Mouse mandibular-derived osteoclast progenitors have differences in intrinsic properties compared with femoral-derived progenitors.

Craniofacial osteoclasts are essential for site-specific processes such as alveolar bone resorption, tooth eruption, and orthodontic tooth movement. Much of the current understanding of osteoclast development and function comes from studies using long bone-derived cells. Minimal investigation has been done to explore skeletal site differences. The overall goal of this study was to determine if mandibular- and femoral-derived osteoclasts represent distinct populations. To test this hypothesis, bone marrow cells were initially analyzed from the mandible and femur of 2-month-old mice. It was shown that mandibular-derived osteoclasts have enhanced size (mm2) compared with femoral-derived osteoclasts. Since bone marrow macrophages are a heterogenous population, we additionally selected for monocytes and demonstrated that mandibular-derived monocytes also form osteoclasts with increased size compared with femoral-derived monocytes. Osteoclast precursor populations from both skeletal sites were analyzed by flow cytometry. A newly described Ly6CHigh+ population as well as the Ly6Cint population was increased in the mandibular-derived cells. The difference in differentiation potential between monocyte cultures suggests that the increase in the Ly6CHigh+ population may explain the enhanced differentiation potential in mandibular-derived cells. Monocyte genes such as Pu.1, C/ebp-a, and Prdm1 are increased in expression in mandibular-derived monocytes compared with femoral-derived monocytes. As expected with enhanced differentiation, osteoclast genes including Nfatc1, Dc-stamp, Ctsk, and Rank are upregulated in mandibular-derived osteoclast precursors. Future studies will determine how changes in the environment of the mandible lead to changes in percentages of osteoclast progenitors and their differentiation potential.

Eyelid and Brow Rejuvenation: Technical Pearls and Outcomes of Upper Blepharoplasty with or without Ptosis Correction and Browlift.

BACKGROUND: Eyelid ptosis may present with upper lid dermatochalasis and brow ptosis. When indicated, ptosis correction (PC) is advocated during upper blepharoplasty (UB). Here, we aimed to report our outcomes following UB and PC. METHODS: A retrospective review of patients that underwent UB from November 2018 to March 2020 was performed. Patient demographics, clinical characteristics, and revisions were recorded. Cox regression was performed to assess predictors of revision. RESULTS: Overall, 278 patients with 533 UB were included. Mean age was 67.3 years. Mean follow-up was 8.3 months. In 169 (31.7%) cases, a browlift was performed. UB and PC were performed in 109 (20.5%) cases, of which 60 (55%) involved Müller's muscle conjunctival resection, and 49 (45%) were levator repairs. New dry eye symptoms lasting ≥3 months occurred in 4 (0.8%) cases, all of which resolved. Revision rate was 3.8% after UB (residual skin [n=11], hypertrophic scar [n=4], Herring's law-related ptosis [n=1]); versus 9.2% after UB and PC (overcorrection [n=4], residual skin [n=4], asymmetry [n=2]). Multivariable analysis demonstrated increased revision rates after UB and PC (p-value=0.008). There was no difference in revision rates between different techniques of PC. CONCLUSIONS: In our study of 278 patients presenting for dermatochalasis, up to 21% of cases required ptosis correction in addition to upper blepharoplasty. Ptosis correction is a safe procedure when combined with upper blepharoplasty, regardless of technique used. The revision rate in our series was 9.2% after the combined procedure, which is greater than the revision rate of upper blepharoplasty only, however, comparable to the literature.

Obstructive Sleep Apnea Associated With Increased Failure Rate of Ptosis Repair.

PURPOSE: This study investigates how Obstructive sleep apnea (OSA) affects the outcomes of ptosis repair. We hypothesized that patients with OSA have an increased rate of reoperation after ptosis repair. METHODS: This retrospective cohort study included patients age >18 from the Mayo Clinic who underwent ptosis repair by levator advancement or Müller muscle-conjunctiva resection between 2018 and 2021. Outcomes were measured at 1 to 3 months of follow-up with surgical failure defined as asymmetry or unsatisfactory eyelid height requiring revision surgery within 1 year. RESULTS: A total of 577 patients met the inclusion criteria. There was a statistically significant difference in surgical failure between patients with OSA and those without (20.5% vs. 13.1%, p = 0.02). Patients with OSA showed a statistically significant difference in risk of revision by a factor of 1.70 (95% CI: 1.06-2.07). Revisions were attributed to unsatisfactory eyelid height in 72.6% of patients and eyelid asymmetry in 21.1%. All patients who had revision surgery had satisfactory outcomes. On logistic regression analysis, when adjusting for age and sex, OSA was significantly associated with ptosis revision ( p = 0.007). CONCLUSIONS: OSA increases risk of surgical failure and need for revision surgery in patients undergoing blepharoptosis repair but is not a sole risk factor.

