Rezafungin Versus Caspofungin in a Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and Invasive Candidiasis: The STRIVE Trial.

BACKGROUND: Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). METHODS: Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. RESULTS: Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. CONCLUSIONS: RZF was safe and efficacious in the treatment of candidemia and/or IC. CLINICAL TRIALS REGISTRATION: NCT02734862.

Sequential chemo-hypofractionated RT versus concurrent standard CRT for locally advanced NSCLC: GRADE recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

INTRODUCTION: Almost 30% of non-small cell lung cancer (NSCLC) patients have locally advanced-stage disease. In this setting, definitive radiotherapy concurrent to chemotherapy plus adjuvant immunotherapy (cCRT + IO) is the standard of care, although only 40% of these patients are eligible for this approach. AIMS: A comparison between cCRT and hypofractionated radiotherapy regimens (hypo-fx RT) with the addition of sequential chemotherapy (sCHT) could be useful for future combinations with immunotherapy. We developed a recommendation about the clinical question of whether CHT and moderately hypo-fx RT are comparable to cCRT for locally advanced NSCLC MATERIALS AND METHODS: The panel used GRADE methodology and the Evidence to Decision (EtD) framework. After a systematic literature search, five studies were eligible. We identified the following outcomes: progression-free survival (PFS), overall survival (OS), freedom from locoregional recurrence (FFLR), deterioration of quality of life (QoL), treatment-related deaths, severe G3-G4 toxicity, late pulmonary toxicity G3-G4, and acute esophageal toxicity G3-G4. RESULTS: The probability of OS and G3-G4 late lung toxicity seems to be worse in patients submitted to sCHT and hypo-fx RT. The panel judged unfavorable the balance benefits/harms. CONCLUSIONS: The final recommendation was that sCHT followed by moderately hypo-fx RT should not be considered as an alternative to cCRT in unresectable stage III NSCLC patients.

Drug-Drug Interactions of Glecaprevir and Pibrentasvir Coadministered With Human Immunodeficiency Virus Antiretrovirals.

BACKGROUND: Treatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1-6 infection, including patients with HIV coinfection. METHODS: A series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure. RESULTS: Glecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents. CONCLUSIONS: Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients Coinfected With Hepatitis C Virus and Human Immunodeficiency Virus Type 1: The EXPEDITION-2 Study.

Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis. Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate. Results: In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment. Conclusions: Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir. Clinical trial registration: NCT02738138.

TURQUOISE-I Part 1b: Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with Ribavirin for Hepatitis C Virus Infection in HIV-1 Coinfected Patients on Darunavir.

Background: Ombitasvir/paritaprevir/ritonavir with dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) is approved for hepatitis C virus (HCV) genotype 1 (GT1) treatment in HIV-1 coinfected patients. In healthy controls, coadministration of OBV/PTV/r + DSV + darunavir (DRV) lowered DRV trough concentration (Ctrough) levels. To assess the clinical significance of this change, TURQUOISE-I, Part 1b, evaluated the efficacy and safety of OBV/PTV/r + DSV + RBV in coinfected patients on stable, DRV-containing antiretroviral therapy (ART). Methods: Patients were HCV treatment-naive or interferon-experienced, had CD4+ lymphocyte count ≥200 cells/µL or ≥14%, and plasma HIV-1 RNA suppression on once-daily (QD) DRV-containing ART at screening. Patients were randomized to maintain DRV 800 mg QD or switch to twice-daily (BID) DRV 600 mg; all received OBV/PTV/r + DSV + RBV for 12 weeks. Results: Twenty-two patients were enrolled and achieved SVR12. No adverse events led to discontinuation. Coadministration had minimal impact on DRV maximum observed plasma concentration and area under the curve; DRV Ctrough levels were slightly lower with DRV QD and BID. No patient experienced plasma HIV-1 RNA >200 copies/mL during treatment. Conclusions: HCV GT1/HIV-1 coinfected patients on stable DRV-containing ART achieved 100% SVR12 while maintaining plasma HIV-1 RNA suppression. Despite DRV exposure changes, episodes of intermittent HIV-1 viremia were infrequent.

