Comparison of labio-palatal incisor movement between two wear protocols: a retrospective cohort study.

OBJECTIVES: To investigate the accuracy of the Invisalign appliance in achieving predicted angular tooth movement of the maxillary central incisors, to locate the center of rotation in a labio-palatal direction, and to investigate any difference between 1-weekly and 2-weekly wear protocols. MATERIALS AND METHODS: This study involved a retrospective sample of two groups of 46 Class I adult subjects treated non-extraction with different protocols of 1-weekly and 2-weekly wear. The pretreatment, predicted outcome and achieved outcome digital models were superimposed and measured using metrology software. Angular and center-of-rotation measurements in the sagittal plane for the maxillary right central incisor were analyzed. RESULTS: There was a statistically significant difference between predicted and achieved angular measurements (P < .005) for labial tooth movements regardless of wear protocol. For palatal movements, no statistically significant difference was observed (P > .05). A small amount of overexpression was observed in some cases. Regarding crown and root control, uncontrolled tipping was the most predictable. No statistically significant difference was found between predicted and achieved center of rotation, but the confidence interval was wide. No statistically significant difference (P > .05) was found between the two wear protocols for the parameters measured. CONCLUSIONS: For maxillary central incisors, labial angular movements were not as accurate as palatal movements. Overcorrection could be recommended with careful clinical monitoring due to the possibility of overexpression. Control of root movements may be unpredictable, and further research is required to draw stronger conclusions. For the parameters measured in this clinical sample, there was no difference between the two wear protocols.

CX3CR1 deficiency-induced TIL tumor restriction as a novel addition for CAR-T design in solid malignancies.

Advances in the understanding of the tumor microenvironment have led to development of immunotherapeutic strategies, such as chimeric antigen receptor T cells (CAR-Ts). However, despite success in blood malignancies, CAR-T therapies in solid tumors have been hampered by their restricted infiltration. Here, we used our understanding of early cytotoxic lymphocyte infiltration of human lymphocytes in solid tumors in vivo to investigate the receptors in normal, adjacent, and tumor tissues of primary non-small-cell lung cancer specimens. We found that CX3CL1-CX3CR1 reduction restricts cytotoxic cells from the solid-tumor bed, contributing to tumor escape. Based on this, we designed a CAR-T construct using the well-established natural killer group 2, member D (NKG2D) CAR-T expression together with overexpression of CX3CR1 to promote their infiltration. These CAR-Ts infiltrate tumors at higher rates than control-activated T cells or IL-15-overexpressing NKG2D CAR-Ts. This construct also had similar functionality in a liver-cancer model, demonstrating potential efficacy in other solid malignancies.

A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: The COVID-SED study.

BACKGROUND: Mechanically ventilated patients have experienced greater periods of prolonged deep sedation during the coronavirus disease (COVID-19) pandemic. Multiple studies from the pre-COVID era demonstrate that early deep sedation is associated with worse outcome. Despite this, there is a lack of data on sedation depth and its impact on outcome for mechanically ventilated patients during the COVID-19 pandemic. We sought to characterize the emergency department (ED) and intensive care unit (ICU) sedation practices during the COVID-19 pandemic, and to determine if early deep sedation was associated with worse clinical outcomes. STUDY DESIGN AND METHODS: Dual-center, retrospective cohort study conducted over 6 months (March-August, 2020), involving consecutive, mechanically ventilated adults. All sedation-related data during the first 48 h were collected. Deep sedation was defined as Richmond Agitation-Sedation Scale of - 3 to - 5 or Riker Sedation-Agitation Scale of 1-3. To examine impact of early sedation depth on hospital mortality (primary outcome), we used a multivariable logistic regression model. Secondary outcomes included ventilator-, ICU-, and hospital-free days. RESULTS: 391 patients were studied, and 283 (72.4%) experienced early deep sedation. Deeply sedated patients received higher cumulative doses of fentanyl, propofol, midazolam, and ketamine when compared to light sedation. Deep sedation patients experienced fewer ventilator-, ICU-, and hospital-free days, and greater mortality (30.4% versus 11.1%) when compared to light sedation (p < 0.01 for all). After adjusting for confounders, early deep sedation remained significantly associated with higher mortality (adjusted OR 3.44; 95% CI 1.65-7.17; p < 0.01). These results were stable in the subgroup of patients with COVID-19. CONCLUSIONS: The management of sedation for mechanically ventilated patients in the ICU has changed during the COVID pandemic. Early deep sedation is common and independently associated with worse clinical outcomes. A protocol-driven approach to sedation, targeting light sedation as early as possible, should continue to remain the default approach.

