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Imaging neuronal activity with high and homogeneous spatial resolution across the field-of-view (FOV) and limited invasiveness in deep brain regions is fundamental for the progress of neuroscience, yet is a major technical challenge. We achieved this goal by correcting optical aberrations in gradient index lens-based ultrathin (≤500 µm) microendoscopes using aspheric microlenses generated through 3D-microprinting. Corrected microendoscopes had extended FOV ( eFOV ) with homogeneous spatial resolution for two-photon fluorescence imaging and required no modification of the optical set-up. Synthetic calcium imaging data showed that, compared to uncorrected endoscopes, eFOV -microendoscopes led to improved signal-to-noise ratio and more precise evaluation of correlated neuronal activity. We experimentally validated these predictions in awake head-fixed mice. Moreover, using eFOV- microendoscopes we demonstrated cell-specific encoding of behavioral state-dependent information in distributed functional subnetworks in a primary somatosensory thalamic nucleus. eFOV- microendoscopes are, therefore, small-cross-section ready-to-use tools for deep two-photon functional imaging with unprecedentedly high and homogeneous spatial resolution.

Sleep involves a relative disconnection from the environment, yet sensory stimuli can still trigger awakenings. The mechanism underlying sensory vigilance and stimulus discrimination during sleep remains unclear. Here, we showed that neutral auditory stimuli evoked responses across parallel auditory and non-auditory pathways, including the auditory cortex and thalamus, the hippocampus and centro-medial thalamus (CMT). Using a convolutional neural network, we identified CMT activity as the most discriminant hub for auditory-evoked sleep-to-wake transitions among all recorded structures. Furthermore, we found that prior associative learning of auditory cues with danger (conditioned stimulus, CS+) resulted in increased awakening upon CS+ exposure during NREM, but not REM, sleep. These sleep-to-wake transitions were blocked by optogenetic silencing of CMT neurons during CS+ exposure in sleeping mice. Altogether, these results suggest a central role of the CMT neurons in the residual processing of behaviorally-relevant information in the sleeping brain functioning as one of the major hubs for awakening in response to danger. The extent to which the sleeping brain can discern safety from danger is poorly understood. In mice, the authors show that centro-medial thalamic neurons detect threat-related sounds and selectively trigger awakenings during NREM, but not REM, sleep.

Two-photon (2P) fluorescence imaging through gradient index (GRIN) lens-based endoscopes is fundamental to investigate the functional properties of neural populations in deep brain circuits. However, GRIN lenses have intrinsic optical aberrations, which severely degrade their imaging performance. GRIN aberrations decrease the signal-to-noise ratio (SNR) and spatial resolution of fluorescence signals, especially in lateral portions of the field-of-view (FOV), leading to restricted FOV and smaller number of recorded neurons. This is especially relevant for GRIN lenses of several millimeters in length, which are needed to reach the deeper regions of the rodent brain. We have previously demonstrated a novel method to enlarge the FOV and improve the spatial resolution of 2P microendoscopes based on GRIN lenses of length <4.1 mm (Antonini et al., 2020). However, previously developed microendoscopes were too short to reach the most ventral regions of the mouse brain. In this study, we combined optical simulations with fabrication of aspherical polymer microlenses through three-dimensional (3D) microprinting to correct for optical aberrations in long (length >6 mm) GRIN lens-based microendoscopes (diameter, 500 µm). Long corrected microendoscopes had improved spatial resolution, enabling imaging in significantly enlarged FOVs. Moreover, using synthetic calcium data we showed that aberration correction enabled detection of cells with higher SNR of fluorescent signals and decreased cross-contamination between neurons. Finally, we applied long corrected microendoscopes to perform large-scale and high-precision recordings of calcium signals in populations of neurons in the olfactory cortex, a brain region laying approximately 5 mm from the brain surface, of awake head-fixed mice. Long corrected microendoscopes are powerful new tools enabling population imaging with unprecedented large FOV and high spatial resolution in the most ventral regions of the mouse brain.

