Microsporum canis pseudomycetoma and disseminated Mycobacterium genavense infection in an HIV/AIDS patient, an unusual combination.

Pseudomycetomas are rare fungal subcutaneous infections caused by dermatophytes, which are mainly observed in immunocompromised patients. Mycobacterium genavense is considered an opportunistic pathogen in people living with HIV/AIDS (PLWHA), clinically resembling the presentation of Mycobacterium avium complex (MAC). Here, we describe the case of a 26-year-old PLWHA with a 3-month history of a 4cm tumoral, duroelastic and painful lesion located on the back. Histopathology of the tumoral lesion revealed chronic granulomatous inflammation with grains composed of PAS-positive and Grocott-positive septate hyphae, as well as acid-fast bacilli (AFB). Culture on Sabouraud and lactrimel agar developed colonies that were later identified as Microsporum canis. In successive samples, the AFB were identified as M. genavense by restriction analysis of PCR products. Immunocompromised PLWHA not only suffer increased susceptibility to diseases due to unusual pathogens but also atypical clinical presentation of frequently encountered pathogens.

Large language models as assistance for glaucoma surgical cases: a ChatGPT vs. Google Gemini comparison.

PURPOSE: The aim of this study was to define the capability of ChatGPT-4 and Google Gemini in analyzing detailed glaucoma case descriptions and suggesting an accurate surgical plan. METHODS: Retrospective analysis of 60 medical records of surgical glaucoma was divided into "ordinary" (n = 40) and "challenging" (n = 20) scenarios. Case descriptions were entered into ChatGPT and Bard's interfaces with the question "What kind of surgery would you perform?" and repeated three times to analyze the answers' consistency. After collecting the answers, we assessed the level of agreement with the unified opinion of three glaucoma surgeons. Moreover, we graded the quality of the responses with scores from 1 (poor quality) to 5 (excellent quality), according to the Global Quality Score (GQS) and compared the results. RESULTS: ChatGPT surgical choice was consistent with those of glaucoma specialists in 35/60 cases (58%), compared to 19/60 (32%) of Gemini (p = 0.0001). Gemini was not able to complete the task in 16 cases (27%). Trabeculectomy was the most frequent choice for both chatbots (53% and 50% for ChatGPT and Gemini, respectively). In "challenging" cases, ChatGPT agreed with specialists in 9/20 choices (45%), outperforming Google Gemini performances (4/20, 20%). Overall, GQS scores were 3.5 ± 1.2 and 2.1 ± 1.5 for ChatGPT and Gemini (p = 0.002). This difference was even more marked if focusing only on "challenging" cases (1.5 ± 1.4 vs. 3.0 ± 1.5, p = 0.001). CONCLUSION: ChatGPT-4 showed a good analysis performance for glaucoma surgical cases, either ordinary or challenging. On the other side, Google Gemini showed strong limitations in this setting, presenting high rates of unprecise or missed answers.

Exploring AI-chatbots' capability to suggest surgical planning in ophthalmology: ChatGPT versus Google Gemini analysis of retinal detachment cases.

BACKGROUND: We aimed to define the capability of three different publicly available large language models, Chat Generative Pretrained Transformer (ChatGPT-3.5), ChatGPT-4 and Google Gemini in analysing retinal detachment cases and suggesting the best possible surgical planning. METHODS: Analysis of 54 retinal detachments records entered into ChatGPT and Gemini's interfaces. After asking 'Specify what kind of surgical planning you would suggest and the eventual intraocular tamponade.' and collecting the given answers, we assessed the level of agreement with the common opinion of three expert vitreoretinal surgeons. Moreover, ChatGPT and Gemini answers were graded 1-5 (from poor to excellent quality), according to the Global Quality Score (GQS). RESULTS: After excluding 4 controversial cases, 50 cases were included. Overall, ChatGPT-3.5, ChatGPT-4 and Google Gemini surgical choices agreed with those of vitreoretinal surgeons in 40/50 (80%), 42/50 (84%) and 35/50 (70%) of cases. Google Gemini was not able to respond in five cases. Contingency analysis showed significant differences between ChatGPT-4 and Gemini (p=0.03). ChatGPT's GQS were 3.9±0.8 and 4.2±0.7 for versions 3.5 and 4, while Gemini scored 3.5±1.1. There was no statistical difference between the two ChatGPTs (p=0.22), while both outperformed Gemini scores (p=0.03 and p=0.002, respectively). The main source of error was endotamponade choice (14% for ChatGPT-3.5 and 4, and 12% for Google Gemini). Only ChatGPT-4 was able to suggest a combined phacovitrectomy approach. CONCLUSION: In conclusion, Google Gemini and ChatGPT evaluated vitreoretinal patients' records in a coherent manner, showing a good level of agreement with expert surgeons. According to the GQS, ChatGPT's recommendations were much more accurate and precise.

