Geometric Cuts by an Autonomous Laser Osteotome Increase Stability in Mandibular Reconstruction With Free Fibula Grafts: A Cadaver Study.

BACKGROUND: Nonunion and plate exposure represent a major complication after mandibular reconstruction with free fibula flaps. These drawbacks may be resolved by geometric osteotomies increasing intersegmental bone contact area and stability. PURPOSE: The aim of this study was to compare intersegmental bone contact and stability of geometric osteotomies to straight osteotomies in mandibular reconstructions with free fibula grafts performed by robot-guided erbium-doped yttrium aluminum garnet laser osteotomy. STUDY DESIGN, SETTING, SAMPLE: This cadaveric in-vitro study was performed on fresh frozen human skull and fibula specimens. Computed tomography (CT) scans of all specimens were performed for virtual planning of mandibular resections and three-segment fibula reconstructions. The virtual planning was implemented in a Cold Ablation Robot-guided Laser Osteotome. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: For predictor variables, straight and geometric puzzle-shaped osteotomies were designed at resection of the mandible and corresponding fibula reconstruction. MAIN OUTCOME VARIABLES: The primary outcome variable was the stability of the reconstructed mandible investigated by shearing tests. Moreover, secondary outcome variables were the duration of the laser osteotomies, the contact surface area, and the accuracy of the reconstruction, both evaluated on postsurgical CT scans. COVARIATES: Covariables were not applicable. ANALYSES: Data were reported as mean values (± standard deviation) and were statistically analyzed using an independent-sample t-test at a significance level of α = 0.05. Root mean square deviation was tested for accuracy. RESULTS: Eight skulls and 16 fibula specimens were used for the study. One hundred twelve successful laser osteotomies (96 straight and 16 geometrical) could be performed. Geometric osteotomies increased stability (110.2 ± 36.2 N vs 37.9 ± 20.1 N, P < .001) compared to straight osteotomies. Geometric osteotomy of the fibula took longer than straight osteotomies (10.9 ± 5.1 min vs 5.9 ± 2.2 min, P = .028) but could provide larger contact surface (431.2 ± 148.5 mm2 vs 226.1 ± 50.8 mm2, P = .04). Heat map analysis revealed a mean deviation between preoperational planning and postreconstructive CT scan of -0.8 ± 2.4 mm and a root mean square deviation of 2.51 mm. CONCLUSION AND RELEVANCE: Mandibular resection and reconstruction by fibula grafts can be accurately performed by a Cold Ablation Robot-guided Laser Osteotome without need for cutting guides. Osteotomy planning with geometric cuts offers higher stability and an increased bone contact area, which may enhance healing of the reconstructed mandible.

Molnupiravir is effective in patients with haematological malignancies.

Patients with hematologic malignancies are particularly vulnerable to severe infectious complications. SARS-CoV-2 infection is associated with a high risk of severe course and death in this patient population. In addition, immune deficits associated with both the blood cancer and the treatment used make vaccination against SARS-CoV-2 less effective than in immunocompetent individuals. Molnupiravir is one of the first oral antiviral drugs to demonstrate a significant benefit in reducing hospitalisation and death in COVID-19 in the general population. In this context, 175 haematology patients with diagnosed COVID-19, and treated with MOL between January and April 2022, came under our scrutiny with a view to defining their clinical characteristics and outcomes. The most common underlying conditions were lymphomas (45%), multiple myelomas (21%) and acute leukaemias or myelodysplastic syndrome (35%). Of all, 77% of the patients were vaccinated, and half of them received a booster. At 28 days after the breakthrough COVID-19 diagnosis, 35 (20%) subjects required hospital admission. Out of those patients, seven (4%) died during the follow-up due to the progression of COVID. Our results corroborate what has been established to date with regard to the positive clinical and safety outcomes of MOL in haematology patients with mild or moderate COVID-19.

Clinical efficacy and tolerability of venetoclax plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia-a real-world analysis of the Polish Adult Leukemia Study Group.

