Triad resonance for internal waves in a uniformly stratified fluid: Rogue waves and breathers.

Three-wave (triad) resonance in a uniformly stratified fluid is investigated as a case study of energy transfer among oscillatory modes. The existence of a degenerate triad is demonstrated explicitly, where two components have identical group velocity. An illuminating example is a resonance involving waves from modes 1, 3, 5 families, but many other combinations are possible. The physical applications and nonlinear dynamics of rogue waves derived analytically in the literature are examined. Exact solutions with four free parameters (two related to the amplitudes of the background plane waves, two related to the frequencies of slowly varying envelopes) describe motions localized in both space and time. The differences between rogue waves of the degenerate versus the nondegenerate cases are highlighted. The phase and profile of the degenerate case rogue waves are correlated. The volume or energy of the rogue wave (defined as the total extent or energy contents of the fluid set in motion for the duration of the rogue wave) may change drastically, if the wave envelope parameters vary. Pulsating modes (breathers) have been studied previously by layered-fluid and modified Korteweg-de Vries models. Here we extend the consideration to stratified fluids but for the simpler case of nondegenerate triads. Instabilities of fission and fusion of breathers are confirmed computationally with Floquet analysis. This knowledge should prove useful for energy transfer processes in the oceans.

Robustness and stability of doubly periodic patterns of the focusing nonlinear Schrödinger equation.

The nonlinear Schrödinger equation possesses doubly periodic solutions expressible in terms of the Jacobi elliptic functions. Such solutions can be realized through doubly periodic patterns observed in experiments in fluid mechanics and optics. Stability and robustness of these doubly periodic wave profiles in the focusing regime are studied computationally by using two approaches. First, linear stability is considered by Floquet theory. Growth will occur if the eigenvalues of the monodromy matrix are of a modulus larger than unity. This is verified by numerical simulations with input patterns of different periods. Initial patterns associated with larger eigenvalues will disintegrate faster due to instability. Second, formation of these doubly periodic patterns from a tranquil background is scrutinized. Doubly periodic profiles are generated by perturbing a continuous wave with one Fourier mode, with or without the additional presence of random noise. Effects of varying phase difference, perturbation amplitude, and randomness are studied. Varying the phase angle has a dramatic influence. Periodic patterns will only emerge if the perturbation amplitude is not too weak. The growth of higher-order harmonics, as well as the formation of breathers and repeating patterns, serve as a manifestation of the classical problem of Fermi-Pasta-Ulam-Tsingou recurrence.

Stepwise osteotomy protocol for zygomatic implant placement under navigation in patients with extra-sinus trajectory.

This technical note describes a stepwise osteotomy for zygomatic implant placement with an extra-sinus trajectory under navigation using virtual markers for registration. The stepwise osteotomy protocol divides the trajectory of the zygomatic implant osteotomy into three consecutive co-axial components. The aim is to achieve better control of the osteotomy under navigation and to minimize or eliminate any intermittent free-hand drilling. The stepwise osteotomy protocol facilitates the use of shorter drills to finish the zygomatic implant osteotomy at the entry location before switching back to the long drill to complete the whole osteotomy. This protocol has been applied in a patient and the preliminary result is promising. However, the clinical effectiveness of this approach requires further investigation in prospective clinical studies.

Fermi-Pasta-Ulam-Tsingou recurrence and cascading mechanism for resonant three-wave interactions.