Ocular Involvement in Systemic Sclerosis: Updated Review and New Insights on Microvascular Impairment.

Systemic sclerosis (SSc) is a chronic multisystemic disease characterized by immunological activation, diffuse vasculopathy, and generalized fibrosis exhibiting a variety of symptoms. A recognized precursor of SSc is Raynaud's phenomenon, which is part of the very early disease of systemic sclerosis (VEDOSS) in combination with nailfold videocapillaroscopy (NVC) impairment. The pathophysiology of ocular involvement, alterations in internal organs, and body integumentary system involvement in SSc patients are complicated and poorly understood, with multiple mechanisms presumptively working together. The most prevalent ocular symptoms of SSc are abnormalities of the eyelids and conjunctiva as well as dry eye syndrome, due to fibroblasts' dysfunction and inflammation of the ocular surface. In particular, lagophthalmos, blepharophimosis limitation of eyelid motion, eyelid telangiectasia, and rigidity or tightening of the lids may affect up to two-third of the patients. In addition, reduction in central corneal thickness, iris defects and higher rates of glaucoma were reported. In the first reports based on retinography or fluorescein angiography, about 50% of SSc patients showed signs of vascular disease: peripheral artery occlusion, thinning of retinal pigment epithelium and choroidal capillaries, ischemic areas surrounded by intraretinal extravasation and microaneurysms, and peripheral capillary non-perfusion. Successively, thanks to the advent of optical coherence tomography angiography (OCTA), several studies highlighted significant impairment of either the choriocapillaris and retinal vascular plexuses, also correlating with NVC involvement and skin disease, even in VEDOSS disease. Given the sensitivity of this technique, ocular micro-vasculopathy may act as a tool for early SSc identification and discriminate between disease stages.

Ranibizumab Port Delivery System in Neovascular Age-Related Macular Degeneration: Where Do We Stand? Overview of Pharmacokinetics, Clinical Results, and Future Directions.

The ranibizumab (RBZ) port delivery system (PDS) is a device designed to continuously deliver RBZ in the vitreous chamber for the treatment of neovascular age-related macular degeneration (nAMD). It is implanted during a surgical procedure and can provide sustained release of the medication for several months. This review, updated to January 2024, focuses on past clinical studies as well as current and forthcoming trials looking into a PDS with RBZ. In the phase 2 LADDER trial, the mean time to first refill of a PDS with RBZ 100 mg/mL was 15.8 months, with the pharmacokinetic (PK) profile showing a sustained concentration of RBZ in the blood and aqueous humor. More recently, a PDS with RBZ (100 mg/mL) refilled every 24 weeks was shown to be non-inferior to a monthly intravitreal injection (IVI) with RBZ (0.5 mg) over 40 and 92 weeks in the phase 3 ARCHWAY trial. The refill every 24 weeks allowed for a RBZ vitreous exposure within the concentration range of monthly intravitreal injections (IVIs), and the expected half-life (106 days) was comparable with the in vitro results. Nonetheless, vitreous hemorrhage and endophthalmitis were more common side effects in PDS patients. In conclusion, a PDS continuously delivering RBZ has a clinical effectiveness level comparable with IVI treatment. However, a greater frequency of unfavorable occurrences highlights the need for procedure optimization for a wider adoption. Ongoing trials and possible future approaches need to be addressed.

Exclusive Ru-106 brachytherapy for the management of a recurrent corneo: Conjunctival squamous cell carcinoma.

