Reappraising the Use of Systemic Immunomodulators for Psoriasis and Eczema in the Military.

INTRODUCTION: Psoriasis and atopic dermatitis are chronic, immune-mediated skin disorders that are disqualifying for entrance into the military. Both conditions can cause difficulty wearing body armor and other protective equipment when poorly controlled, limiting a service member's ability to train and deploy worldwide. In addition, these conditions may be exacerbated by military service because of increased exposure to austere environments, extreme temperatures, stress, skin injury, bug bites, and vaccinations Service members have limited treatment options because of restrictions on systemic medications that can be used while deployed. Newer systemic medications-in particular, biologics and oral immunomodulators-have evolved to be both extremely effective and safe. We review more recent treatment options for psoriasis and atopic dermatitis in the context of DoD's regulations guiding entry and retention of personnel with psoriasis and eczema and make recommendations regarding updating DoD policy for systemic treatment options. MATERIALS AND METHODS: A literature search was performed using PubMed, Embase, and Ovid with the last search done in the fall of 2023 from all years to date. These articles were further screened based on inclusion and exclusion criteria. In total, 25 articles were included in this review. An Internet search was also performed on the DoD's regulations guiding entry and retention of personnel with psoriasis and eczema. In addition, we examined medical requirements for deployment to the U.S. Central Command and U.S. European Command. RESULTS: Currently, U.S. Central Command and U.S. European Command do not allow the use of medications with special storage and handling requirements on deployments. Newer biologics are safe and efficacious but require refrigeration, although other immunomodulators like deucravacitinib and apremilast are oral pills and do not have cold-storage requirements. However, the use of biologics in austere environments may be feasible because of increased intervals between dosing and the ability to store refrigerated medical supplies in most deployed environments. For military service members with psoriasis, risankizumab and deucravacitinib are excellent options given their favorable safety and efficacy profiles. Of the biologics available for atopic dermatitis, dupilumab is the safest and effective systemic medication available. The Janus kinase inhibitors have also demonstrated excellent efficacy in treating atopic dermatitis, but more safety data are needed because of potential adverse events to include heart-related events, blood clots, and cancers. CONCLUSIONS: Systemic treatments have evolved to become highly specific for both eczema and psoriasis. These newer biologics and immunomodulators may be compatible with use in the deployed setting, especially those that have long dosing intervals and proven efficacy and safety. Of the biologics, dupilumab and risankizumab offer the best efficacy, safety, and dosing intervals for atopic dermatitis and psoriasis, respectively. Deucravcitinib is a recently FDA-approved oral immunomodulator for psoriasis that has an excellent safety profile and efficacy. Allowing the use of these medications on deployments will enable more people with moderate to severe psoriasis and eczema to join and remain in the military while receiving effective treatment.

A Comparison of HPSP and USU Graduates' Preparation for Residency.

INTRODUCTION: Military medical students enter residency through two main pathways: (1) The Uniformed Services University (USU) and (2) the Armed Services Health Professions Scholarship Program (HPSP). The purpose of this study was to compare how these two pathways prepare military medical students for residency. METHODS: We conducted semi-structured interviews with 18 experienced military residency program directors (PDs) in order to explore their perceptions of the preparedness of USU and HPSP graduates. We used a transcendental phenomenological qualitative research design to bracket our biases and guide our data analysis. Our research team coded each of the interview transcripts. We then organized these codes into themes, which served as the results of our study. RESULTS: Five themes emerged from our data regarding the residents' preparedness: (1) Ability to navigate the military culture, (2) understanding of the military's medical mission, (3) clinical preparation, (4) ability to navigate the Military Health System (MHS), and (5) teamwork. The PDs described how USU graduates better understand the military's medical mission and are more easily able to navigate the military culture and the MHS because of their lived experiences during military medical school. They also discussed the various levels of clinical preparation of HPSP graduates, in contrast to the USU graduates' more consistent skills and abilities. Finally, the PDs believed both groups to be strong team players. CONCLUSIONS: USU students were consistently prepared for a strong start to residency because of their military medical school training. HPSP students often experienced a steep learning curve because of the newness of the military culture and MHS.

The Military Medical Officer's Current-Day Professional Identity: An Enhanced Model.