Evolution of resonant three-wave interaction is governed by quadratic nonlinearities. While propagating localized modes and inverse scattering mechanisms have been studied, transient states such as rogue waves and breathers are not fully understood. Modulation instability modes can trigger growth of disturbances and the eventual development of breathers. Here we study computationally the dynamics beyond the first formation of breathers, and demonstrate repeating patterns of breathers as a manifestation of the Fermi-Pasta-Ulam-Tsingou recurrence (FPUT). While nonlinearity governs the actual dynamics, the range of wave numbers for modulation instability remains a useful indicator. Depending on the stability characteristics of the fundamental mode and the higher-order harmonics ("sidebands"), "regular" and "staggered" FPUT patterns can arise. A "cascading mechanism" provides analytical verification, as the fundamental and sideband modes attain the same magnitude at one particular instant, signifying the first occurrence of a breather. A triangular spectrum is also computed, similar to experimental observations of optical pulses. Such spectra can elucidate the spreading of energy among the sidebands and components of the triad resonance. The concept of "effective energy" is examined and the eigenvalues of the inverse scattering mechanism are computed. Both approaches are utilized to correlate with the occurrence of regular or staggered FPUT. These numerical and analytical studies can enhance our understanding of wave interactions in fluid mechanics and optics.

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding.

Puromycin-sensitive aminopeptidase (E.C. 3.4.11.14, UniProt P55786), a zinc metallopeptidase belonging to the M1 family, degrades a number of bioactive peptides as well as peptides released from the proteasome, including polyglutamine. We report the crystal structure of PSA at 2.3 Ǻ. Overall, the enzyme adopts a V-shaped architecture with four domains characteristic of the M1 family aminopeptidases, but it is in a less compact conformation compared to most M1 enzymes of known structure. A microtubule binding sequence is present in a C-terminal HEAT repeat domain of the enzyme in a position where it might serve to mediate interaction with tubulin. In the catalytic metallopeptidase domain, an elongated active site groove lined with aromatic and hydrophobic residues and a large S1 subsite may play a role in broad substrate recognition. The structure with bound polyglutamine shows a possible interacting mode of this peptide, which is supported by mutation.

Development and characterization of nanobodies that specifically target the oncogenic Phosphatase of Regenerating Liver-3 (PRL-3) and impact its interaction with a known binding partner, CNNM3.

Phosphatase of Regenerating Liver-3 (PRL-3) is associated with cancer progression and metastasis. The mechanisms that drive PRL-3's oncogenic functions are not well understood, partly due to a lack of research tools available to study this protein. We have begun to address these issues by developing alpaca-derived single domain antibodies, or nanobodies, targeting PRL-3 with a KD of 30-300 nM and no activity towards highly homologous family members PRL-1 and PRL-2. We found that longer and charged N-terminal tags on PRL-3, such as GFP and FLAG, changed PRL-3 localization compared to untagged protein, indicating that the nanobodies may provide new insights into PRL-3 trafficking and function. The nanobodies perform equally, if not better, than commercially available antibodies in immunofluorescence and immunoprecipitation. Finally, hydrogen-deuterium exchange mass spectrometry (HDX-MS) showed that the nanobodies bind partially within the PRL-3 active site and can interfere with PRL-3 phosphatase activity. Co-immunoprecipitation with a known PRL-3 active site binding partner, the CBS domain of metal transporter CNNM3, showed that the nanobodies reduced the amount of PRL-3:CBS inter-action. The potential of blocking this interaction is highly relevant in cancer, as multiple research groups have shown that PRL-3 binding to CNNM proteins is sufficient to promote metastatic growth in mouse models. The anti-PRL-3 nanobodies represent an important expansion of the research tools available to study PRL-3 function and can be used to define the role of PRL-3 in cancer progression.

Decentralized governance and artificial intelligence policy with blockchain-based voting in federated learning.