A Dual-Center Cohort Study on The Association Between Early Deep Sedation and Clinical Outcomes in Mechanically Ventilated Patients During the COVID-19 Pandemic: the COVID-SED Study.

Background : Mechanically ventilated patients have experienced greater periods of prolonged deep sedation during the coronavirus disease (COVID-19) pandemic. Multiple studies from the pre-COVID era demonstrate that early deep sedation is associated with worse outcome. Despite this, there is a lack of data on sedation depth and its impact on outcome for mechanically ventilated patients during the COVID-19 pandemic. We sought to characterize the emergency department (ED) and intensive care unit (ICU) sedation practices during the COVID-19 pandemic, and to determine if early deep sedation was associated with worse clinical outcomes. Study Design and Methods : Dual-center, retrospective cohort study conducted over six months (March - August, 2020), involving consecutive, mechanically ventilated adults. All sedation-related data during the first 48 hours were collected. Deep sedation was defined as Richmond Agitation-Sedation Scale of -3 to -5 or Riker Sedation-Agitation Scale of 1 - 3. To examine impact of early sedation depth on hospital mortality (primary outcome) we used a multivariable logistic regression model. Secondary outcomes included ventilator-, ICU-, and hospital-free days. Results : 391 patients were studied, and 283 (72.4%) experienced early deep sedation. Deeply sedated patients received higher cumulative doses of fentanyl, propofol, midazolam, and ketamine when compared to light sedation. Deep sedation patients experienced fewer ventilator-, ICU-, and hospital-free days, and greater mortality (30.4% versus 11.1%) when compared to light sedation ( p < 0.01 for all). After adjusting for confounders, early deep sedation remained significantly associated with higher mortality (adjusted OR 3.44; 95% CI 1.65 - 7.17; p <0.01). These results were stable in the subgroup of patients with COVID-19. Conclusions : The management of sedation for mechanically ventilated patients in the ICU has changed during the COVID pandemic. Early deep sedation is common and independently associated with worse clinical outcomes. A protocol-driven approach to sedation, targeting light sedation as early as possible, should continue to remain the default approach. Clinical Trial Registration : Not applicable.

Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis.

Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo. TGFß production by malignant megakaryocytes plays a definitive role promoting myelofibrosis in MPNs. However, TGFß was equally expressed by MSCs derived from MPLWT and MPLW515L expressing mice and the addition of neutralizing anti-TGFß antibody only partially reduced collagen secretion in vitro. Interestingly, profibrotic MSCs displayed increased levels of pSmad3 and pSTAT3 suggesting that inflammatory mediators cooperating with the TGFß-receptor signaling may maintain the aberrant phenotype ex vivo. FGFb is a known suppressor of TGFß signaling. Reduced collagen deposition by FGFb-treated MSCs derived from MPLW515L mice suggests that the activating pathway is vulnerable to this suppressive mediator. Therefore, our findings have implications for the future investigation of therapies to reverse fibrosis in MPNs.

Effectiveness of implant surface debridement using particle beams at differing air pressures.

Because implant surface decontamination is challenging, air powder abrasive systems have been suggested as an alternative debridement method. This in vitro study investigated the effectiveness of different powder formulations and air pressures in cleaning implant surfaces and the extent of surface damage. A validated ink model of implant biofilm was used. Sterile 4.1 × 10 mm Grade 4 titanium implants were coated in a blue indelible ink to form a uniform, visually detectable biofilm-like layer over the implant threads and mounted into a bone replica material with bony defects to approximate peri-implantitis. Air powder abrasive treatments were undertaken using glycine, sodium bicarbonate, or calcium carbonate powder at air pressures of 25, 35, 45, and 55 psi. Digital macro photographs of the threads were stitched to give composite images of the threads, so the amount of ink remaining could be quantified as the residual area and expressed as a percentage. Implant surfaces were also examined with scanning electron microscopy to grade the surface changes. No treatment cleaned all the surface of the threads. The powders were ranked in order of decreasing effectiveness and decreasing surface change into the same sequence of calcium carbonate followed by sodium bicarbonate followed by glycine. Higher air pressure improved cleaning and increased surface change, with a plateau effect evident. All powders caused some level of surface alteration, with rounding of surface projections most evident. With air powder abrasive systems, there is a trade-off between cleaning efficacy and surface damage. Using this laboratory model, sodium bicarbonate and calcium carbonate powders were the most effective for surface cleaning when used at air pressures as low as 25 psi.