BACKGROUND: As the landscapes of war have evolved, so too has the role of the military medical officer (MMO). Colonel (Retired) Barry Wolcott developed a "vector" model in the 1990s, illustrating the dual professional role of the MMO. Since then, propelled by the War on Terror, MMOs have adapted to treating patients in volatile, uncertain, complex, and ambiguous operational environments. This study, therefore, aimed to explore modern-day aspects of the MMO's role in order to enhance Wolcott's depiction of the MMO's professional identity in contemporary operational environments. MATERIALS AND METHODS: We used the qualitative phenomenological tradition to design our study. We interviewed military physicians from a variety of specialties in order to explore their experiences and professional identity as MMOs. Our research team then coded each of these interview transcripts. We organized these codes into categories, which served as the themes of our study. RESULTS: The following themes emerged from our data regarding the role of the MMO in the operational environment: Primary roles (officer, physician, educator, and diplomat) and aptitudes (innovation, advocacy, cultural competency, and leadership). The MMO's roles as officer and physician often intersect, with dual foci on the mission and the patient. The MMO also serves as an educator to medics and line officers. In addition, they act as diplomats both outside and within the military. Within each of these primary roles, the MMO innovatively prepares for future landscapes of war and advocates for both the individual warfighter and the unit/command. Finally, the MMO navigates both foreign and internal cultural differences and demonstrates leadership in enabling the military's mission. CONCLUSIONS: The role of the MMO is complex and multifaceted. The recognition of the contemporary MMO's unique skill set is essential for the effective education and training of future military health care leaders. The value of capitalizing on this unique skill set has been demonstrated in recent civ-mil responses. Because their intricate skill set is specialized for the operational environment, long-term retention of MMOs is key to force readiness.

Basement membrane defects in CD151-associated glomerular disease.

BACKGROUND: CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin ɑ3ß1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease. METHODS: Next-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9. RESULTS: We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence. CONCLUSIONS: Our results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. A higher resolution version of the Graphical abstract is available as Supplementary information.

Use of normal saline and incidence of dyselectrolytaemia in children following kidney transplantation.

BACKGROUND: The use of hypotonic fluid, such as 0.45% saline, following kidney transplantation (KT) in children is associated with a high incidence of electrolyte imbalance, especially hyponatraemia. This can result in serious adverse events, such as cerebral oedema and seizures. The aim of this study was to investigate the incidence of electrolyte disturbance in children when 0.9% saline was the intravenous fluid used in the first 72 h following KT. METHODS: This is a retrospective, observational study of 50 consecutive KT undertaken between January 2017 and January 2019 at a single centre. RESULTS: The median age at KT was 9.2 years (IQR 4-14) and 16 (32%) were females. Thirty-two (64%) were living related donor (LRD) KT and 22 (44%) were carried out in children < 20 kg. The mean volume of fluid administered intra-operatively, and on Day 1, Day 2 and Day 3, were 73 ml/kg, 124 ml/kg, 97 ml/kg and 86 ml/kg, respectively. Hyponatraemia was noted in 4%, hypernatraemia in 18%, hyperkalaemia in 18%, hyperchloraemia in 68% and low bicarbonate was seen in 88%. Fifteen percent of the children had an episode of hyperglycaemia. None of the children developed symptomatic dyselectrolytaemia. There was delayed graft function (DGF) in 4 (8%) recipients - all deceased donor (DD) KT, including 2 who received donations after circulatory death. CONCLUSIONS: While the use of 0.9% saline is associated with a high incidence of electrolyte disturbances, including hyperkalaemia, it reduces the risk of hyponatraemia. None of the children developed a symptomatic electrolyte abnormality. A higher resolution version of the Graphical abstract is available as Supplementary information.

Young adults have worse kidney transplant outcomes than other age groups.