Pharmacokinetic Evaluation of Darunavir Administered Once or Twice Daily in Combination with Ritonavir or the Three-Direct-Acting Antiviral Regimen of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir in Adults Coinfected with Hepatitis C and Human Immunodeficiency Viruses.

The three-direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin (RBV) is approved for treatment of hepatitis C virus (HCV) genotype 1 (GT1)/human immunodeficiency virus type 1 (HIV-1) coinfection. Results of a pharmacokinetic substudy of 3D and darunavir are presented. HCV/HIV-1-coinfected subjects were randomized to maintain an antiretroviral regimen with darunavir at 800 mg once daily (QD) or switched to a regimen with darunavir at 600 mg twice daily (BID). On study day 1, subjects received 3D and RBV plus darunavir for 12 weeks. Pharmacokinetic parameters were compared for darunavir and ritonavir with and without 3D (week 4 and day -1). Pharmacokinetic parameters of 3D were compared to historical data. Ten subjects received darunavir QD, and 12 subjects received darunavir BID. The central value ratios (90% confidence interval [CI]) for maximum concentrations (Cmax), area under the plasma concentration-time curve between 0 and 24 h postdose (AUC24), and trough plasma concentration at 24 h postdose (C24) of darunavir administered QD with 3D versus administration of darunavir alone were 0.92 (0.72, 1.18), 0.83 (0.71, 0.98), and 0.64 (0.44, 0.93), respectively. The ratios (90% CI) for darunavir Cmax, AUC12, and C12 administered BID with 3D were 0.92 (0.76, 1.12), 0.88 (0.73, 1.05), and 0.73 (0.58, 0.92), respectively. Exposures of 3D were similar to or slightly lower than those in historical data. All darunavir trough concentrations (Ctrough) associated with an HIV-1 RNA level of >40 copies/ml were above the darunavir 50% effective concentration (EC50) of 550 ng/ml for resistant virus. In conclusion, the 3D regimen with darunavir QD or BID did not affect darunavir Cmax and AUC, whereas the darunavir Ctrough decreased. Changes in pharmacokinetic parameters of 3D were not considered clinically significant. Episodes of intermittent HIV-1 viremia were infrequent and were not associated with darunavir Ctrough values below 550 ng/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT01939197.).

Estimation of patient setup uncertainty using BrainLAB Exatrac X-Ray 6D system in image-guided radiotherapy.

The purpose of this study was to evaluate setup uncertainties for brain sites with ExacTrac X-Ray 6D system and to provide optimal margin guidelines. Fifteen patients with brain tumor were included in this study. Two X-ray images with ExacTrac X-Ray 6D system were used to verify patient position and tumor target localization before each treatment. The 6D fusion software first generates various sets of DRRs with position variations in both three translational and three rotational directions (six degrees of freedom) for the CT images. Setup variations (translation and rotation) after correction were recorded and corrected before treatment. The 3D deviations are expressed as mean ± standard deviation. The random error (Σ(σi)), systematic error (µi), and group systematic error (M(µi)) for the different X-ray were calculated using the definitions of van Herk.(1) Mean setup errors were calculated from X-ray images acquired after all fractions. There is moderate patient-to-patient variation in the vertical direction and small variations in systematic errors and magnitudes of random errors are smaller. The global systematic errors were measured to be less than 2.0 mm in each direction. Random component of all patients are smaller ranging from 0.1-0.3 mm small. The safety margin (SM) to the lateral, is 0.5 mm and 2.6 mm for van Herk(1) and Stroom et al.,(2) respectively, craniocaudal axis is 1.5 mm and 3.4 mm, respectively, and with respect to the antero-posterior axis, 2.3 mm and 3.9 mm. Daily X-ray imaging is essential to compare and assess the accuracy of treatment delivery to different anatomical locations.

Fractionated stereotactic radiosurgery for patients with brain metastases.