BACKGROUND: We report a case of personalized exclusive brachytherapy treatment for the management of a highly recurrent squamous cell conjunctival carcinoma with corneal invasion. CASE DESCRIPTION: This is a case of a Caucasian 81-years-old man who presented 10 years ago to our clinic with a pink-white para-limbal mass with dilated feeder arteries and mild leukoplakia. Excisional biopsy confirmed the presence of conjunctival intraepithelial neoplasia (CIN). Successively, he underwent two 4-weeks cycles of Mytomicin C topical therapy and a second excisional surgery, due to several recurrences of the lesion. At the last relapse, the pink-white peri-limbic mass which invaded the corneal limbus, determining corneal opacification from 5- to 7-clock hours, was confirmed by anterior segment optical coherence tomography (AS-OCT). Due to resistance to MMC therapy and chronic epitheliopathy, an AS-OCT guided exclusive radiotherapy plan was set: a Rhutenium-106 CCD plaque was applied directly over the afflicted corneal surface, the corneal limbus and the neighboring sclera for 24 hours. The remission of both conjunctival and corneal malignancy was complete 2 months after surgery and no signs of recurrence were highlighted at AS-OCT analysis at the 2-year follow up. CONCLUSION: Brachytherapy treatment showed optimal management of both corneal and conjunctival involvement, with a free-of-disease follow-up of 24-months. This result suggests that, in specific conditions, Ru-106 brachytherapy could be an effective option of treatment even if not associated with surgical excision.

Taser-Related Ocular Injuries: A Review of the Literature and Medico-Legal Implications.

PURPOSE: Electric weapons have dangers associated with their use, such as burns and trauma related with the impacts of uncontrolled falls, even though they often minimize morbidity and mortality. The exact visual outcome of the damage inflicted is unknown, even though numerous studies have been documented in the literature about the ocular damage induced by the use of these tools. METHODS: We present a narrative review of types of eye damage associated with the use of the Taser. The following search terms were used to identify eligible articles through the PubMed database: "TASER", "Conducted Electric Weapons", "CEWs". RESULTS: A total of 15 articles were included with information about 38 patients with eye damage associated with the use of taser. The majority of patients were males. In most cases the mechanism of injury was the penetration of the probe inside the eye. Clinical manifestations of ocular damage were present in only 18 out of 38 cases and varied according to the type of damage mechanism. Indeed, the cases in which the probe had penetrated the eye showed more severe clinical manifestations with a poor visual outcome. CONCLUSION: In conclusion, the introduction of taser use for law enforcement requires serious consideration and adequate training for officers.

Mechanical characteristics of glioblastoma and peritumoral tumor-free human brain tissue.

BACKGROUND: The diagnosis of brain tumor is a serious event for the affected patient. Surgical resection is a crucial part in the treatment of brain tumors. However, the distinction between tumor and brain tissue can be difficult, even for experienced neurosurgeons. This is especially true in the case of gliomas. In this project we examined whether the biomechanical parameters elasticity and stress relaxation behavior are suitable as additional differentiation criteria between tumorous (glioblastoma multiforme; glioblastoma, IDH-wildtype; GBM) and non-tumorous, peritumoral tissue. METHODS: Indentation measurements were used to examine non-tumorous human brain tissue and GBM samples for the biomechanical properties of elasticity and stress-relaxation behavior. The results of these measurements were then used in a classification algorithm (Logistic Regression) to distinguish between tumor and non-tumor. RESULTS: Differences could be found in elasticity spread and relaxation behavior between tumorous and non-tumorous tissue. Classification was successful with a sensitivity/recall of 83% (sd = 12%) and a precision of 85% (sd = 9%) for detecting tumorous tissue. CONCLUSION: The findings imply that the data on mechanical characteristics, with particular attention to stress relaxation behavior, can serve as an extra element in differentiating tumorous brain tissue from non-tumorous brain tissue.

Phase unwrapping for MHz optical coherence elastography and application to brain tumor tissue.