The circadian regulator PER1 promotes cell reprogramming by inhibiting inflammatory signaling from macrophages.

Circadian regulation of gene expression is prevalent and plays critical roles in cell differentiation. However, its roles in the reprogramming of differentiated cells remain largely unknown. Here, we found that one of the master circadian regulators PER1 promoted virus-mediated reprogramming of mouse embryonic fibroblasts (MEFs) to induced neurons (iNs) and induced pluripotent stem cells (iPSCs). Unexpectedly, PER1 achieved this by repressing inflammatory activation of contaminating macrophages in the MEF culture, rather than by directly modulating the reprogrammability of MEFs. More specifically, we found that transduced viruses activated inflammatory genes in macrophages, such as Tnf encoding TNFα, one of the central inflammatory regulators and an autocrine activator of macrophages. TNFα inhibited iN reprogramming, whereas a TNFα inhibitor promoted iN reprogramming, connecting the inflammatory responses to iN reprogramming. In addition, macrophages were induced to proliferate and mature by non-macrophage cells serving as feeders, which also supported up-regulation of TNFα in macrophages without virus transduction. Furthermore, the 2 inflammatory responses were repressed by the circadian regulator PER1 in macrophages, making reprogrammability dependent on time-of-day of virus transduction. Similar results were obtained with iPSC reprogramming, suggesting a wide occurrence of macrophage-mediated inhibition of cell reprogramming. This study uncovers mechanistic links between cell reprogramming, bystander inflammatory macrophages, and circadian rhythms, which are particularly relevant to in vivo reprogramming and organoid formation incorporating immune cells.

Advancing Global Health Equity: The Role of the Liberal Arts in Health Professional Education.

Much innovation has taken place in the development of medical schools and licensure exam processes across the African continent. Still, little attention has been paid to education that enables the multidisciplinary, critical thinking needed to understand and help shape the larger social systems in which health care is delivered. Although more than half of medical schools in Canada, the United Kingdom, and the United States offer at least one medical humanities course, this is less common in Africa. We report on the "liberal arts approach" to medical curricula undertaken by the University of Global Health Equity beginning in 2019. The first six-month semester of the curriculum, called Foundations in Social Medicine, includes courses in critical thinking and communication, African history and global political economy, medical anthropology and social medicine, psychology and health, gender and social justice, information technology and health, and community-based training. Additionally, an inquiry-based pedagogy with relatively small classes is featured within an overall institutional culture that emphasizes health equity. We identify key competencies for physicians interested in pursuing global health equity and how such competencies relate to liberal arts integration into the African medical school curriculum and pedagogical approach. We conclude with a call for a research agenda that can better evaluate the impact of such innovations on physicians' education and subsequent practices.

Phlpp1 Expression in Osteoblasts Plays a Modest Role in Bone Homeostasis.

Prior work demonstrated that Phlpp1 deficiency alters limb length and bone mass, but the cell types involved and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within bone-forming osteoblasts, we crossed Phlpp1 floxed mice with mice harboring type 1 collagen (Col1a12.3kb)-Cre. Mineralization of bone marrow stromal cell cultures derived from Phlpp1 cKOCol1a1 was unchanged, but levels of inflammatory genes (eg, Ifng, Il6, Ccl8) and receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratios were enhanced by either Phlpp1 ablation or chemical inhibition. Micro-computed tomography of the distal femur and L5 vertebral body of 12-week-old mice revealed no alteration in bone volume per total volume, but compromised femoral bone microarchitecture within Phlpp1 cKOCol1a1 conditional knockout females. Bone histomorphometry of the proximal tibia documented no changes in osteoblast or osteoclast number per bone surface but slight reductions in osteoclast surface per bone surface. Overall, our data show that deletion of Phlpp1 in type 1 collagen-expressing cells does not significantly alter attainment of peak bone mass of either males or females, but may enhance inflammatory gene expression and the ratio of RANKL/OPG. Future studies examining the role of Phlpp1 within models of advanced age, inflammation, or osteocytes, as well as functional redundancy with the related Phlpp2 isoform are warranted. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.