Introduction: Fruit losses in the supply chain owing to improper handling and a lack of proper control are common in the industry. As losses are caused by the inefficiency of the export method, selecting the appropriate export method is a possible solution. Several organizations employ only a single strategy, which is mainly based on a first-in-first-out approach. Such a policy is easy to manage but inefficient. Given that the batch of fruits may become overripe during transportation, frontline operators do not have the authority or immediate support to change the fruit dispatching strategy. Thus, this study aims to develop a dynamic strategy simulator to determine the sequence of delivery based on forecasting information projected from probabilistic data to reduce the amount of fruit loss. Methods: The proposed method to accomplish asynchronous federated learning (FL) is based on blockchain technology and a serially interacting smart contract. In this method, each party in the chain updates its model parameters and uses a voting system to reach a consensus. This study employs blockchain technology with smart contracts to serially enable asynchronous FL, with each party in the chain updating its parameter model. A smart contract combines a global model with a voting system to reach a common consensus. Its artificial intelligence (AI) and Internet of Things engine further strengthen the support for implementing the Long Short-Term Memory (LSTM) forecasting model. Based on AI technology, a system was constructed using FL in a decentralized governance AI policy on a blockchain network platform. Results: With mangoes being selected as the category of fruit in the study, the system improves the cost-effectiveness of the fruit (mango) supply chain. In the proposed approach, the simulation outcomes show fewer mangoes lost (0.035%) and operational costs reduced. Discussion: The proposed method shows improved cost-effectiveness in the fruit supply chain through the use of AI technology and blockchain. To evaluate the effectiveness of the proposed method, an Indonesian mango supply chain business case study has been selected. The results of the Indonesian mango supply chain case study indicate the effectiveness of the proposed approach in reducing fruit loss and operational costs.

Tai chi as an adjunctive therapy for individuals who plateau after vestibular rehabilitation.

OBJECTIVE: This study aimed to evaluate the effectiveness of tai chi on balance in patients with improved but persistent dizziness and imbalance following completion of traditional vestibular rehabilitation therapy. METHOD: Patients who completed vestibular rehabilitation therapy with persistent imbalance were prospectively enrolled in a tai chi programme comprising eight weekly classes. Balance was assessed before the first and after the eighth session using the Dynamic Gait Index, Activities-Specific Balance Confidence scale and Dizziness Handicap Inventory. RESULTS: A total of 37 participants (34 females, 3 males) completed the programme with balance testing. Mean age was 76.8 years (range, 56-91 years). Mean Dynamic Gait Index significantly increased after completion of tai chi (p < 0.00001). Mean Activities-Specific Balance Confidence scale score increased from 63.6 to 67.9 per cent (p = 0.046). A subset (n = 18) of patients completed a Dizziness Handicap Inventory without significant post-therapeutic change (p = 0.62). Most (36 of 37; 97.3 per cent) patients demonstrated post-therapy improvement on one or more assessments. CONCLUSION: Tai chi is a viable adjunct to improve balance in patients who complete a vestibular rehabilitation therapy programme.

Polypharmacy Predicts Onset and Transition of Frailty, Malnutrition, and Adverse Outcomes in Peritoneal Dialysis Patient.

BACKGROUND: Polypharmacy, frailty and malnutrition are known predictors of adverse outcomes in dialysis patients. Little has reported about their interaction and composite prognostic values. We aimed to describe the interaction between polypharmacy, frailty, nutrition, hospitalization, and survival in peritoneal dialysis patients. METHODS: In this prospective cohort study, we recruited 573 peritoneal dialysis patients. Drug burden was measured by medication number and daily pill load. Frailty and nutrition were assessed by the validated Frailty Score (FQ) and Subjective Global Assessment (SGA) respectively. All patients were followed for two years. Primary outcome was all-cause mortality. Secondary outcomes were fall and fracture episodes, hospitalization, change in FQ and SGA. RESULTS: At baseline, each patient took 7.5 ± 2.6 medications with 15.5 ± 8.5 tablets per day. Medication number, but not daily pill load predicted baseline FQ (p = 0.004) and SGA (p = 0.03). Over 2 years, there were 69 fall and 1,606 hospitalization episodes. In addition, 148 (25.8%) patients died, while FQ and SGA changed by 0.73 ± 4.23 and -0.07 ± 1.06 respectively in survivors. Medication number (hospitalization: p = 0.02, survival: p = 0.005), FQ (hospitalization: p < 0.001; survival: p = 0.01) predicted hospitalization and survival. Medication number also predicted fall episodes (p = 0.02) and frailty progression (p = 0.002). Daily pill load did not predict any of these outcomes. CONCLUSIONS: Drug burden is high in peritoneal dialysis patients, and it carries important prognostic implication. Medication number but not pill load significantly predicted onset and progression of frailty, malnutrition, fall, hospitalization, and mortality.

