment of oxidative stress, inflammation and mitochondrial dysfunction. These changes can lead to reduced muscle strength, and the secretion of detrimental endothelial factors, resulting in endothelial dysfunction, blood–brain barrier disruption, and damage to neurons and microglia, ultimately accelerating the onset of cognitive disorders in the elderly. In addition, we aimed to describe the mechanisms that potentially explain how preserving muscular function with resistance training could prevent brain function deterioration, including the production of different factors that allow an improved endothelial function, haemodynamic parameters and brain plasticity, ultimately delaying the onset of cognitive impairment and chronic diseases. image

Zusammenfassung Leitlinien sind etablierte Instrumente der evidenzbasierten Medizin. Bei der Anwendung im Öffentlichen Gesundheitsdienst stellen komplexe Public Health Interventionen jedoch eine Herausforderung dar. Der Beitrag skizziert diese beispielhaft und geht dabei auf unsichere und kontextabhängige Evidenz, die Vielzahl von Entscheidungskriterien und Akteure sowie Legitimitätsaspekte ein. Um diesen Herausforderungen zu begegnen, bedarf es u.a. transparente, partizipative und methodisch diverse Prozesse.

The majority of patients with brain tumors experience cognitive dysfunction, frequently at presentation, and often worsening over time. The potential cognitive effects of systemic cancer therapy and the cancer process itself are also recognized in non-CNS tumors. Although there are strategies to minimize the cognitive burden for patients, including for those with intracranial disease undergoing radiotherapy, there are few effective treatments for cognitive impairments once they develop. Therefore, when making clinical decisions in cancer care, it is imperative to consider cognitive risks and benefits associated with specific interventions. To better aid in this decision-making process, this chapter reviews cancer-related cognitive effects, impact of different systemic therapeutic modalities with CNS involvement and intracranial radiation, mitigating strategies, and the assessment of cognitive function.

Conventional contrast-enhanced MRI is very limited in its ability to differentiate tumor from post-treatment radiation effect (PTRE) in brain tumor patients following radiation therapy. T2*-weighted dynamic susceptibility contrast (DSC) perfusion MRI is a well-established method of advanced functional imaging that can provide valuable additional information in the form of relative cerebral blood volume (rCBV) to differentiate these entities. It is common to think of new or enlarging contrast-enhancing lesions in the post radiotherapy setting as either all PTRE or all tumor, when they are often actually composed of an admixture of them. A more recent application of DSC-MRI called fractional tumor burden (FTB) is able to provide quantitative information of the amount of PTRE vs. tumor in any such lesion. While there is some evidence that rCBV may predict outcome in brain tumor patients, larger, well-designed clinical trials are needed to validate rCBV as a biomarker to predict survival. In addition, more standardization of technique as well as knowledge of the precision of DSC-MRI is needed for more widespread adoption of this useful imaging method beyond academic centers.