Background: Our aim was to describe the clinical outcome and safety of the sequential treatment with off-label dalbavancin in patients with spondylodiscitis that is caused by methicillin-resistant Staphylococcus aureus (MRSA). Methods: We retrospectively included all patients >18 years of age with spondylodiscitis that is caused by MRSA that was treated with dalbavancin from January 2018–January 2021, recording the instances of clinical cure/failure, adverse events, and the need to be re-hospitalized after the initiation of dalbavancin. In 2/15 patients, we performed therapeutic drug monitoring (TDM) for dalbavancin. Results: We included 15 patients, 53.3% of them were females, with a median age of 67.9 years (57.4–78.5); 100% patients reported back pain, while a fever was present only in 2/15 cases. The spondylodiscitis was localized in 86.6% cases at the lumbar level. A median of a 2-week in-hospital intravenous vancomycin was followed by dalbavancin with a median duration of 12 weeks (12–16). All patients reported a clinical cure, except for a woman who is still on a suppressive treatment. No patient needed to be re-hospitalized, access to emergency department, or experienced adverse events. The TDM for dalbavancin showed that more than 90% of the determinations were above the pharmacodynamic target against staphylococci. Conclusions: The results from our unique, even if it was small, cohort demonstrated that dalbavancin can be a safe/effective option as a sequential treatment in patients with serious infections requiring prolonged antibiotic therapy, such as spondylodiscitis.

Background A study including 166 subjects was performed to investigate the frequency and persistence over a 6-month interval of concurrent oral and anal Human Papillomavirus (HPV) infections in Human Immunodeficiency Virus (HIV)-infected men who have sex with men (MSM). Methods Patients with no previously documented HPV-related anogenital lesion/disease were recruited to participate in a longitudinal study. Polymerase chain reaction (PCR) was performed to detect HPV from oral and anal swabs and to detect Human Herpes Virus 8 (HHV-8) DNA in saliva on 2 separate specimen series, one collected at baseline and the other collected 6 months later. A multivariate logistic analysis was performed using anal HPV infection as the dependent variable versus a set of covariates: age, HIV plasma viral load, CD4+ count, hepatitis B virus (HBV) serology, hepatitis C virus (HCV) serology, syphilis serology and HHV-8 viral shedding. A stepwise elimination of covariates with a p-value > 0.1 was performed. Results The overall prevalence of HPV did not vary significantly between the baseline and the follow-up, either in the oral (20.1 and 21.3%, respectively) or the anal specimens (88.6 and 86.3%). The prevalence of high-risk (HR) genotypes among the HPV-positive specimens was similar in the oral and anal infections (mean values 24.3% and 20.9%). Among 68 patients with either a HR, low-risk (LR) or undetermined genotype at baseline, 75% had persistent HPV and the persistence rates were 71.4% in HR infections and 76.7% in LR infections. There was a lack of genotype concordance between oral and anal HPV samples. The prevalence of HR HPV in anus appeared to be higher in the younger patients, peaking (> 25%) in the 43-50 years age group. A decrease of the high level of anal prevalence of all genotypes of HPV in the patients > 50 years was evident. HHV-8 oral shedding was positively related to HPV anal infection (p = 0.0046). A significant correlation was found between the persistence of HHV-8 shedding and HIV viral load by logistic bivariate analysis (Odds Ratio of HHV-8 persistence for 1-log increase of HIV viral load = 1.725 ± 0.397, p = 0.018). Conclusions A high prevalence of HPV infection was found in our cohort of HIV-infected MSM, with a negative correlation between anal HPV infection and CD4 cell count.