Stereotactic radiosurgery (SRS) delivered in 2-5 fractions (multi-fraction SRS) has been employed in patients with brain metastases as an alternative to single-fraction SRS with the aim to reduce late radiation-induced toxicity while maintaining high local control rate. In the present study we have evaluated the efficacy and toxicity of multi-fraction SRS in patients with 1-3 brain metastases. Between March 2006 and October 2012, 135 patients (63 men and 72 women) with 171 brain metastases have been treated with multi-fraction SRS (3 × 9 Gy or 3 × 12 Gy). At a median follow-up of 11.4 months, 16 lesions recurred locally. The 1- and 2-year local control rates were 88 and 72 %, respectively. The 1- and 2-year survival rates were 57 and 25 %, and respective distant failure rates were 52 and 73 %. Seventy-eight percent of patients succumbed to their extracranial disease and 22 % died of progressive intracranial disease. Multivariate analysis showed that melanoma histology was predictive of local failure (p = 0.02; HR 6.1, 95 % CI 1.5-24). Specifically, the 1-year local control rates were 68 % for melanoma, 92 % for breast carcinoma, and 88 % for NSCLC, respectively. Stable extracranial disease (p = 0.004) and Karnofsky performance status (p = 0.01) were predictive of longer survival. Radiologic changes suggestive of radionecrosis occurred in 12 (7 %) out of 171 lesions, with an actuarial risk of 9 % at 1 year and 17 % at 2 years, respectively. In conclusion, multi-fraction SRS appears to be an effective and safe treatment modality for brain metastases. It may represent an alternative to single-dose SRS for patients with large lesions or lesions located near critical structures.

Fe-Ni porphyrin/mesoporous titania thin film electrodes: a bioinspired nanoarchitecture for photoelectrocatalysis.

Porphyrin and porphyrinoid derivatives have been extensively studied in the assembly of catalysts and sensors, seeking biomimetic and bioinspired activity. In particular, Fe and Ni porphyrins can be used for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) by immobilization of these molecular catalysts on semiconductor materials. In this study, we designed a hybrid material containing a crystalline mesoporous TiO2 thin film in which the catalytic centres are Ni-porphyrin (NiP), Fe-porphyrin (FeP), and a NiP/FeP bimetallic system to assess whether the coexistence of both metalloporphyrins improves the OER activity. The obtained photoelectrodes were physicochemically and morphologically characterized through high-resolution FE-SEM images, UV-vis and Raman spectroscopies, cyclic voltammetry, and impedance measurements. The results show a differential behavior of the mono- and bimetallic porphyrin systems, where the Fe(iii) centre in FeP may increase the acidity and lower the reduction potential of the Ni2+/3+ couple when co-deposited with NiP leading to an improved photoelectrochemical water-oxidation performance. We have validated the cooperative effect of both metal complexes within this novel system, where the µ-peroxo-bridged interaction between Fe and Ni is integrated into a supramolecular heterometallic structure of porphyrins.

Dynomics: A Novel and Promising Approach for Improved Breast Cancer Prognosis Prediction.

Traditional imaging techniques for breast cancer (BC) diagnosis and prediction, such as X-rays and magnetic resonance imaging (MRI), demonstrate varying sensitivity and specificity due to clinical and technological factors. Consequently, positron emission tomography (PET), capable of detecting abnormal metabolic activity, has emerged as a more effective tool, providing critical quantitative and qualitative tumor-related metabolic information. This study leverages a public clinical dataset of dynamic 18F-Fluorothymidine (FLT) PET scans from BC patients, extending conventional static radiomics methods to the time domain-termed as 'Dynomics'. Radiomic features were extracted from both static and dynamic PET images on lesion and reference tissue masks. The extracted features were used to train an XGBoost model for classifying tumor versus reference tissue and complete versus partial responders to neoadjuvant chemotherapy. The results underscored the superiority of dynamic and static radiomics over standard PET imaging, achieving accuracy of 94% in tumor tissue classification. Notably, in predicting BC prognosis, dynomics delivered the highest performance, achieving accuracy of 86%, thereby outperforming both static radiomics and standard PET data. This study illustrates the enhanced clinical utility of dynomics in yielding more precise and reliable information for BC diagnosis and prognosis, paving the way for improved treatment strategies.