During neuro-oncologic surgery, phase-sensitive optical coherence elastography (OCE) can be valuable for distinguishing between healthy and diseased tissue. However, the phase unwrapping process required to retrieve the original phase signal is a challenging and critical task. To address this issue, we demonstrate a one-dimensional unwrapping algorithm that recovers the phase signal from a 3.2 MHz OCE system. With a processing time of approximately 0.11 s per frame on the GPU, multiple 2π wraps are detected and corrected. By utilizing this approach, exact and reproducible information on tissue deformation can be obtained with pixel accuracy over the entire acquisition time. Measurements of brain tumor-mimicking phantoms and human ex vivo brain tumor samples verified the algorithm's reliability. The tissue samples were subjected to a 200 ms short air pulse. A correlation with histological findings confirmed the algorithm's dependability.

Microvascular Changes after Epiretinal Membrane Vitrectomy with Intraoperative Intravitreal Dexamethasone Implant: An OCT Angiography Analysis.

BACKGROUND: We aimed to explore microvascular changes evaluated with optical coherence tomography angiography (OCTA) in patients undergoing epiretinal membrane (ERM) pars-plana vitrectomy (PPV) combined with intravitreal Ozurdex implantation, compared with standard PPV. (2) Methods: Prospective interventional analysis on 25 eyes undergoing PPV + Ozurdex (Group A) and 25 eyes undergoing PPV alone. Best corrected visual acuity (BCVA) and OCTA parameters, such as vessel density (VD) of the superficial and deep capillary plexi (SCP and DCP) in the whole 6.4 mm × 6.4 mm and fovea area, were evaluated preoperatively and 3 months after surgery. (3) Results: Postoperative BCVA significantly improved in both groups. No cases of post-operative cystoid macular edema (CME) were reported in Group A vs. two eyes in Group B. In Group A we found a statistically significant increase of SCP's VD in either the whole image (from 42.1 ± 4.1 to 45.6 ± 4.3%, p = 0.01) and the fovea image (from 38.5 ± 7.5 to 41.7 ± 4.2%, p = 0.03). In Group B, we reported no significant variations in the SCP's VDs. In the DCP, VD significantly increased only in the whole image in Group A. Stage 4 ERMs showed the greatest improvement in VD, especially in Group A. (4) Conclusions: Intraoperative Ozurdex prompted a significant BCVA recovery and limited the occurrence of postoperative CME compared to the standard procedure. Moreover, Ozurdex implant is associated with a better restoration of microvascular structure in SCP and DCP.

Chorioretinal biomarkers in hypothalamic amenorrhea.

PURPOSE: The aim of our study was to evaluate changes in the retinal and choriocapillaris circulations in patients with hypothalamic amenorrhea. METHODS: Prospective, cross-sectional observational study on 25 patients (50 eyes) diagnosed with hypothalamic amenorrhea and 25 age-matched healthy women. Optical coherence tomography angiography (OCTA) was used to evaluate the vessel density (VD) of superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris VD layers in whole 6.4 × 6.4-mm image and in fovea grid-based image. In patients' group, systemic parameters were collected: body mass index (BMI), endometrial rhyme thickness, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, insulin, and cortisol. RESULTS: SCP and DCP did not show any statistical difference when comparing patients and controls (all p > 0.05). Differently, choriocapillaris VD in the whole region showed a non-significant tendency toward higher values in the patients group in both eyes (p = 0.038 for right eye [RE], p = 0.044 for left eye [LE]). Foveal choriocapillaris VD was higher in hypothalamic amenorrhea women vs. healthy controls (66.0 ± 2.4 vs. 63.7 ± 6.6%, p = 0.136 for RE; 65.0 ± 2.4 vs. 61.6 ± 7.0%, p = 0.005 for LE). Focusing on correlation with systemic parameters, SCP and DCP foveal density had a medium/high effect size with endometrial rhyme, along with DCP in the fovea area vs. cortisol and SCP in the whole area vs. FSH. CONCLUSION: When comparing hypothalamic amenorrhea patients to healthy subjects, OCTA detected changes in the choriocapillaris layer, showing increased VD in the early stage of the systemic pathology, suggesting that microvascular "compaction" could be a first phase of hypoestrogenism adaptation.

Incidental Finding of Suprachoroidal Space's Silicone Oil Migration: A Tumor-Mimicking Lesion and Its Clinical Management.