Leptospirosis and the Environment: A Review and Future Directions.

Leptospirosis is a zoonotic disease of global importance with significant morbidity and mortality. However, the disease is frequently overlooked and underdiagnosed, leading to uncertainty of the true scale and severity of the disease. A neglected tropical disease, leptospirosis disproportionately impacts disadvantaged socioeconomic communities most vulnerable to outbreaks of zoonotic disease, due to contact with infectious animals and contaminated soils and waters. With growing evidence that Leptospira survives, persists, and reproduces in the environment, this paper reviews the current understanding of the pathogen in the environment and highlights the unknowns that are most important for future study. Through a systematic Boolean review of the literature, our study finds that detailed field-based study of Leptospira prevalence, survival, and transmission in natural waters and soils is lacking from the current literature. This review identified a strong need for assessment of physical characteristics and biogeochemical processes that support long-term viability of Leptospira in the environment followed by epidemiological assessment of the transmission and movement of the same strains of Leptospira in the present wildlife and livestock as the first steps in improving our understanding of the environmental stage of the leptospirosis transmission cycle.

Surgical Anatomy of the Microscopic and Endoscopic Transorbital Approach to the Middle Fossa and Cavernous Sinus: Anatomo-Radiological Study with Clinical Applications.

BACKGROUND: The transorbital approaches (TOAs) have acquired growing notoriety, thanks to their ability to offer alternative corridors to the skull base. However, the limited access and the unfamiliarity with this surgical perspective make recognition of key landmarks difficult, especially for less experienced surgeons. The study wants to offer a detailed description of the anatomy to comprehend the potential and limitations of TOAs. METHODS: Measurements of the orbit region and the surrounding areas were performed on two hundred high-resolution CT scans and thirty-nine dry skulls. Five specimens were dissected to illustrate the TOA, and one was used to perform the extradural clinoidectomy. Three clinical cases highlighted the surgical applications. RESULTS: A step-by-step description of the key steps of the TOA was proposed and a comparison with the transcranial anterior clinoidectomy was discussed. The mean work distance was 6.1 ± 0.4 cm, and the lateral working angle increased 20 ± 5.4° after removing the lateral orbital rim. CONCLUSIONS: TOAs are indicated in selected cases when tumor involves the lateral portion of the cavernous sinus or the middle skull base, obtaining a direct decompression of the optic nerve and avoiding excessive manipulation of the neurovascular structures. Comprehension of surgical anatomy of the orbit and its surrounding structures is essential to safely perform these approaches.

Conditional Loss of MEF2C Expression in Osteoclasts Leads to a Sex-Specific Osteopenic Phenotype.

Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that the reduced expression of MEF2C contributes to osteopetrosis and the dysregulation of pathological bone remodeling. Our current study aims to determine how MEF2C contributes to osteoclast differentiation and to analyze the skeletal phenotype of Mef2c-cKO mice (Cfms-cre; Mef2cfl/fl). qRT-PCR and Western blot demonstrated that Mef2c expression is highest during the early days of osteoclast differentiation. Osteoclast genes, including c-Fos, c-Jun, Dc-stamp, Cathepsin K, and Nfatc1, had a significant reduction in expression, along with a reduction in osteoclast size. Despite reduced CTX activity, female Mef2c cKO mice were osteopenic, with decreased bone formation as determined via a P1NP ELISA, and a reduced number of osteoblasts. There was no difference between male WT and Mef2c-cKO mice. Our results suggest that Mef2c is critical for osteoclastogenesis, and that its dysregulation leads to a sex-specific osteopenic phenotype.

Monitoring Cigarette Smoking and Relapse in Young Adults With and Without Remote Biochemical Verification: Randomized Brief Cessation Study.