Clinical and Radiographic Outcomes of Repair of Spondylolitic Spondylolisthesis via Direct Pars Repair.

STUDY DESIGN: A retrospective chart review. OBJECTIVE: The objective of this study is to investigate whether direct pars repair achieves bone healing and symptom relief in patients with spondylolitic spondylolisthesis. SUMMARY OF BACKGROUND DATA: While most cases of spondylolysis can be managed non-operatively, a small percentage of patients require surgical intervention. The outcome of direct pars repair via a standard pedicle-screw with wiring technique is controversial in patients with lumbar spondylolitic spondylolisthesis. METHODS: Medical records of patients who had undergone an open surgical pars repair were retrospectively reviewed. Standard demographic and surgical parameters were collected. All patients underwent a primary repair of the pars with autograft or bone morphogenetic protein and instrumentation using a pedicle-screw with spinous process wiring. At 6-12 months after surgery, patient's pain symptoms and postoperative CT scans were independently reviewed to assess healing; graded as non-union, partial union, or solid union. RESULTS: There were 68 patients identified (33 male and 35 female) with an average age of 18.6 years. Mean estimated blood loss was 139 ml, and mean length of hospital stay was 3.7 days. CT evaluation revealed 35 (52%) solid unions, 21 (31%) partial unions, and 12 (18%) non-unions requiring revisions. Thirty-four (50%) patients had no postop pain, 24 (35%) had mild pain, 10 (15%) had persistent pain. The majority of patients with non-unions on CT had mild or persistent pain. Patients with no or mild pain tended to be younger than those with persistent pain (17.5 years vs 24.6 years, P=0.163). CONCLUSION: This study demonstrated a partial or complete union rate of 82% and a postoperative persistent pain rate of 15%. These figures are comparable to the previous study and this pedicle-screw with wiring technique can be worth trying before interbody fusion for spondylolytic spondylolisthesis to preserve anatomical lumbar motion.

Sunlight-Driven Photocatalysis for a Set of 3D Metal-Porphyrin Frameworks Based on a Planar Tetracarboxylic Ligand and Lanthanide Ions.

Metal-porphyrin frameworks (MPFs) with trivalent lanthanide ions are the most sought-after materials in the past decade. Their porosities are usually complemented by optical properties imparted by the metal nodes, making them attractive multifunctional materials. Here, we report a novel family of 3D MPFs obtained through solvothermal reactions between tetrakis(4-carboxyphenyl) porphyrin (H4TCPP) and different lanthanide sources, yielding an isostructural family of compounds along the lanthanide series: [Ln2(DMF)(TCPP)1.5] for Ln = La, Ce, Nd, Pr, Er, Y, Tb, Dy, Sm, Eu, Gd, and Tm. Photoluminescent properties of selected phases were explored at room temperature. Also, the photocatalytic performance exhibited by these compounds under sunlight exposure is promising for its implementation in organic pollutant degradation. In order to study the photocatalytic activity of Ln-TCPPs in an aqueous medium, methylene blue (MB) was used as a contaminant model. The efficiency for MB degradation was Sm > Y > Yb > Gd > Er > Eu > either no catalyst or no light, obtaining more than 70% degradation at 120 min with Sm-TCPP. These results open the possibility of using these compounds in optical and optoelectronic devices for water remediation and sensing.

Untailored vs. Gender- and Body-Mass-Index-Tailored Skeletal Muscle Mass Index (SMI) to Assess Sarcopenia in Advanced Head and Neck Squamous Cell Carcinoma (HNSCC).