The migration of silicone oil into the suprachoroidal region is a rare complication of vitrectomy. A 70-year-old man was admitted to our ocular oncology unit with a choroidal elevation in the nasal area, as well as signs of pars plana vitrectomy surgery performed about 5 years ago for retinal detachment. The patient underwent ocular ultrasound, visual field test, fluorangiography, and magnetic resonance imaging, which led to the diagnosis of silicone oil migration in the suprachoroidal space. Silicone oil may move into the suprachoroidal area, mimicking choroidal neoformation. It is important to have a comprehensive diagnosis and then set up the appropriate treatment. [Ophthalmic Surg Lasers Imaging Retina 2024;55:104-108.].

Inferior implant of XEN63 Gel stent in a refractory open-angle glaucoma due to silicone oil tamponade: A case report.

BACKGROUND: To discuss the efficacy of an inferior implant of XEN 63 gel stent in a patient with refractory glaucoma after trabeculectomy failure and vitreoretinal surgery with silicone oil tamponade. CASE DESCRIPTION: We report the case of a 73-year-old man with a history of refractory open glaucoma with trabeculectomy failure. He experienced recurrent retinal detachments with silicone oil tamponade, with uncontrolled intra-ocular pressure (IOP) after silicone oil removal. Due to the presence of oil emulsion in the anterior chamber, the chosen location for XEN 63 implantation was the infero-temporal quadrant. Mild hyphema and vitreous hemorrhage were seen post-operatively, but were self-limiting. At week 1, the intraocular pressure was 8 mmHg with a well-formed bleb seen in anterior segment optical coherence tomography (AS-OCT). At 6 month follow up, the patient maintained a IOP of 12 mmHg without topical hypotensive drugs. Slit lamp examination revealed a widespread, developed bleb with no signs of inflammation. CONCLUSION: In this case of refractory glaucoma in a vitrectomized eye with previous oil tamponade, the inferior placement of the XEN 63 gel stent delivered an adequate intraocular pressure even at 6-months follow up, with a diffuse functional infero-nasal bleb seen with AS-OCT.

Evaluation of ocular surface following PreserFlo Microshunt implantation: Functional outcomes and quality of life.

BACKGROUND: This study aimed to evaluate the impact of PreserFlo Microshunt on the ocular surface, focusing on both objective and subjective parameters. METHODS: Prospective-observational study on 48 eyes undergoing PreserFlo Microshunt implantation, standalone or combined with phacoemulsification. At baseline, 1-month, 6-months and 12-months post-operative follow-ups, we performed Ocular Surface Disease Index (OSDI) questionnaire, Schirmer's test (ST), Tear-film break-up time (TBUT), fluoresceine staining (FS), tear osmolarity and minimum corneal epithelial thickness (Epi-ThkMIN. ) measurements. RESULTS: OSDI score improved from 37.43 ± 17.49 at baseline, to 24.13 ± 12.55 at 1-month (p = 0.003) and to 12.89 ± 8.54 and 13.09 ± 10.22 at 6-months and 12-months (p < 0.0001). TBUT and ST, in a similar way, non-significantly increased at 1-month, but then improved at 6-months and 12-months (p < 0.05 for both). Tear osmolarity significantly decreased from 308.2 ± 7.3 mOsm/L at baseline, to 303.3 ± 8.2 mOsm/L, 295.6.2 ± 7.0 mOsm/L and 297.6 ± 6.8 mOsm/L at 1-month, 6-months and 12-months (p < 0.05 for all). Epi-ThkMIN was stable when comparing baseline (44.9 ± 5.7 µm) and 1-month (p = 0.28), and successively increased in 6-months (47.8 ± 5.5 µm, p = 0.02) and 12-months (48.0 ± 3.6 µm, p = 0.01). In subgroup analysis, OSDI score and tear osmolarity were significantly higher at 1-month in combined group compared to standalone group (p = 0.03 and p = 0.02, respectively), but reaching comparable values in successive follow-ups. Further, Oxford scale grades for FS were significantly improved when comparing baseline-6-months and baseline-12-months. CONCLUSION: PreserFlo implantation improved ocular surface subjective symptoms, increased TBUT and ST, and reduced FS, highlighting the potential benefits of this surgical intervention. Moreover, we reported significant improvements of tear osmolarity and corneal epithelium.

Ultrasonic Aspirator for Tissue Contact Detection: An Online Classification on Time-Series.