BACKGROUND: Technological advancements to study young adult smoking, relapse, and to deliver interventions remotely offer conceptual appeal, but the incorporation of technological enhancement must demonstrate benefit over traditional methods without adversely affecting outcomes. Further, integrating remote biochemical verification of smoking and abstinence may yield value in the confirmation of self-reported smoking, in addition to ecologically valid, real-time assessments. OBJECTIVE: The goal of this study was to evaluate the impact of remote biochemical verification on 24-hour self-reported smoking and biochemical verification agreement, retention, compliance with remote sessions, and abstinence during a brief, 5-week cessation attempt and relapse monitoring phase. METHODS: Participants (N=39; aged 18-25 years; mean age 21.6, SD 2.1 years; n=22, 56% male; n=29, 74% White) who smoked cigarettes daily engaged in a 5-week cessation and monitoring study (including a 48-hour quit attempt and provision of tobacco treatment in the form of nicotine replacement therapy, brief cessation counseling, and financial incentives for abstinence during the 2-day quit attempt only). Smoking (cigarettes per day) was self-reported through ecological momentary assessment (EMA) procedures, and participants were randomized to either (1) the inclusion of remote biochemical verification (EMA + remote carbon monoxide [rCO]) 2× per day or (2) in-person, weekly CO (wCO). Groups were compared on the following outcomes: (1) agreement in self-reported smoking and breath carbon monoxide (CO) at common study time points, (2) EMA session compliance, (3) retention in study procedures, and (4) abstinence from smoking during the 2-day quit attempt and at the end of the 5-week study. RESULTS: No significant differences were demonstrated between the rCO group and the wCO (weekly in-person study visit) group on agreement between 24-hour self-reported smoking and breath CO (moderate to poor), compliance with remote sessions, or retention, though these outcomes numerically favored the wCO group. Abstinence was numerically higher in the wCO group after the 2-day quit attempt and significantly different at the end of treatment (day 35), favoring the wCO group. CONCLUSIONS: Though study results should be interpreted with caution given the small sample size, findings suggest that the inclusion of rCO breath added to EMA compared to EMA with weekly, in-person CO collection in young adults did not yield benefit and may have even adversely affected outcomes. Our results suggest that technological advancements may improve data accuracy through objective measurement but may also introduce barriers and burdens and could result in higher rates of missing data. The inclusion of technology to inform smoking cessation research and intervention delivery among young adults should consider (1) the research question and necessity of biochemical verification and then (2) how to seamlessly incorporate monitoring into personalized and dynamic systems to avoid the added burden and detrimental effects to compliance and honesty in self-report.

Medical Therapy in Patients with Moderate to Severe, Steroid-Resistant, Thyroid Eye Disease.

Background: Corticosteroid therapy is often employed in thyroid eye disease (TED), but its efficacy is variable. Teprotumumab and tocilizumab have been considered as effective alternatives. This study aims to evaluate their clinical outcomes and safety in patients with steroid-resistant TED. Methods: A retrospective case-control study was conducted between 2018 and 2022 within a national multicenter health system. Thirty-seven patients with moderate to severe steroid-resistant TED treated with teprotumumab or tocilizumab (cases) were compared with steroid-naïve patients treated with similar therapy (controls). Due to lack of steroid-naïve patients treated with tocilizumab, a control subgroup for tocilizumab was not included in the analysis. Demographic and clinical characteristics were described. Proptosis, diplopia, clinical activity score (CAS), and disease severity (European Group on Graves' orbitopathy classification) were evaluated at weeks 0, 12, 24, and 52 after therapy initiation. Results: Thirty-one patients received teprotumumab (13 cases and 18 controls) and 6 received tocilizumab (cases). The mean age was 57 years (standard deviation ±14.3), median duration of TED was 11.5 months (interquartile range [IQR]: 7.2-17.7), and median excess proptosis was 4 mm (IQR: 2-8) above the upper limit of normal for sex and race. At week 24, in the teprotumumab cases, 81% had proptosis response (reduction of ≥2 mm), 45.5% resolution of diplopia, 85.7% disease inactivation (CAS <3), and 58.3% reverted to mild disease severity. There were comparable results in teprotumumab controls, with no significant differences between subgroups. In the tocilizumab cases, 50% had a proptosis response, 16.7% resolution of diplopia, 100% disease inactivation, and 75% returned to mild disease. In the teprotumumab cases, there was a trend toward worsening proptosis and diplopia between weeks 24 and 52. In the same time frame, the tocilizumab cases had a trend toward worsening diplopia, disease activity, and severity. In the teprotumumab subgroup, 46.2% experienced otic changes and 23.1% hyperglycemia. In the tocilizumab subgroup, there were no reported adverse events. Conclusions: Teprotumumab and tocilizumab improved inflammation in patients with moderate to severe TED who had failed previous steroid therapy. Additionally, the teprotumumab cases demonstrated similar improvement in proptosis and diplopia to the teprotumumab controls. Further evaluation, particularly regarding the long-term response and side effect profile, of these medications in steroid-resistant TED is needed.

Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

CONTEXT: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING: Multicenter. PARTICIPANTS: Patients with moderate-to-severe, active TED. INTERVENTION: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Predictors of Surgical Versus Medical Management of Eyes in the Setting of Orbital Fracture at an Academic Level I Trauma Center.

We present clinical and imaging predictors of ocular injuries that required medical management versus surgical intervention in cases of orbital fractures. From 2014 to 2020, a retrospective review of patients with orbital fractures who received ophthalmologic consultation and computed scan (CT) analysis at a level I trauma center was performed. Inclusion criteria were patients with confirmed orbital fracture on CT and ophthalmology consultation. Patient demographics, associated injuries, comorbidities, management, and outcomes were collected. Two hundred and one patients and 224 eyes (11.4% bilateral orbital fractures) were included. Overall, 21.9% of orbital fractures presented with a significant concomitant ocular injury. Associated facial fractures were present in 68.8% of eyes. Management included surgical treatment in 33.5% of eyes and ophthalmology-directed medical treatment in 17.4%. On multivariate analysis, clinical predictors of surgical intervention were retinal hemorrhage (OR=4.7 (1.0-21.0), P =0.0437), motor vehicle accident injury (OR=2.7 (1.4-5.1), P =0.0030) and diplopia (OR=2.8 (1.5-5.3), P =0.0011). Imaging predictors of surgical intervention were herniation of orbital contents (OR=2.1 (1.1-4.0), P =0.0281) and multiple wall fractures (OR=1.9 (1.01-3.6), P =0.0450). Predictors of medical management were corneal abrasion (OR=7.7 (1.9-31.4), P =0.0041), periorbital laceration (OR=5.7 (2.1-15.6), P =0.0006), and traumatic iritis (OR=4.7 (1.1-20.3), P =0.0444). We demonstrated a 22% incidence of concomitant ocular trauma in orbital fracture patients at our level I trauma center. Predictors of the surgical intervention included multiple wall fractures, herniation of orbital contents, retinal hemorrhage, diplopia, and motor vehicle accident injury. These findings emphasize the importance of a multidisciplinary team in managing ocular and facial trauma.

Incidence and Characteristics of Facial and Ophthalmic Injuries From Domestic Mammal Bites: Parts of the data in the manuscript were presented at the American Academy of Ophthalmology Annual Meeting, 2022.

PURPOSE: To determine population-based incidence and characteristics of facial and ophthalmic injuries from domestic mammal bites in Olmsted County, Minnesota. DESIGN: Retrospective, population-based cohort study. METHODS: The Rochester Epidemiology Project (REP) was used to identify all potential cases of facial injuries from domestic mammal bites in Olmsted County, Minnesota from January 1, 1999, to December 31, 2015. Subjects were categorized into 2 cohorts: the ophthalmic cohort, which included persons with ocular and periocular injuries with or without facial injuries, and the non-ophthalmic cohort, which included persons with facial injuries only. The incidence and characteristics of facial and ophthalmic injuries from domestic mammal bites were assessed. RESULTS: There were 245 patients with facial injuries, 47 ophthalmic and 198 non-ophthalmic. The overall age- and sex-adjusted incidence of facial injuries was 9.0 (CI = 7.9-10.1) per 100,000 persons per year, 1.7 (CI = 1.2-2.2) ophthalmic and 7.3 (CI = 6.3-8.3) non-ophthalmic. Rates of facial injuries were highest in patients younger than 5 years and lowest in patients 50 years or older, 49.1 (CI = 41.3-61.6) and 1.3 (CI = 0.7-2.5), respectively (P < .001). All facial injuries were caused by either dog (92%) or cat (8%) bites. Patients with ophthalmic injuries received more intravenous prophylactic antibiotics (18% vs 1%, P < .001), wound closure (83% vs 58%, P < .001), and hospital admission (6% vs 0%, P = .007) than patients with non-ophthalmic injuries. Facial injury complications were infrequent (14, 6%) and included soft tissue infection and prominent scar. CONCLUSIONS: Although domestic mammal bites to the face are quite common, ocular injury occurs in a minority of cases.

