Biological relapse in multiple myeloma: Outcome and treatment strategies in a Spanish real-world setting.

Recommendations regarding the best time to start treatment in patients with relapsed/refractory multiple myeloma (RRMM) after biological relapse/progression (BR) are unclear. This observational, prospective, multicenter registry aimed to evaluate the impact on time to progression (TTP) of treatment initiation at BR versus at symptomatic clinical relapse (ClinR) based on the Spanish routine practice in adult patients with RRMM. Patients had two or less previous treatment lines and at least one previous partial response. Baseline characteristics and treatment outcomes were recorded, and survival was analyzed. Of 225 patients, 110 were treated at BR (TxBR group) and 115 at ClinR (TxClinR group) according to the investigators' criteria. The proportion of patients with higher ECOG, previous noncomplete remission (CR), and second relapse were significantly higher in the TxBR group compared to the TxClinR group. TheTxClinR group showed improved outcomes, including TTP, compared to the TxBR group. Progression-free survival increased in the TxClinR group (56.2 months) compared to the TxBR group (32.5 months) (p = 0.0137), and median overall survival also increased (p = 0.0897). Median TTP was significantly longer in patients relapsing from a CR (50.4 months) and in their first relapse (38.7 months) compared to those relapsing from a non-CR response (32.9 months) and in their second relapse (25.2 months). Physicians seemed to start treatment earlier in RRMM patients with poor prognosis features. Previous responses to anti-MM treatment and the number of prior treatment lines were identified as prognosis factors, whereby relapse from CR and first relapse were associated with a longer time to progression.

Replica symmetry breaking in 1D Rayleigh scattering system: theory and validations.

Spin glass theory, as a paradigm for describing disordered magnetic systems, constitutes a prominent subject of study within statistical physics. Replica symmetry breaking (RSB), as one of the pivotal concepts for the understanding of spin glass theory, means that under identical conditions, disordered systems can yield distinct states with nontrivial correlations. Random fiber laser (RFL) based on Rayleigh scattering (RS) is a complex disordered system, owing to the disorder and stochasticity of RS. In this work, for the first time, a precise theoretical model is elaborated for studying the photonic phase transition via the platform of RS-based RFL, in which we clearly reveal that, apart from the pump power, the photon phase variation in RFL is also an analogy to the temperature term in spin-glass phase transition, leading to a novel insight into the intrinsic mechanisms of photonic phase transition. In addition, based on this model and real-time high-fidelity detection spectral evolution, we theoretically predict and experimentally observe the mode-asymmetric characteristics of photonic phase transition in RS-based RFL. This finding contributes to a deeper understanding of the photonic RSB regime and the dynamics of RS-based RFL.

Observation of the photonic Hall effect and photonic magnetoresistance in random lasers.

Modulation of scattering in random lasers (RLs) by magnetic fields has attracted much attention due to its rich physical insights. We fabricate magnetic gain polymer optical fiber to generate RLs. From macroscopic experimental phenomena, with the increase of the magnetic field strength, the magnetic transverse photocurrent exists in disordered multiple scattering of RLs and the emission intensity of RLs decreases, which is the experimental observation of photonic Hall effect (PHE) and photonic magnetoresistance (PMR) in RLs. At the microscopic level, based on the field dependence theory of magnetic disorder in scattered nanoparticles and the replica symmetry breaking theory, the magnetic-induced transverse diffusion of photons reduces the scattering disorder, and then decreases the intensity fluctuation disorder of RLs. Our work establishes a connection between the above two effects and RLs, visualizes the influence of magnetic field on RL scattering at the microscopic level, which is crucial for the design of RLs.

Observation of Replica Symmetry Breaking in Standard Mode-Locked Fiber Laser.

We report the first experimental demonstration of the replica symmetry breaking (RSB) phenomenon in a fiber laser system supporting standard mode-locking (SML) regime. Though theoretically predicted, this photonic glassy phase remained experimentally undisclosed so far. We employ an ytterbium-based mode-locked fiber laser with a very rich phase diagram. Two phase transitions are observed separating three different regimes: cw, quasi-mode-locking (QML), and SML. The regimes are intrinsically related to the distinct dynamics of intensity fluctuations in the laser spectra. We set the connection between the RSB glassy phase with frustrated modes and onset of L-shaped intensity distributions in the QML regime, which impact directly the replica overlap measure.

Low respiratory quotient correlates with high mortality in patients undergoing mechanical ventilation.

OBJECTIVE: Oxygen consumption (VO2), carbon dioxide generation (VCO2), and respiratory quotient (RQ), which is the ratio of VO2 to VCO2, are critical indicators of human metabolism. To seek a link between the patient's metabolism and pathophysiology of critical illness, we investigated the correlation of these values with mortality in critical care patients. METHODS: This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Age 18 years or older healthy volunteers and patients who underwent mechanical ventilation were enrolled. A high-fidelity automation device, which accuracy is equivalent to the gold standard Douglas Bag technique, was used to measure VO2, VCO2, and RQ at a wide range of fraction of inspired oxygen (FIO2). RESULTS: We included a total of 21 subjects including 8 post-cardiothoracic surgery patients, 7 intensive care patients, 3 patients from the emergency room, and 3 healthy volunteers. This study included 10 critical care patients, whose metabolic measurements were performed in the ER and ICU, and 6 died. VO2, VCO2, and RQ of survivors were 282 +/- 95 mL/min, 202 +/- 81 mL/min, and 0.70 +/- 0.10, and those of non-survivors were 240 +/- 87 mL/min, 140 +/- 66 mL/min, and 0.57 +/- 0.08 (p = 0.34, p = 0.10, and p < 0.01), respectively. The difference of RQ was statistically significant (p < 0.01) and it remained significant when the subjects with FIO2 < 0.5 were excluded (p < 0.05). CONCLUSIONS: Low RQ correlated with high mortality, which may potentially indicate a decompensation of the oxygen metabolism in critically ill patients.