(1) Background: Sarcopenia lasting >1 year might be considered a chronic condition in many HNSCC patients. CT-scan-derived Skeletal Muscle Mass Index (SMI) is an established surrogate of sarcopenia; yet, the cut-off reported in the literature (literature-based, lb-SMI < 43.2) is mainly based on the risk of chemoradiotherapy-induced toxicity, and the optimal value to discriminate OS is under-investigated. (2) Methods: The effect on OS of the lb-SMI cutoff was compared with an untailored OS-oriented SMI cutoff obtained in a cohort of consecutive advanced HNSCC patients treated with primary chemoradiotherapy, bio-chemotherapy or chemo-immunotherapy (cohort-specific, cs-SMI cutoff). Gender- and BMI-tailored (gt-SMI and bt-SMI) cut-offs were also evaluated. Cutoff values were identified by using the maximally selected rank statistics for OS. (3) Results: In 115 HNSCC patients, the cs-SMI cutoff was 31.50, which was lower compared to the lb-SMI reported cut-off. The optimal cut-off separately determined in females, males, overweight and non-overweight patients were 46.02, 34.37, 27.32 and 34.73, respectively. gt-SMI categorization had the highest effect on survival (p < 0.0001); its prognostic value was independent of the treatment setting or the primary location and was retained in a multivariate cox-regression analysis for OS including other HNSCC-specific prognostic factors (p = 0.0004). (4) Conclusions: A tailored SMI assessment would improve clinical management of sarcopenia in chemoradiotherapy-, bio-chemotherapy- or chemo-immunotherapy-treated HNSCC patients. Gender-based SMI could be used for prognostication in HNSCC patients.

Breast Volume Is a Predictor of Higher Heart Dose in Whole-Breast Supine Free-Breathing Volumetric-Modulated Arc Therapy Planning.

In breast cancer volumetric-modulated arc therapy (VMAT) planning, the rotation of the gantry around the target implies a greater dose spreading to the whole heart, compared to tangential-field standard treatment. A consecutive cohort of 121 breast cancer patients treated with the VMAT technique was investigated. The correlation of breast volume, heart volume and lung volume with mean heart dose (mHD) and mean and maximum LAD dose (mLAD dose, MLAD dose) was tested, and a subsequent a linear regression analysis was carried out. VMAT treatment plans from 56 left breast cancer and 65 right breast cancer patients were analyzed. For right-sided patients, breast volume was significantly correlated with mHD, mLAD and MLAD dose, while for left-sided patients, breast volume was significantly correlated with mHD and mLAD, while heart volume and lung volume were correlated with mHD, mLAD and MLAD dose. Breast volume was the only predictor of increased heart and LAD dose (p ≤ 0.001) for right-sided patients. In left-sided patients, heart and lung were also predictors of increased mHD (p = 0.005, p ≤ 0.001) and mean LAD dose (p = 0.009, p ≤ 0.001). In this study, we observed an increase in heart and LAD doses in larger-breasted patients treated with VMAT planning. In right-sided patients, breast volume was shown to be the only predictor of increased heart dose and LAD dose.

Outpatient Treatment with AZD7442 (Tixagevimab/Cilgavimab) Prevented COVID-19 Hospitalizations over 6 Months and Reduced Symptom Progression in the TACKLE Randomized Trial.

INTRODUCTION: We assessed effects of AZD7442 (tixagevimab/cilgavimab) on deaths from any cause or hospitalizations due to coronavirus disease 2019 (COVID-19) and symptom severity and longer-term safety in the TACKLE adult outpatient treatment study. METHODS: Participants received 600 mg AZD7442 (n = 452) or placebo (n = 451) ≤ 7 days of COVID-19 symptom onset. RESULTS: Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 (key secondary endpoint) occurred in 20/399 (5.0%) participants receiving AZD7442 versus 40/407 (9.8%) receiving placebo [relative risk reduction (RRR) 49.1%; 95% confidence interval (CI) 14.5, 69.7; p = 0.009] or 50.7% (95% CI 17.5, 70.5; p = 0.006) after excluding participants unblinded before day 169 for consideration of vaccination). AZD7442 reduced progression of COVID-19 symptoms versus placebo through to day 29 (RRR 12.5%; 95% CI 0.5, 23.0) and improved most symptoms within 1-2 weeks. Over median safety follow-up of 170 days, adverse events occurred in 174 (38.5%) and 196 (43.5%) participants receiving AZD7442 or placebo, respectively. Cardiac serious adverse events occurred in two (0.4%) and three (0.7%) participants receiving AZD7442 or placebo, respectively. CONCLUSIONS: AZD7442 was well tolerated and reduced hospitalization and mortality through 6 months, and symptom burden through 29 days, in outpatients with mild-to-moderate COVID-19. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04723394. ( https://beta. CLINICALTRIALS: gov/study/NCT04723394 ).