Casting a Wider NET: Pancreatic Exocrine Insufficiency Induced by Somatostatin Analogues among Patients with Neuroendocrine Tumours?

Somatostatin-analogues (SSAs) are a first-line treatment of unresectable neuroendocrine tumours (NETs). However, SSAs inhibit pancreatic secretions, which could lead to pancreatic exocrine insufficiency (PEI). PEI is known to be detrimental to patient quality of life and nutritional status. This study aimed to evaluate the effect of SSAs on pancreatic exocrine function in patients with NETs, using the 13C-mixed triglyceride breath test (13C-MTGT). Exocrine function was assessed using the 13C-MTGT at baseline and after a third SSA injection (two months). A quotient of 13CO2/12CO2 was measured by mass spectrometry, and the cumulative percent dose recovered at 6 h (cPDR) is reported. The secondary endpoints investigated were change in weight, HbA1C, and vitamin D levels. Ten patients completed the study. Exocrine function reduced in all patients (n = 10) following SSA therapy (median reduction from baseline: -23.4% (range: -42.1-0.5%, p = 0.005)). vitamin D levels decreased in all but one patient (median decrease from baseline: -26.5%, (-44.7-10%; p = 0.038)), and median HbA1C levels increased by 8.0% (0-59.3%; p = 0.008). Change in weight was not significant (median decrease from baseline: -0.21% (-4.5-3.5%, p = 1.000)). SSA therapy has a consistent impact on exocrine function from early in the treatment course, but the long-term clinical effects of this remain to be defined. Further studies are required to determine the clinical relevance of this observation and optimise the management of PEI in this cohort.

Alemtuzumab-Induced Thyroid Eye Disease: A Comprehensive Case Series and Review of the Literature.

PURPOSE: To present 5 cases of alemtuzumab-induced thyroid eye disease (AI-TED) and review the literature to highlight the natural history, severity, and outcomes as compared with conventional thyroid eye disease (TED). METHODS: A multi-institutional retrospective case series of patients with AI-TED was compiled. Chart review evaluated for clinical characteristics, imaging findings, and treatment for AI-TED. Additionally, a comprehensive review of the literature identified all previously published cases of AI-TED. RESULTS: Five new patients with AI-TED were included in this series. The average clinical activity score on presentation was 2.8 (range 1-4) and reached an average peak of 5.0 during the active phase of the disease (4-7). Patients were treated medically with selenium (40%) or monoclonal antibodies including teprotumumab or tocilizumab (40%). Surgical treatment with orbital decompression for compressive optic neuropathy was performed on 2 (40%) patients. Combined with 11 previously reported cases, these 16 patients with AI-TED had an average clinical activity score on presentation of 3.3. The average length of the AI-TED phase was 14.0 months, and all patients were treated with medical and/or surgical interventions for their disease. CONCLUSIONS: Clinical and imaging findings in AI-TED mirror that of conventional TED, however, AI-TED may present with greater severity. AI-TED may develop many months after Graves' disease; therefore, providers should be aware of this association and monitor patients for the development of severe TED.

Macrophages and Intervertebral Disc Degeneration.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

Macrophages and Bone Remodeling.

Bone remodeling in the adult skeleton facilitates the removal and replacement of damaged and old bone to maintain bone quality. Tight coordination of bone resorption and bone formation during remodeling crucially maintains skeletal mass. Increasing evidence suggests that many cell types beyond osteoclasts and osteoblasts support bone remodeling, including macrophages and other myeloid lineage cells. Herein, we discuss the origin and functions for macrophages in the bone microenvironment, tissue resident macrophages, osteomacs, as well as newly identified osteomorphs that result from osteoclast fission. We also touch on the role of macrophages during inflammatory bone resorption. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).