The goal of neurosurgical tumor surgery is to remove the tumor completely without damaging healthy brain structures and thereby impairing the patient's neurological functions. This requires careful planning and execution of the operation by experienced neurosurgeons using the latest intraoperative technologies to achieve safe and rapid tumor reduction without harming the patient. To achieve this goal, a standard ultrasonic aspirator designed for tissue removal is equipped with additional intraoperative tissue detection using machine learning methods.Since decision-making in a clinical context must be fast, online contact detection is critical. Data are generated on three types of artificial tissue models in a CNC machine-controlled environment with four different ultrasonic aspirator settings. Contact classification on artificial tissue models is evaluated on four classification algorithms: change point detection (CPD), random forest (RF), recurrent neural network (RNN) and temporal convolutional network (TCN). Data preprocessing steps are applied, and their impacts are investigated. All methods are evaluated on five-fold cross-validation and provide generally good results with a performance of up to 0.977±0.007 in mean F1-score. Preprocessing the data has a positive effect on the classification processes for all methods and consistently improves the metrics. Thus, this work indicates in a first step that contact classification is feasible in an online context for an ultrasonic aspirator. Further research is necessary on different tissue types, as well as hand-held use to more closely resemble the intraoperative clinical conditions.

Un desafío terapéutico: la heterorresistencia en Mycobacterium tuberculosis / An emerging problem: heteroresistance in Mycobacterium tuberculosis

Resumen Se considera infección mixta por Mycobacterium tuberculosis (Mtb) a la coexistencia en forma simul tánea y en un mismo paciente de 2 cepas diferentes de Mtb o 2 variantes distintas de la misma cepa. Cuando una de las variantes selecciona mutaciones de resistencia, se denomina heterorresistencia (HTR) monoclonal; en caso de que sean 2 cepas diferentes, una sensible y una resistente (o cepas con diferentes patrones de resistencia), se denomina HTR policlo nal. Se presentan 3 pacientes, HIV/sida, todos con reiterados problemas de adherencia al tratamiento, en los cuales a través de la secuenciación genómica completa de Mtb se diagnosticó HTR monoclonal con coexistencia de 2 variantes de la misma cepa aisladas de muestras de pulmón y ganglios linfáticos, con diferentes perfiles de resistencia en cada uno de los casos. Es importante pensar en la posibilidad de HTR, principalmente en pacientes con múltiples intentos terapéuticos previos y altas poblaciones bacilares, como en el sida avanzado, dado que esta situación compromete potencialmente los resultados del tratamiento al coexistir cepas o variantes de ce pas sensibles y resistentes.

Abstract Mixed infection by Mycobacterium tuberculosis (Mtb) consists in the simultaneous coexistence in the same patient of two different strains of Mtb or 2 different variants of the same strain. When one of the variants selects for resistance mutations, it is called monoclonal heteroresistance (HTR); if there are 2 different strains, one sensitive and one resistant (or with different resis tance patterns), it is called polyclonal HTR. Three cases of HIV/AIDS patients are presented, all with repeated treatment adherence problems, in whom monoclonal HTR was diagnosed through Mtb complete genomic sequentiation with the coexistence of two variants of the same strain isolated from samples from lung and lymph nodes, with different resistance profiles in each case. It is important to consider the possibility of HTR, especially in patients with multiple previous therapeu tic attempts and high bacillary populations, such as in advanced AIDS, since this situation potentially com promises treatment results by coexisting sensitive and resistant variants of a strain (or strains).

Stripping of the Posterior Hyaloid for the Treatment of Vitreomacular Traction.

PURPOSE: To describe and evaluate the effectiveness of stripping the posterior hyaloid as vitreomacular traction treatment. METHODS: This prospective, consecutive, interventional study examined 10 eyes of 10 patients who underwent vitrectomy for vitreomacular traction. RESULTS: The best-corrected visual acuity improved from 20/63 (0.5 ± 0.18 logMAR) preoperatively to 20/36 (0.25 ± 0.15 logMAR) 3 months after the surgeries. Optical coherence tomography analysis showed a reduction of the mean foveal thickness from 462 ± 82 µ to 372 ± 28 µ at 3-month follow-up in all the eyes. No postoperative complications were reported. CONCLUSION: Stripping of the posterior hyaloid for the treatment of vitreomacular traction could improve the symptoms and visual acuity of patients, alleviating the traction on the macula and avoiding secondary retinal damage as macular hole formation.