Computational study on the transmission of the SARS-CoV-2 virus through aerosol in an elevator cabin: Effect of the ventilation system.

Aerosol transmission is now well-established as a route in the spread of the SARS-CoV-2 virus. Factors influencing the transport of virus-laden particles in an elevator cabin are investigated computationally and include human respiratory events, locations of the infected person(s), and the ventilation system (ventilation mode, ventilation capacity, and vent schemes). "Breath," "cough," and "sneeze" are defined quantitatively by the fluid jet velocities and particle sizes. For natural ventilation, most particles exhaled by sneezing and coughing tend to deposit on surfaces quickly, but aerosol generated by breathing will remain suspended in the air longer. For forced ventilation, motions of particles under different ventilation capacities are compared. Larger particles otherwise deposited readily on solid surfaces may be slowed down by airflow. Air currents also accelerate the motions of smaller particles, facilitating the subsequent deposition of micrometer or sub-micrometer particles. Locations of the infected person(s) lead to different spreading scenarios due to the distinctive motions of the particles generated by the various respiratory events. Sneeze particles will likely contaminate the person in front of the infected passenger only. Cough particles will increase the risk of all the people around the injector. Breath particles tend to spread throughout the confined environment. An optimized vent scheme is introduced and can reduce particles suspended in the air by up to 80% as compared with commonly used schemes. The purification function of this vent model is robust to various positions of the infected passenger.

Four-wave mixing and coherently coupled Schrödinger equations: Cascading processes and Fermi-Pasta-Ulam-Tsingou recurrence.

Modulation instability, breather formation, and the Fermi-Pasta-Ulam-Tsingou recurrence (FPUT) phenomena are studied in this article. Physically, such nonlinear systems arise when the medium is slightly anisotropic, e.g., optical fibers with weak birefringence where the slowly varying pulse envelopes are governed by these coherently coupled Schrödinger equations. The Darboux transformation is used to calculate a class of breathers where the carrier envelope depends on the transverse coordinate of the Schrödinger equations. A "cascading mechanism" is utilized to elucidate the initial stages of FPUT. More precisely, higher order nonlinear terms that are exponentially small initially can grow rapidly. A breather is formed when the linear mode and higher order ones attain roughly the same magnitude. The conditions for generating various breathers and connections with modulation instability are elucidated. The growth phase then subsides and the cycle is repeated, leading to FPUT. Unequal initial conditions for the two waveguides produce symmetry breaking, with "eye-shaped" breathers in one waveguide and "four-petal" modes in the other. An analytical formula for the time or distance of breather formation for a two-waveguide system is proposed, based on the disturbance amplitude and instability growth rate. Excellent agreement with numerical simulations is achieved. Furthermore, the roles of modulation instability for FPUT are elucidated with illustrative case studies. In particular, depending on whether the second harmonic falls within the unstable band, FPUT patterns with one single or two distinct wavelength(s) are observed. For applications to temporal optical waveguides, the present formulation can predict the distance along a weakly birefringent fiber needed to observe FPUT.

Single-cell RNA sequencing identifies molecular targets associated with poor in vitro maturation performance of oocytes collected from ovarian stimulation.