BACKGROUND: The objective of this study was to establish if renal transplant outcomes (graft and patient survival) for young adults in England were worse than for other age groups. METHODS: Outcomes for all renal transplant recipients in England (n = 26 874) were collected from Hospital Episode Statistics and the Office for National Statistics databases over 12 years. Graft and patient outcomes, follow-up and admissions were studied for all patients, stratified by age bands. RESULTS: Young adults (14-23 years) had substantially greater likelihood [hazard ratio (HR) = 1.26, 95% confidence interval (CI) 1.10-1.19; P < 0.001] of kidney transplant failure than any other age band. They had a higher non-attendance rate for clinic appointments (1.6 versus 1.2/year; P < 0.001) and more emergency admissions post-transplantation (25% of young adults on average are admitted each year, compared with 15-20% of 34- to 43-year olds). Taking into account deprivation, ethnicity, transplant type and transplant centre, in the 14- to 23-year group, return to dialysis remained significantly worse than all other age bands (HR = 1.41, 95% CI 1.26-1.57). For the whole cohort, increasing deprivation related to poorer outcomes and black ethnicity was associated with poorer outcomes. However, neither ethnicity nor deprivation was over-represented in the young adult cohort. CONCLUSIONS: Young adults who receive a kidney transplant have a significant increased likelihood of a return to dialysis in the first 10 years post-transplant when compared with those aged 34-43 years in multivariable analysis.

Destination Therapy: Standardizing the Role of Palliative Medicine and Delineating the DT-LVAD Journey.

CONTEXT: Destination therapy (DT) patients face significant challenges as they transition from chronic left ventricular assist device (LVAD) support to comfort-oriented care. Integration of palliative medicine (PM) into the multidisciplinary team is important to facilitate advanced care planning (ACP) and improve quality of life (QoL). OBJECTIVES: We evaluated the impact of a structured programmatic approach to the end-of-life (EOL) process in DT patients as measured by QoL surveys and the utilization of ACP. METHODS: We instituted a four prong intervention approach: 1) delineated the path from implant to EOL by defining specific stages, including a transitional phase where care limits were agreed upon, 2) standardized the role of PM, 3) held transitional care meetings to support shared decision-making, and 4) held multidisciplinary team debriefings to facilitate communication. Preintervention and postintervention outcomes were measured for patients/caregivers by using the QUAL-E/QUAL-E (family) QoL instrument. Wilcoxon signed-ranks test compared nonparametric variables. RESULTS: All patients (n = 41)/caregivers (n = 28) reported improved QoL measures (patient P = 0.035/caregiver P = 0.046). Preparedness plans increased from 52% to 73% after implementation and advance directives increased from 71% to 83%. Fifty-nine percent of the patients completed an outpatient PM clinic visit; 51% completed/scheduled a second visit. Clinician outcomes improved including satisfaction with multidisciplinary team communication/expectations, ACP processes, and EOL management. CONCLUSION: A programmatic approach that standardizes the role of PM and delineates the patient's path from implant to EOL improved quality outcomes and increased implementation of ACP. A defined communication process allowed the multidisciplinary team to have a clear patient management approach.

The Carnitine Shuttle Pathway is Altered in Patients With Neovascular Age-Related Macular Degeneration.

Purpose: To identify metabolites and metabolic pathways altered in neovascular age-related macular degeneration (NVAMD). Methods: We performed metabolomics analysis using high-resolution C18 liquid chromatography-mass spectrometry on plasma samples from 100 NVAMD patients and 192 controls. Data for mass/charge ratio ranging from 85 to 850 were captured, and metabolic features were extracted using xMSanalyzer. Nested feature selection was used to identify metabolites that discriminated between NVAMD patients and controls. Pathway analysis was performed with Mummichog 2.0. Hierarchical clustering was used to examine the relationship between the discriminating metabolites and NVAMD patients and controls. Results: Of the 10,917 metabolic features analyzed, a set of 159 was identified that distinguished NVAMD patients from controls (area under the curve of 0.83). Of these features, 39 were annotated with confidence and included multiple carnitine metabolites. Pathway analysis revealed that the carnitine shuttle pathway was significantly altered in NVAMD patients (P = 0.0001). Tandem mass spectrometry confirmed the molecular identity of five carnitine shuttle pathway acylcarnitine intermediates that were increased in NVAMD patients. Hierarchical cluster analysis revealed that 51% of the NVAMD patients had similar metabolic profiles, whereas the remaining 49% displayed greater variability in their metabolic profiles. Conclusions: Multiple long-chain acylcarnitines that are part of the carnitine shuttle pathway were significantly increased in NVAMD patients compared to controls, suggesting that fatty acid metabolism may be involved in NVAMD pathophysiology. Cluster analysis suggested that clinically indistinguishable NVAMD patients can be separated into distinct subgroups based on metabolic profiles.