The results of the MURANO trial showed encouraging progression-free survival (PFS) and overall survival (OS) in relapsed/refractory chronic lymphocytic leukemia (RR-CLL) patients treated with venetoclax-rituximab (VEN-R). A retrospective analysis was performed to evaluate the efficacy and safety of VEN-R within the Polish Adult Leukemia Study Group (PALG) centers. The study group included 117 patients with RR-CLL (with early relapse after immunochemotherapy or bearing TP53 aberrations) treated with VEN-R in 2019-2023 outside clinical trials. Patients were treated with a median of 2 (range 1-9) previous lines of therapy. Twenty-two participants were previously treated with BTKi (18.8% out of 117). The median follow-up was 20.3 months (range 0.27-39.1). The overall response rate (ORR) was 95.3% in the group of patients in whom a response to treatment was assessed and 86.3% for all patients. Twenty patients (17.1% out of 117) achieved a complete response (CR), 81 (69.2%) achieved a partial response (PR), and in 5 patients (4.3%), disease progression was noted (assessed as the best response during treatment). The median PFS in the whole cohort was 36.97 (95% CI 24.5, not reached) months, and the median OS was not reached (95% CI 27.03, not reached). Thirty-six patients died during the follow-up, 10 (8.5%; 27.8% of deaths) due to COVID-19 infection. All grade neutropenia (n = 87/117, 74.4%; grade 3 or higher n = 67/117, 57.3%) was the most common treatment adverse event. Forty-five patients (38.5%) remained on treatment, and twenty-two (18.8%) completed 24 months of therapy, while it was discontinued in fifty cases (42.7%). In this real-world setting of early access in very high-risk RR-CLL patients, the VEN-R regimen was associated with shorter median PFS compared with the results of the MURANO trial. This outcome, however, could be attributed to patients' exposure to SARS-CoV-2 infection and the aggressive course of the disease as very high-risk patients, after multiple lines of prior therapies, were included in the Polish Ministry of Health reimbursement program.

Down-phase auditory stimulation is not able to counteract pharmacologically or physiologically increased sleep depth in traumatic brain injury rats.

Modulation of slow-wave activity, either via pharmacological sleep induction by administering sodium oxybate or sleep restriction followed by a strong dissipation of sleep pressure, has been associated with preserved posttraumatic cognition and reduced diffuse axonal injury in traumatic brain injury rats. Although these classical strategies provided promising preclinical results, they lacked the specificity and/or translatability needed to move forward into clinical applications. Therefore, we recently developed and implemented a rodent auditory stimulation method that is a scalable, less invasive and clinically meaningful approach to modulate slow-wave activity by targeting a particular phase of slow waves. Here, we assessed the feasibility of down-phase targeted auditory stimulation of slow waves and evaluated its comparative modulatory strength in relation to the previously employed slow-wave activity modulators in our rat model of traumatic brain injury. Our results indicate that, in spite of effectively reducing slow-wave activity in both healthy and traumatic brain injury rats via down-phase targeted stimulation, this method was not sufficiently strong to counteract the boost in slow-wave activity associated with classical modulators, nor to alter concomitant posttraumatic outcomes. Therefore, the usefulness and effectiveness of auditory stimulation as potential standalone therapeutic strategy in the context of traumatic brain injury warrants further exploration.

Reasons and consequences of COVID-19 vaccine failure in patients with chronic lymphocytic leukemia.

People with hematologic malignancies are at a high risk of morbidity and mortality from COVID-19. The response to vaccination is highly limited in patients with chronic lymphocytic leukemia. Less than half of the patients develop antibody response, suggesting that they remain at risk of SARS-CoV-2 infection even after the vaccination. Reasons for inadequate response to COVID-19 vaccination in chronic lymphocytic leukemia are multifactorial and attributed to disease-related immune dysregulation and patient- and therapy-related factors. The negative predictors of response to vaccination include hypogammaglobulinemia, advanced age, current active treatment, and past treatment anti-CD20 monoclonal antibodies. Despite using booster doses and heterologous immunization to improve humoral and cellular immunity, some patients with chronic lymphocytic leukemia will fail to respond. Active treatment at the time of vaccination and a recent history of anti-CD20 monoclonal antibodies use are the strongest predictors of the non-response. Current data support informing patients with chronic lymphocytic leukemia and other hematologic malignancies about the risk of infection regardless of vaccination. These individuals and members of their households should continue extreme preventive actions despite relaxed local regulations. Other emerging non-vaccine preventive strategies include passive and post-exposure prevention with monoclonal antibodies.

Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Effect of New Thiophene-Derived Aminophosphonic Derivatives on Growth of Terrestrial Plants. Part 2. Their Ecotoxicological Impact and Phytotoxicity Test Toward Herbicidal Application in Agriculture.

Background: The aim of this work was to evaluate phytotoxicity of the thiophene derivatives against three persistent weeds of a high degree of resistance (Galinsoga parviflora Cav., Rumex acetosa L., and Chenopodium album) as well as their ecotoxicological impact on Heterocypris incongruens. In addition, Aliivibrio fischeri was measured. Two of eight described aminophosphonates, namely dimethyl N-(2-methoxyphenyl)amino(2-thienyl)methylphosphonate (2d) and dimethyl N-(tert-butyl)- (2-thienyl)methylphosphonate (2h), have never been reported before. Methods: The phytotoxicity of tested aminophosphonates toward their potential application as soil-applied herbicides was evaluated according to the OECD 208 Guideline. Ecotoxicological properties of investigated compounds were made using the OSTRACODTOXKITTM and Microtox® tests. Results: Obtained results showed that four aminophosphonates have interesting herbicidal properties and N-(2-methylphenyl)amino- (2-thienyl)methylphosphonate (2a) was found to kill efficiently the most resistant plant Chenopodium album. None of the tested compounds showed important toxicity against Aliivibrio fischeri. However, their toxic impact on Heterocypris incongruens was significantly elevated. Conclusions: The aminophosphonate 2a showed herbicidal potential and it is not toxic against tested bacteria (EC50 over 1000 mg/L). It was found to be moderately toxic against ostracods [mortality 48% at 10 mg/kg of soil dry weight (s.d.w.)] and this problem should be solved by the use of the controlled release from a polymeric carrier.

Sleep Modulation Alleviates Axonal Damage and Cognitive Decline after Rodent Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It produces diffuse axonal injury (DAI), which contributes to cognitive impairment, but effective disease-modifying treatment strategies are missing. We have recently developed a rat model of closed skull TBI that reproduces human TBI consequences, including DAI and clinical sequelae such as memory impairment. Here, we investigated whether sleep modulation after trauma has an impact on DAI and memory outcome. We assessed cognition with the novel object recognition test and stained for amyloid precursor protein, a DAI marker. We found that both sleep induction and restriction acutely after TBI enhanced encephalographic slow-wave activity, markedly reduced diffuse axonal damage in the cortex and hippocampus, and improved memory impairment 2 weeks after trauma. These results suggest that enhancing slow-wave sleep acutely after trauma may have a beneficial disease-modifying effect in subjects with acute TBI. SIGNIFICANCE STATEMENT: Traumatic brain injury (TBI) is a clinically important entity. Cognitive deficits belong to the most prevalent chronic posttraumatic symptoms, most likely due to diffuse axonal injury (DAI). A growing body of evidence suggests a role of sleep in the clearance of waste products in the brain, possibly including amyloid precursor protein (APP), a marker of DAI. In this study, we provide evidence that enhancement of slow-wave oscillatory activity in the delta-frequency range decreases the APP-immunoreactivity and preserves cognitive abilities after trauma, potentially offering novel, noninvasive treatment options for traumatic injury.

Evaluation of ecotoxicological impact of new pyrrole-derived aminophosphonates using selected bioassay battery.