A Metabolic Gene Survey Pinpoints Fucosylation as a Key Pathway Underlying the Suppressive Function of Regulatory T Cells in Cancer.

Forkhead box P3 (Foxp3)-expressing regulatory T cells (Treg) are the guardians of controlled immune reactions and prevent the development of autoimmune diseases. However, in the tumor context, their increased number suppresses antitumor immune responses, indicating the importance of understanding the mechanisms behind their function and stability. Metabolic reprogramming can affect Foxp3 regulation and, therefore, Treg suppressive function and fitness. Here, we performed a metabolic CRISPR/Cas9 screen and pinpointed novel candidate positive and negative metabolic regulators of Foxp3. Among the positive regulators, we revealed that targeting the GDP-fucose transporter Slc35c1, and more broadly fucosylation (Fuco), in Tregs compromises their proliferation and suppressive function both in vitro and in vivo, leading to alteration of the tumor microenvironment and impaired tumor progression and protumoral immune responses. Pharmacologic inhibition of Fuco dampened tumor immunosuppression mostly by targeting Tregs, thus resulting in reduced tumor growth. In order to substantiate these findings in humans, tumoral Tregs from patients with colorectal cancer were clustered on the basis of the expression of Fuco-related genes. FucoLOW Tregs were found to exhibit a more immunogenic profile compared with FucoHIGH Tregs. Furthermore, an enrichment of a FucoLOW signature, mainly derived from Tregs, correlated with better prognosis and response to immune checkpoint blockade in melanoma patients. In conclusion, Slc35c1-dependent Fuco is able to regulate the suppressive function of Tregs, and measuring its expression in Tregs might pave the way towards a useful biomarker model for patients with cancer. See related Spotlight by Silveria and DuPage, p. 1570.

[An emerging problem: heteroresistance in Mycobacterium tuberculosis]. / Un desafío terapéutico: la heterorresistencia en Mycobacterium tuberculosis.

Mixed infection by Mycobacterium tuberculosis (Mtb) consists in the simultaneous coexistence in the same patient of two different strains of Mtb or 2 different variants of the same strain. When one of the variants selects for resistance mutations, it is called monoclonal heteroresistance (HTR); if there are 2 different strains, one sensitive and one resistant (or with different resistance patterns), it is called polyclonal HTR. Three cases of HIV/AIDS patients are presented, all with repeated treatment adherence problems, in whom monoclonal HTR was diagnosed through Mtb complete genomic sequentiation with the coexistence of two variants of the same strain isolated from samples from lung and lymph nodes, with different resistance profiles in each case. It is important to consider the possibility of HTR, especially in patients with multiple previous therapeutic attempts and high bacillary populations, such as in advanced AIDS, since this situation potentially compromises treatment results by coexisting sensitive and resistant variants of a strain (or strains).

Se considera infección mixta por Mycobacterium tuberculosis (Mtb) a la coexistencia en forma simultánea y en un mismo paciente de 2 cepas diferentes de Mtb o 2 variantes distintas de la misma cepa. Cuando una de las variantes selecciona mutaciones de resistencia, se denomina heterorresistencia (HTR) monoclonal; en caso de que sean 2 cepas diferentes, una sensible y una resistente (o cepas con diferentes patrones de resistencia), se denomina HTR policlonal. Se presentan 3 pacientes, HIV/sida, todos con reiterados problemas de adherencia al tratamiento, en los cuales a través de la secuenciación genómica completa de Mtb se diagnosticó HTR monoclonal con coexistencia de 2 variantes de la misma cepa aisladas de muestras de pulmón y ganglios linfáticos, con diferentes perfiles de resistencia en cada uno de los casos. Es importante pensar en la posibilidad de HTR, principalmente en pacientes con múltiples intentos terapéuticos previos y altas poblaciones bacilares, como en el sida avanzado, dado que esta situación compromete potencialmente los resultados del tratamiento al coexistir cepas o variantes de cepas sensibles y resistentes.