Azidothymidine Sensitizes Primary Effusion Lymphoma Cells to Kaposi Sarcoma-Associated Herpesvirus-Specific CD4+ T Cell Control and Inhibits vIRF3 Function.

Kaposi sarcoma-associated herpesvirus (KSHV) is linked with the development of Kaposi sarcoma and the B lymphocyte disorders primary effusion lymphoma (PEL) and multi-centric Castleman disease. T cell immunity limits KSHV infection and disease, however the virus employs multiple mechanisms to inhibit efficient control by these effectors. Thus KSHV-specific CD4+ T cells poorly recognize most PEL cells and even where they can, they are unable to kill them. To make KSHV-infected cells more sensitive to T cell control we treated PEL cells with the thymidine analogue azidothymidine (AZT), which sensitizes PEL lines to Fas-ligand and TRAIL challenge; effector mechanisms which T cells use. PELs co-cultured with KSHV-specific CD4+ T cells in the absence of AZT showed no control of PEL outgrowth. However in the presence of AZT PEL outgrowth was controlled in an MHC-restricted manner. To investigate how AZT sensitizes PELs to immune control we first examined BJAB cells transduced with individual KSHV-latent genes for their ability to resist apoptosis mediated by stimuli delivered through Fas and TRAIL receptors. This showed that in addition to the previously described vFLIP protein, expression of vIRF3 also inhibited apoptosis delivered by these stimuli. Importantly vIRF3 mediated protection from these apoptotic stimuli was inhibited in the presence of AZT as was a second vIRF3 associated phenotype, the downregulation of surface MHC class II. Although both vFLIP and vIRF3 are expressed in PELs, we propose that inhibiting vIRF3 function with AZT may be sufficient to restore T cell control of these tumor cells.

Boston type 1 keratoprosthesis from patient selection through postoperative management: a review for the keratoprosthetic surgeon.

For the anterior segment surgeon, the implantation of Boston type 1 keratoprosthesis is a multistep process that begins with careful patient selection. Success depends on thorough preoperative evaluation, detailed surgical planning, and frequent postoperative follow-up. New practice patterns have emerged for each of these phases as the international experience with keratoprosthesis grows. This review details special considerations that can improve outcomes and also allow surgeons to consider its use in challenging patient populations at each step.

Corneal Ectasia and Hydrops in Ocular Hypotony: The Corneal Crease.

PURPOSE: To report the association of chronic ocular hypotony with the development of progressive corneal ectasia and hydrops. METHODS: Retrospective case series. RESULTS: Three patients with ocular hypotony were referred for corneal evaluation and found to have ectasia and acute corneal hydrops in their hypotonous eye(s). Clinically, the globes were easily deformable with either external digital palpation and/or simple blinking. All 3 patients had a history of chronic iridocyclitis, including one with juvenile idiopathic arthritis. In each case, the area of thinning was narrow and arcuate in configuration, distinctive from other ectatic disorders. Also uncharacteristically, the acute hydrops resolved rapidly within 2 to 3 weeks without surgical intervention. In 1 case, severe thinning with perforation occurred requiring urgent penetrating keratoplasty. CONCLUSIONS: This case series demonstrates a unique clinical entity in which corneal ectasia and hydrops developed in the setting of ocular hypotony and easily deformable corneas, in a pattern unlike previously described forms of ectasia. Acute hydrops, even with associated corneal perforation, demonstrated a short and self-limited course. Corneal ectasia and irregular astigmatism should be suspected as a cause of unexplained visual loss in the ever-increasing number of patients with chronic, stable ocular hypotony. Further study is warranted to determine the pathophysiology of corneal ectasia in this setting, which may include mechanical and inflammatory factors.

Effects of childhood experiences on cortisol levels in depressed adults.

OBJECTIVE: To evaluate the impact of childhood abuse and parental bonding on cortisol levels in depressed adults. METHODS: Mean afternoon cortisol levels were measured in 192 depressed adult patients at the beginning of a treatment trial. Childhood experiences of physical and sexual abuse were ascertained by interview, and perceived parenting by self-report. RESULTS: Maternal affectionless control, childhood sexual and physical abuse were all associated with cortisol levels. CONCLUSION: Childhood experiences, especially maternal affectionless control, appear to be related to hypothalamic pituitary adrenal axis function in depressed adults.