Antibodies are proteins produced by the body's immune system to specifically combat foreign substances, such as viruses. Tixagevimab and cilgavimab are a pair of antibodies that bind to a specific part of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). When they bind to the virus, they reduce its ability to cause disease. These antibodies were tested in a clinical trial to see if they could prevent people with COVID-19 from being hospitalized or dying. Around 900 adults took part in this clinical trial. These people all had COVID-19 but were not sick enough to be in hospital. Half of this group were treated with a dose of tixagevimab and cilgavimab, given as two injections. The other half received a placebo (injections that look exactly like the tixagevimab and cilgavimab injections but contain no medicine). The study found that, over 6 months, people with COVID-19 who received tixagevimab and cilgavimab were less likely to need to go to hospital than people who received the placebo. They were also less likely to die of COVID-19. Tixagevimab and cilgavimab also helped to improve COVID-19 symptoms. People who received the antibodies saw their symptoms improve faster than people who received the placebo. They were also less likely to have symptoms that got worse. Most people felt better within 1­2 weeks of getting treatment. No safety issues were found with tixagevimab and cilgavimab compared with placebo.

Association of Dry Eye with Laryngopharyngeal Reflux in Clinical Practice.

BACKGROUND: Dry eye disease (DED) is a common disorder, accounting for up to 35% of the general population. Therefore, we hypothesized that laryngopharyngeal reflux (LPR), inducing refluxate rising into airways, may involve the ocular surface and may either induce or worsen DED. AIM: To investigate the prevalence and relevance of suspected LPR in DED patients and subjects with refractive problems (RP) without DED, they were defined as non-dry eye group (NEG) in clinical practice. METHODS: This retrospective study included consecutive patients evaluated because of dry eye-like symptoms at eight tertiary ophthalmological clinics. Parameters included reflux symptom index (RSI), ocular surface disease index (OSDI), symptom assessment in dry eye (SANDE) for frequency and severity, Schirmer test, tear break-up time (BUT), and Oxford grading. RESULTS: The study included 245 subjects (72.5% females; mean age 56.3 years), 152 DED patients, and 93 sex- and age-matched NEG subjects. Pathological RSI (score>13) was detected in 80 subjects (32.6%); 68 (85%) with DED and 12 (15%) CG (OR = 8; p < .0001). In NEG, pathological RSI was associated with higher SANDE (Frequency and Severity), OSDI, and Schirmer scores (OR = 16.36; 14.51; 12.54; and 7.22, respectively. In DED patients, pathological RSI was associated with higher OSDI values (OR = 8.75). CONCLUSION: Patients with DED are at eight times higher risk for having pathological RSI than NEG patients. Moreover, pathological RSI was associated with more severe ocular symptoms both in DED and non-DED patients. The role of LPR in definite DED patients remains to be clarified, but this condition deserves to be investigated in managing patients with DED symptoms.

Pseudotumor Cerebri Syndrome Without Headache in an Obese Male With Eight Restricted Cerebrospinal Fluid (CSF) Oligoclonal Bands: A Case Report.

Pseudotumor cerebri syndrome (PTCS) is a condition caused by an abnormal elevation of intracranial pressure (ICH), which may be primary (idiopathic intracranial hypertension) or because of an identifiable secondary cause. We present a rare case of an obese male who complained of gradual bilateral vision loss for one year without headaches and tinnitus. On fundoscopy, he had high-grade bilateral papilledema and, on lumbar puncture, he had an elevated intracranial pressure of 260 mmH2O. Cerebrospinal fluid (CSF) was unique for eight restricted oligoclonal bands while extensive other demyelinating workup was negative. He was started on acetazolamide initially and subsequently proceeded with bilateral optic nerve sheath fenestration (ONSF) with mild improvement in the right eye and no improvement in the left eye. Although the causative mechanism of PTCS is a matter of debate, immune-mediated processes are one of the proposed mechanisms that may play a role in the pathophysiology of PTCS, evidenced by the presence of oligoclonal bands (OCBs) and pro-inflammatory markers in CSF. PTCS diagnosed in men and patients with OCBs poses an increased risk of vision loss as this case and literature documented. Therefore, prompt treatment through therapeutic lumbar punctures, acetazolamide therapy concurrently with weight loss, and surgical intervention in severe or refractory cases are necessary.