Six new dimethyl N-arylamino(2-pyrrolyl)methylphosphonates 2a-f were synthesized by the modified aza-Pudovik reaction. Their ecotoxicological impact using battery of bioassay was assessed using Microtox and Ostracodtoxit tests as well as phytotoxicity towards two plants, dicotyledonous radish (Raphanus sativus) and monocotyledonous oat (Avena sativa) following the OECD 208 Guideline. Ecotoxicological properties of compounds 2a-f in aspect of acute and chronic toxicity were evaluated using Heterocypris incongruens and Aliivibrio fisheri tests. The obtained results showed that tested aminophosphonates 2a-f have moderate-to-high phyto- and ecotoxicological impact. They are toxic for both plants but more toxic against dicotyledonous. The investigated compounds showed important ecotoxicity against Heterocypris incongruens crustaceans and Aliivibrio fisheri bacteria. It was found that the substituents of the phenyl ring plays a key role in the degree of toxicity. Results showed that investigated compounds are ecologically toxic and that any of their application should be implemented with care.

Novel N-Arylaminophosphonates Bearing a Pyrrole Moiety and Their Ecotoxicological Properties.

A wide range of biological activities of aminophosphonates predisposes them to find applications as anticancer, antiviral, antimicrobial, antifungal, or herbicidal agents. Despite a number of positive aspects of the use of aminophosphonates, their applications may cause a risk to the environment, which is well exemplified by the case of glyphosate. Therefore, scientists see a pressing need to rate ecotoxicity of aminophosphonates. Nowadays, it is recommended to use comprehensive tools to carry out appropriate and effective risk assessments of toxic substances. For these purposes, tests based on the acute toxicity of the luminescent bacteria Aliivibrio fischeri, as well as the measurement of sub-chronic toxicity of the crustacean Heterocypris incongruens seem to be the most convenient. A series of five diphenyl N-arylamino(pyrrole-2-yl)methylphosphonates was synthesized and preliminary evaluation of their ecotoxicological properties was performed. In order to carry out such investigations, we applied the two biotests mentioned above. Results showed that the N-(4-nitrophenyl) derivative was the most toxic for bacteria in comparison to other tested compounds. As for crustaceans, N-phenyl and N-naphthyl derivatives were found to be the most harmful, simultaneously being relatively harmless for bacteria. Such a phenomenon are discussed in correlation with the literature, while its reason is discussed with respect to the aspect of structure of the tested compounds.

The Effect of New Thiophene-Derived Aminophosphonic Derivatives on Growth of Terrestrial Plants: A Seedling Emergence and Growth Test.

The aim of this work was to synthesize selected thiophene-derived aminophosphonic systems and evaluate the phytotoxicity of newly obtained products according to the OECD 208 Guideline. Seven new thiophene-derived N-substituted dimethyl aminomethylphosphonic acid esters 2a-h were synthesized by the addition of an appropriate phosphite to azomethine bond of starting Schiff bases 1a-h, and NMR spectroscopic properties of aminophosphonates were investigated. These eight compounds were analyzed in regard to their phytotoxicity towards two plants, radish (Raphanus sativus) and oat (Avena sativa). On the basis of the obtained results, it was found that tested aminophosphonates 2a-h showed an ecotoxicological impact against selected plants, albeit to various degrees.

Therapy-related peripheral neuropathy in multiple myeloma patients.

This review discusses the most common issues concerning multiple myeloma (MM)-related peripheral neuropathy (PN). This is an important MM complication, observed in up to 54% of newly diagnosed patients, caused by the disease itself or its treatment. Although its aetiology is largely unknown, a number of mechanisms are suspected. It is important to know the neurological status of a patient, as many new antimyeloma medicines can trigger or exacerbate any pre-existing neuropathy. Examples include thalidomide-induced and bortezomib-induced PN (TiPN and BiTN, respectively), which are key MM treatment options. TiPN is usually sensory and sensorimotor, whereas BiPN is typically sensory. The mechanisms of chemotherapy-induced neurotoxicity in MM are well known; thalidomide seems to induce PN through its antiangiogenic properties, whereas bortezomib neurotoxicity is connected with disrupted calcium homeostasis. TiPN incidence ranges from 25% to 75%, and its prevalence and severity appears to be dose-dependent. BiPN incidence is almost 40% and is dose-related as well. Poor (25%) reversibility of TiPN prompted the recommendations for dose and exposure reduction, whereas BiPN cases are mostly reversible (64%). Peripheral sensory neuropathy is very rare in patients receiving bendamustine monotherapy. Because of this favourable toxicity profile, bendamustine may be considered a promising option for combination therapies in pre-existing PN in myeloma patients. Considering the lack of curative therapy for treatment-emergent PN, prevention is a key management strategy in MM patients. All patients should be evaluated for PN before the administration of a neurotoxic drug, and those under treatment should be closely monitored by a neurologist.