STUDY QUESTION: What is the transcriptome signature associated with poor performance of rescue IVM (rIVM) oocytes and how can we rejuvenate them? SUMMARY ANSWER: The GATA-1/CREB1/WNT signalling axis was repressed in rIVM oocytes, particularly those of poor quality; restoration of this axis may produce more usable rIVM oocytes. WHAT IS KNOWN ALREADY: rIVM aims to produce mature oocytes (MII) for IVF through IVM of immature oocytes collected from stimulated ovaries. It is not popular due to limited success rate in infertility treatment. Genetic aberrations, cellular stress and the absence of cumulus cell support in oocytes could account for the failure of rIVM. STUDY DESIGN, SIZE, DURATION: We applied single-cell RNA sequencing (scRNA-seq) to capture the transcriptomes of human in vivo oocytes (IVO) (n = 10) from 7 donors and rIVM oocytes (n = 10) from 10 donors. The effects of maternal age and ovarian responses on rIVM oocyte transcriptomes were also studied. In parallel, we studied the effect of gallic acid on the maturation rate of mouse oocytes cultured in IVM medium with (n = 84) and without (n = 85) gallic acid. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human oocytes were collected from donors aged 28-41 years with a body mass index of <30. RNA extraction, cDNA generation, library construction and sequencing were performed in one preparation. scRNA-seq data were then processed and analysed. Selected genes in the rIVM versus IVO comparison were validated by quantitative real-time PCR. For the gallic acid study, we collected immature oocytes from 5-month-old mice and studied the effect of 10-µM gallic acid on their maturation rate. MAIN RESULTS AND THE ROLE OF CHANCE: The transcriptome profiles of rIVM/IVO oocytes showed distinctive differences. A total of 1559 differentially expressed genes (DEGs, genes with at least 2-fold change and adjusted P < 0.05) were found to be enriched in metabolic processes, biosynthesis and oxidative phosphorylation. Among these DEGs, we identified a repression of WNT/ß-catenin signalling in rIVM when compared with IVO oocytes. We found that oestradiol levels exhibited a significant age-independent correlation with the IVO mature oocyte ratio (MII ratio) for each donor. rIVM oocytes from women with a high MII ratio were found to have over-represented cellular processes such as anti-apoptosis. To further identify targets that contribute to the poor clinical outcomes of rIVM, we compared oocytes collected from young donors with a high MII ratio with oocytes from donors of advanced maternal age and lower MII ratio, and revealed that CREB1 is an important regulator. Thus, our study identified that GATA-1/CREB1/WNT signalling was repressed in both rIVM oocytes versus IVO oocytes and in rIVM oocytes of lower versus higher quality. Consequently we investigated gallic acid, as a potential antioxidant substrate in human rIVM medium, and found that it increased the mouse oocyte maturation rate by 31.1%. LARGE SCALE DATA: Raw data from this study can be accessed through GSE158539. LIMITATIONS, REASONS FOR CAUTION: In the rIVM oocytes of the high- and low-quality comparison, the number of samples was limited after data filtering with stringent selection criteria. For the oocyte stage identification, we were unable to predict the presence of oocyte spindle, so polar body extrusion was the only indicator. WIDER IMPLICATIONS OF THE FINDINGS: This study showed that GATA-1/CREB1/WNT signalling was repressed in rIVM oocytes compared with IVO oocytes and was further downregulated in low-quality rIVM oocytes, providing us the foundation of subsequent follow-up research on human oocytes and raising safety concerns about the clinical use of rescued oocytes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Collaborative Research Fund, Research Grants Council, C4054-16G, and Research Committee Funding (Research Sustainability of Major RGC Funding Schemes), The Chinese University of Hong Kong. The authors have no conflicts of interest to declare.

Ruptured Superficial Femoral Artery Anastomotic Pseudoaneurysm after 30 Years.

INTRODUCTION: Anastomotic pseudoaneurysms are a complication of vascular reconstructive surgery with the majority in the femoral region. Although rare, ruptured femoral anastomotic pseudoaneurysms have high mortality and require emergency surgery. CASE PRESENTATION: A 60-year-old male with a history of a left leg crush injury was treated with a superficial femoral artery interposition vein graft 30 years ago. He presented nowadays with a three-day history of severe pain in his left thigh. CT angiography demonstrated a ruptured anastomotic pseudoaneurysm with contrast extravasation into an intramuscular hematoma. He had significant scarring from his previous surgeries which made the leg hostile for an open repair. Therefore, percutaneous access selectively cannulated the left iliofemoral vasculature. An angiogram showed a distal superficial femoral artery pseudoaneurysm. Subsequently, two 10mmx15cm Viabahn covered stents (Gore & Associates, Flagstaff, AZ) were placed bridging healthy superficial femoral artery. A completion angiogram demonstrated no extravasation into the pseudoaneurysm. The patient recovered and was discharged home two days postoperatively. CONCLUSION: Ruptured femoral anastomotic pseudoaneurysms are traditionally repaired with open pseudoaneurysm excision and arterial reconstruction, although endovascular repair has been reported. Furthermore, most femoral anastomotic pseudoaneurysms form less than 10 years after initial operation. We present a unique case of ruptured superficial femoral artery pseudoaneurysm, 30 years after the initial operation. Endovascular stents offer effective treatment for ruptured anastomotic pseudoaneurysms.