Miller Fisher Syndrome Presenting Without Areflexia, Ophthalmoplegia, and Albuminocytological Dissociation: A Case Report.

Miller Fisher syndrome (MFS) is a rare variant of Guillain-Barré syndrome (GBS) with a prevalence of one to two people per million each year. Viral and/or bacterial infection often precedes the classic triad of areflexia, ophthalmoplegia, and ataxia. Bulbar involvement is uncommon but can lead to extensive workup to rule out stroke, myasthenia gravis (MG), and other neuromuscular disorders. We present a case of a 32-year-old healthy male with a past medical history of Lyme disease as a teenager and sore throat two weeks prior. He presented to the hospital with rapidly ascending paresthesias in bilateral upper and lower extremities, urinary incontinence, and mild slurred speech. Exam on presentation revealed mild dysmetria in bilateral upper and lower limbs. The remainder of the exam was negative. Neuroradiological imaging, including magnetic resonance imaging (MRI) with and without contrast of the brain and the cervical and lumbar spine, did not show any acute process or abnormal enhancement. Lumbar puncture revealed cerebrospinal fluid (CSF) with normal protein and cell count, and hence no albuminocytological dissociation (ACD). Immunoserology was positive for Epstein-Barr virus (EBV) immunoglobulin G (IgG) but negative for immunoglobulin M (IgM). Despite the absent ACD, areflexia, and no third, fourth, and sixth cranial nerve deficits, there was high suspicion for GBS due to acutely rapid ascending paresthesia, mild dysarthria, and mild ataxia. The patient was started on intravenous immunoglobulin (IVIG) 2 mg/kg divided into five days within 24 hours of admission. The patient developed areflexia in all limbs on the second day of admission and complained of double vision. On the third day of admission, the patient's negative respiratory force (NIF) declined to -23, and he was intubated for airway protection. Our patient completed five days of IVIG. Positive anti-GQ1b antibodies further supported the diagnosis of MFS. After a seven-day ICU stay and 20 days of aggressive inpatient rehabilitation, the patient could do most of the activities of daily living independently. After six weeks, he was back to his normal baseline and restarted his job.

Total neoadjuvant therapy for the treatment of locally advanced rectal cancer: a systematic minireview.

Colorectal carcinoma is the second leading cause of cancer-related deaths, and indeed, rectal cancer accounting for approximately one third of newly diagnosed patients. Gold standard in the treatment of rectal cancer is a multimodality approach, aiming at a good control of the local disease. Distant recurrences are the major cause of mortality. Currently, Locally Advanced Rectal Cancer (LARC) patients undergo a combined treatment of chemotherapy and radiotherapy, followed by surgery. Eventually, more chemotherapy, namely adjuvant chemotherapy (aCT), may be necessary. Total Neoadjuvant Therapy (TNT) is an emerging approach aimed to reduce distant metastases and improve local control. Several ongoing studies are analyzing whether this new approach could improve oncological outcomes. Published results were encouraging, but the heterogeneity of protocols in use, makes the comparison and interpretation of data rather complex. One of the major concerns regarding TNT administration is related to its effect on larger and more advanced cancers that might not undergo similar down-staging as smaller, early-stage tumors. This minireview, based on a systematic literature search of randomized clinical trials and meta-analysis, summarizes current knowledge on TNT. The aim was to confirm or refute whether or not current practice of TNT is based on relevant evidence, to establish the quality of that evidence, and to address any uncertainty or variation in practice that may be occurring. A tentative grouping of general study characteristics, clinical features and treatments characteristics has been undertaken to evaluate if the reported studies are sufficiently homogeneous in terms of subjects involved, interventions, and outcomes to provide a meaningful idea of which patients are more likely to gain from this treatment.