A navigated, robot-driven laser craniotomy tool for frameless depth electrode implantation. An in-vivo recovery animal study.

Objectives: We recently introduced a frameless, navigated, robot-driven laser tool for depth electrode implantation as an alternative to frame-based procedures. This method has only been used in cadaver and non-recovery studies. This is the first study to test the robot-driven laser tool in an in vivo recovery animal study. Methods: A preoperative computed tomography (CT) scan was conducted to plan trajectories in sheep specimens. Burr hole craniotomies were performed using a frameless, navigated, robot-driven laser tool. Depth electrodes were implanted after cut-through detection was confirmed. The electrodes were cut at the skin level postoperatively. Postoperative imaging was performed to verify accuracy. Histopathological analysis was performed on the bone, dura, and cortex samples. Results: Fourteen depth electrodes were implanted in two sheep specimens. Anesthetic protocols did not show any intraoperative irregularities. One sheep was euthanized on the same day of the procedure while the other sheep remained alive for 1 week without neurological deficits. Postoperative MRI and CT showed no intracerebral bleeding, infarction, or unintended damage. The average bone thickness was 6.2 mm (range 4.1-8.0 mm). The angulation of the planned trajectories varied from 65.5° to 87.4°. The deviation of the entry point performed by the frameless laser beam ranged from 0.27 mm to 2.24 mm. The histopathological analysis did not reveal any damage associated with the laser beam. Conclusion: The novel robot-driven laser craniotomy tool showed promising results in this first in vivo recovery study. These findings indicate that laser craniotomies can be performed safely and that cut-through detection is reliable.

Additional genetic abnormalities significantly worsen poor prognosis associated with 1q21 amplification in multiple myeloma patients.

We investigated the prognostic value of amp(1q21) alone and in combination with other abnormalities in newly diagnosed myeloma patients. The study group consisted of 104 patients treated with various induction regimens, mostly thalidomide based (87 patients). Amp(1q21) was detected in 49 (47.1%) of patients; in 26 (25.0%) cases, it was combined with del(13q14), in 7 (6.7%) with del(17p13) and in 15 (14.4%) with t(4;14)(p16;q32). The response rate was significantly better in amp(1q21)-negative than in amp(1q21)-positive patients (74.5% vs 55.1%, p = 0.025; complete response 18.2% vs 4.1%, p = 0.024). The median progression-free survival (PFS) was 33.9 months in patients without amp(1q21) and 10.3 months with this aberration (p = 0.002). The presence of additional abnormalities resulted in significantly shortened PFS when compared with patients with isolated amp(1q21): coexisting del(13q14) resulted in 7.8 vs 29.0 months of PFS (p = 0.024) and del(17p13) resulted in 4.0 vs 24.9 months of PFS (p = 0.034). The presence of amp(1q21) significantly influenced overall survival (OS) as well as PFS resulting in the median OS of 26.6 vs 62.4 months (p = 0.018) in patients without amp(1q21). The presence of additional genetic abnormalities significantly affected OS when compared with patients carrying isolated amp(1q21): for del(13q14) 18.9 vs 58.4 months (p = 0.004) and for del(17p13) 12.0 vs 46.5 months (p = 0.036). On multivariate analysis amp(1q21), del(13q14) and del(17p13) were found to be an independent adverse predictors of shorter PFS and OS. Our results showed that the presence of amp(1q21) was associated with poor prognosis. Moreover additional genetic abnormalities made PFS and OS further shortened.