Two-photon (2P) fluorescence imaging through gradient index (GRIN) lens-based endoscopes is fundamental to investigate the functional properties of neural populations in deep brain circuits. However, GRIN lenses have intrinsic optical aberrations, which severely degrade their imaging performance. GRIN aberrations decrease the signal-to-noise ratio (SNR) and spatial resolution of fluorescence signals, especially in lateral portions of the field-of-view (FOV), leading to restricted FOV and smaller number of recorded neurons. This is especially relevant for GRIN lenses of several millimeters in length, which are needed to reach the deeper regions of the rodent brain. We have previously demonstrated a novel method to enlarge the FOV and improve the spatial resolution of 2P microendoscopes based on GRIN lenses of length <4.1 mm (Antonini et al., 2020). However, previously developed microendoscopes were too short to reach the most ventral regions of the mouse brain. In this study, we combined optical simulations with fabrication of aspherical polymer microlenses through three-dimensional (3D) microprinting to correct for optical aberrations in long (length >6 mm) GRIN lens-based microendoscopes (diameter, 500 µm). Long corrected microendoscopes had improved spatial resolution, enabling imaging in significantly enlarged FOVs. Moreover, using synthetic calcium data we showed that aberration correction enabled detection of cells with higher SNR of fluorescent signals and decreased cross-contamination between neurons. Finally, we applied long corrected microendoscopes to perform large-scale and high-precision recordings of calcium signals in populations of neurons in the olfactory cortex, a brain region laying approximately 5 mm from the brain surface, of awake head-fixed mice. Long corrected microendoscopes are powerful new tools enabling population imaging with unprecedented large FOV and high spatial resolution in the most ventral regions of the mouse brain.

Purpose Non-tuberculous mycobacteria (NTM) account for high clinical burden, and treatment can be challenging. Moreover, accessibility of NTM medications varies across centers. These challenges may lead to unplanned therapeutic changes, discontinuations, potentially affecting patient outcomes. Aim of this survey was to evaluate the accessibility of NTM-targeting drugs in Italy (with a particular focus on clofazimine) in centers associated with the IRENE Registry, a collaborative network of healthcare professionals. Methods A cross-sectional, internet-based, questionnaire-survey on the use and availability of clofazimineand other NTM-targeting drugs was sent to 88 principal investigators of the IRENE network in Italyin 2020. The questionnaires were designed with closed-ended and open-ended questions and distributed using the SurveyMonkey® platform. Results The surveys underscore the more frequent involvement of pulmonologists (42%) and infectious disease specialists (34%) in NTM treating strategies. Respondents were distributed across 18 out of20 Italian regions, with a significant concentration in the north, encompassing university hospitalsand outpatient clinics. Molecular testing is available in 40% of the involved centers, while phenotypic in 30% of the centers. Centers have a multidisciplinary team and an appointed pharmacy service for NTM drugs distribution in 10 and 75% of the cases, respectively. Substantial variability was observed in drug availability and accessibility, drug regimen composition, and drug dosage, particularly for medications like clofazimine. Conclusions This study shows the high heterogeneity of anti-NTM drug availability in Italy and prompts toward a harmonization in antibiotic prescription and access; it also emphasizes the challenges in determining the optimal therapeutic strategies for treating NTM-infections.

Background: Our aim was to describe the clinical outcome and safety of the sequential treatment with off-label dalbavancin in patients with spondylodiscitis that is caused by methicillin-resistant Staphylococcus aureus (MRSA). Methods: We retrospectively included all patients >18 years of age with spondylodiscitis that is caused by MRSA that was treated with dalbavancin from January 2018-January 2021, recording the instances of clinical cure/failure, adverse events, and the need to be re-hospitalized after the initiation of dalbavancin. In 2/15 patients, we performed therapeutic drug monitoring (TDM) for dalbavancin. Results: We included 15 patients, 53.3% of them were females, with a median age of 67.9 years (57.4-78.5); 100% patients reported back pain, while a fever was present only in 2/15 cases. The spondylodiscitis was localized in 86.6% cases at the lumbar level. A median of a 2-week in-hospital intravenous vancomycin was followed by dalbavancin with a median duration of 12 weeks (12-16). All patients reported a clinical cure, except for a woman who is still on a suppressive treatment. No patient needed to be re-hospitalized, access to emergency department, or experienced adverse events. The TDM for dalbavancin showed that more than 90% of the determinations were above the pharmacodynamic target against staphylococci. Conclusions: The results from our unique, even if it was small, cohort demonstrated that dalbavancin can be a safe/effective option as a sequential treatment in patients with serious infections requiring prolonged antibiotic therapy, such as spondylodiscitis.