A systematic review of the effects of advance care planning facilitators training programs.

BACKGROUND: Advance care planning (ACP) is the process of ongoing communication among patients, family and health care professionals regarding what plans for future care are preferred in the event that patients become unable to make their own decisions. Clinicians play an important role in ACP as both initiators and decision coaches. However, lack of training for clinicians has frequently been reported as the reason for low involvement in ACP discussions - hence the present review evaluates the effectiveness of ACP training programs for healthcare professionals to guide the development of novel training programs for them in the future. METHODS: A literature search for intervention studies was conducted independently by two reviewers in July 2018. Participants included all healthcare professionals working with adult patients suffering from terminal illness. The primary outcomes were the professionals' knowledge of and attitudes towards ACP, and self-perceived competence in ACP conversations. The Effective Public Health Practice Project appraisal tool was used to examine the quality of the studies included. RESULTS: A total of 4025 articles were identified, and ten eligible articles, covering 1081 participants, were included in the review. However, there is a lack of high quality randomized controlled trials of providing ACP training for nurses working in non-palliative care hospital settings. The overall quality of the intervention studies was moderate. All the studies included used instructional sessions in their interventions, while some contained group discussion, role-play and the use of advanced technology. The training programs increased the knowledge, attitudes towards shared decision-making, perceived communication skills, confidence, comfort and experiences concerned with discussing end-of-life (EOL) issues. Patient advocacy, job satisfaction and perceived level of adequate training for EOL care were improved. The use of 'decision aids' was rated as acceptable and clinically useful. CONCLUSIONS: Training for healthcare professionals in ACP has positive effects on their knowledge, attitude and skills. The use of decision aids and advanced technology, instructional sessions with role play, training content focused on ACP communication skills and the needs and experience of patient in the ACP process, and a values-based ACP process are all those factors that made the ACP training programs effective.

Immunization of Alpacas (Lama pacos) with Protein Antigens and Production of Antigen-specific Single Domain Antibodies.

In this manuscript, a method for the immunization of alpaca and the use of molecular biology methods to produce antigen-specific single domain antibodies is described and demonstrated. Camelids, such as alpacas and llamas, have become a valuable resource for biomedical research since they produce a novel type of heavy chain-only antibody which can be used to produce single domain antibodies. Because the immune system is highly flexible, single domain antibodies can be made to many different protein antigens, and even different conformations of the antigen, with a very high degree of specificity. These features, among others, make single domain antibodies an invaluable tool for biomedical research. A method for the production of single domain antibodies from alpacas is reported. A protocol for immunization, blood collection, and B-cell isolation is described. The B-cells are used for the construction of an immunized library, which is used in the selection of specific single domain antibodies via panning. Putative specific single domain antibodies obtained via panning are confirmed by pull-down, ELISA, or gel-shift assays. The resulting single domain antibodies can then be used either directly or as a part of an engineered reagent. The uses of single domain antibody and single domain antibody-based regents include structural, biochemical, cellular, in vivo, and therapeutic applications. Single domain antibodies can be produced in large quantities as recombinant proteins in prokaryotic expression systems, purified, and used directly or can be engineered to contain specific markers or tags that can be used as reporters in cellular studies or in diagnostics.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials.

BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. RESULTS: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). CONCLUSIONS: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.