Robotic calvarial bone sampling.

The aim of this study was to assess the feasibility of complex unicortical calvarial harvesting by using the Cold Ablation Robot-Guided Laser Osteotome (CARLO® primo+). A cadaveric study was performed with a progressive complexity of the bone harvesting. This preliminary study on the cadaveric cranial vault area examined the tracking precision, the strategies, settings and durations of harvesting, the accuracy of the unicortical bone cutting, and the risk of dura exposition. All sampling was realised with no more difficulty than that experienced during the standard procedure. No bicortical cutting occurred during CARLO® primo + robot-guided laser cutting. During the second sampling, dura was partially exposed due to improper angulation of the curved osteotome during harvesting. Complex unicortical calvarial harvesting using robot-guided laser appears to be feasible and safe. In the future, robotic approaches will probably replace current surgical techniques using cutting guides and help reduce intraoperative inaccuracies due to the human factor.

A Stepwise Screening Protocol for Multiple Myeloma.

BACKGROUND: Monoclonal gammopathies and multiple myeloma should be screened in the primary care setting. METHODS: The screening strategy consisted of an initial interview supported with the analysis of basic laboratory test results and the increasing laboratory workload in the following steps was developed based on characteristics of patients with multiple myeloma. RESULTS: The developed 3-step screening protocol includes evaluation of myeloma-related bone disease, two renal function markers, and three hematologic markers. In the second step, the erythrocyte sedimentation rate (ESR) and the level of C-reactive protein (CRP) were cross-tabulated to identify persons qualifying for confirmation of the presence of monoclonal component. Patients with diagnosed monoclonal gammopathy should be referred to a specialized center to confirm the diagnosis. The screening protocol testing identified 900 patients with increased ESR and normal level of CRP and 94 of them (10.4%) had positive immunofixation. CONCLUSIONS: The proposed screening strategy resulted in an efficient diagnosis of monoclonal gammopathy. The stepwise approach rationalized the diagnostic workload and cost of screening. The protocol would support primary care physicians, standardizing the knowledge about the clinical manifestation of multiple myeloma and the method of evaluation of symptoms and diagnostic test results.

Early efficacy and safety of obinutuzumab with chemotherapy in previously untreated patients with follicular lymphoma: A real-world retrospective report of the Polish Lymphoma Research Group.

BACKGROUND: The first-line obinutuzumab-based immunochemotherapy improves the outcome of patients with follicular lymphoma (FL) compared with rituximab-based regimens. However, infusion-related reactions occur in almost half of patients during the 1st obinutuzumab administration. OBJECTIVES: The study aimed to evaluate the early effectiveness and safety of obinutuzumab-based induction regimens in a real-world setting. MATERIAL AND METHODS: Outcomes of patients diagnosed with FL and treated with obinutuzumab between January 2020 and September 2021 were analyzed. RESULTS: The study group included 143 treatment-naïve patients with FL. The median age was 52 years (range: 28-89 years); 45.1% of patients had a high-risk disease as assessed using the Follicular Lymphoma International Prognostic Index (FLIPI). Induction chemotherapy included: O-CVP (obinutuzumab, cyclophosphamide, vincristine, prednisolone) in 49.0% of patients, O-CHOP (O-CVP plus doxorubicin) in 28.7% and O-BENDA (obinutuzumab, bendamustine) in 22.4%. Complete response (CR) and partial response (PR) rates were 69.9% and 26.5%, respectively. There was no difference in response rates between different regimens (p = 0.309). Maintenance was started in 115 patients (85.2%). In the 1st cycle, obinutuzumab was administered as a single 1000-milligram infusion in 47.9% of patients, whereas in 52.1%, initial infusions were split over 2 days (100 mg/900 mg). Infusion-related reactions were reported only during the 1st administration of obinutuzumab in 9.1% of patients, with a similar incidence in those receiving the total dose on a single day or split over 2 days (p = 0.458). The most common adverse events were hematological. Five patients died from coronavirus disease 2019 (COVID-19). CONCLUSION: The early responses to induction regimens and adverse events profile were similar for every type of induction treatment. The infusion-related reactions were rare and limited to the 1st dose of obinutuzumab.

The effects of muscimol and AMN082 injections into the medial prefrontal cortex on the expression and extinction of conditioned fear in mice.

The medial prefrontal cortex (mPFC), in particular its infralimbic part, is a key region in mediating the extinction of conditioned fear. There is some evidence that the metabotropic glutamate receptor 7 (mGluR7) may be involved in the mediation or modulation of extinction. The aim of present study was to assess the potential role of mGluR7 in the mPFC in the extinction of conditioned fear in mice by local injections of AMN082, a positive allosteric modulator of mGluR7. Furthermore, for comparison we injected the GABA-A receptor agonist muscimol, which should lead to a temporary inactivation of mPFC. We found impaired between-session extinction of conditioned fear for the muscimol group as well as a decrease in fear expression. However, local injections of AMN082 into the mPFC had no effects. Overall, the results of the experiment add to a growing body of evidence that mPFC, especially the infralimbic region, is crucial in the extinction of fear memory.

Cold ablation robot-guided laser osteotomy in hand, wrist and forearm surgery-A feasibility study.

INTRODUCTION: Traditional bone surgery using saws and chisels is associated with direct contact of instruments with the bone causing friction, heat and pressure and hence, damaging the bone and the surrounding soft tissues. METHOD: Cold ablation laser osteotomy offers new possibilities to perform corrective osteotomies in the field of bone surgery. We introduce the technology of navigated cold ablation robot-guided laser osteotomy, present potential applications, and preliminary pre-clinical cadaver test results in the field of hand-, wrist- and forearm surgery. RESULTS: The cadaver tests showed first promising results for corrections in all planes and axes using different cutting patterns. CONCLUSION: Cold ablation laser osteotomy seems to be a feasible new method to perform osteotomies in the field of hand-, wrist- and forearm surgery. Primary osseous stability could be achieved using various cutting patterns which could lead to reduction of the amount of hardware required for osteosynthesis. Further tests are required to proof the latter and precision.

Advanced cutting strategy for navigated, robot-driven laser craniotomy for stereoelectroencephalography: An in Vivo non-recovery animal study.

Objectives: In this study we aimed to present an updated cutting strategy and updated hardware for a new camera system that can increase cut-through detection using a cold ablation robot-guided laser osteotome. Methods: We performed a preoperative computed tomography scan of each animal. The laser was mounted on a robotic arm and guided by a navigation system based on a tracking camera. Surgery was performed with animals in the prone position. A new cutting strategy was implemented consisting of two circular paths involving inner (full cylindric) and outer (hollow cylindric) sections, with three different ablation phases. The depth electrodes were inserted after cut-through detection was confirmed on either the coaxial camera system or optical coherence tomography signal. Results: A total of 71 precision bone channels were cut in four pig specimens using a robot-guided laser. No signs of hemodynamic or respiratory irregularities were observed during anesthesia. All bone channels were created using the advanced cutting strategy. The new cutting strategy showed no irregularities in either cylindrical (parallel walled; n = 38, 45° = 10, 60° = 14, 90° = 14) or anticonical (walls widening by 2 degrees; n = 33, 45° = 11, 60° = 13, 90° = 9) bone channels. The entrance hole diameters ranged from 2.25-3.7 mm and the exit hole diameters ranged from 1.25 to 2.82 mm. Anchor bolts were successfully inserted in all bone channels. No unintended damage to the cortex was detected after laser guided craniotomy. Conclusion: The new cutting strategy showed promising results in more than 70 precision angulated cylindrical and anti-conical bone channels in this large, in vivo non-recovery animal study. Our findings indicate that the coaxial camera system is feasible for cut-through detection.