Life-Threatening Hematuria as Initial Presentation of a Complicated Transplant Renal Artery Pseudoaneurysm.

In this case report, we describe the clinical course of a complicated transplant renal artery (TRA) pseudoaneurysm, clinically featured by gross and massive hematuria one month after a kidney transplant was performed on a 50 year-old male patient. TRA pseudoaneurysm is a rare but potentially life-threatening complication that may result in bleeding, infection, graft dysfunction/loss, lower limb ischemia/loss, hemorrhagic shock, and death. TRA pseudoaneurysm treatment remains challenging as it needs to be tailored to the patient characteristics including hemodynamic stability, graft function, anatomy, presentation, and pseudoaneurysm features. This publication discusses the clinical scenario of massive gross hematuria that derived from a retroperitoneal hematoma which originated from an actively bleeding TRA pseudoaneurysm. This case highlights the combined approach of endovascular stent placement and subsequent transplant nephrectomy as a last resort in the management of intractable bleeding from a complicated TRA pseudoaneurysm. To the best of our knowledge, this is the first published case report of an actively bleeding TRA anastomotic pseudoaneurysm that caused a massive retroperitoneal bleed that in turn evacuated via the bladder after disrupting the ureter-to-bladder anastomosis. A temporizing hemostatic arterial stent placed percutaneously allowed for a safer and controlled emergency transplant nephrectomy.

COVID-19-Associated Portal Vein Thrombosis Post-Cholecystitis.

This case study describes a 45-year-old Caucasian male with a past medical history of obesity, hypertension, and non-insulin-dependent diabetes mellitus, who in the setting of coronavirus disease 2019 (COVID-19) pneumonia, developed portal vein thrombosis (PVT) presenting as an acute abdomen after hospital discharge from a cholecystitis episode. PVT is a very infrequent thromboembolic condition, classically occurring in patients with systemic conditions such as cirrhosis, malignancy, pancreatitis, diverticulitis, autoimmunity, and thrombophilia. PVT can cause serious complications, such as intestinal infarction, or even death, if not promptly treated. Due to the limited number of reports in the literature describing PVT in the COVID-19 setting, its prevalence, natural history, mechanism, and precise clinical features remain unknown. Therefore, clinical suspicion should be high for PVT, in any COVID-19 patient who presents with abdominal pain or associated signs and symptoms. To the best of our knowledge, this is the first report of COVID-19-associated PVT causing extensive thrombosis in the portal vein and its right branch, occurring in the setting of early-stage cirrhosis after a preceding episode of cholecystitis.

Continuous and repeat metabolic measurements compared between post-cardiothoracic surgery and critical care patients.

OBJECTIVE: Using a system, which accuracy is equivalent to the gold standard Douglas Bag (DB) technique for measuring oxygen consumption (VO2), carbon dioxide generation (VCO2), and respiratory quotient (RQ), we aimed to continuously measure these metabolic indicators and compare the values between post-cardiothoracic surgery and critical care patients. METHODS: This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Age 18 years or older patients who underwent mechanical ventilation were enrolled. RESULTS: We included 4 post-surgery and 6 critical care patients. Of those, 3 critical care patients died. The longest measurement reached to 12 h and 15 min and 50 cycles of repeat measurements were performed. VO2 of the post-surgery patients were 234 ± 14, 262 ± 27, 212 ± 16, and 192 ± 20 mL/min, and those of critical care patients were 122 ± 20, 189 ± 9, 191 ± 7, 191 ± 24, 212 ± 12, and 135 ± 21 mL/min, respectively. The value of VO2 was more variable in the post-surgery patients and the range of each patient was 44, 126, 71, and 67, respectively. SOFA scores were higher in non-survivors and there were negative correlations of RQ with SOFA. CONCLUSIONS: We developed an accurate system that enables continuous and repeat measurements of VO2, VCO2, and RQ. Critical care patients may have less activity in metabolism represented by less variable values of VO2 and VCO2 over time as compared to those of post-cardiothoracic surgery patients. Additionally, an alteration of these values may mean a systemic distinction of the metabolism of critically ill patients.

Intracranial Hypertension following Acute Mesenteric Ischemia: A Case Study on the Multiple Compartment Syndrome.

In this case study, we describe a 25-year-old male who was admitted due to a severe traumatic brain injury, requiring invasive intracranial pressure monitoring. At 48 hours posttrauma, he developed intracranial hypertension refractory to medical treatment without tomographic changes in the brain. Subsequently, intra-abdominal hypertension and tomographic signs of abdominal surgical pathology were observed. An exploratory laparotomy was performed with an intraoperative diagnosis of acute mesenteric ischemia. After surgical intervention for the abdominal pathology, intracranial pressure was restored to physiological values with a favorable recovery of the patient. In this report, the relationship between intracranial pressure and intra-abdominal pressure is discussed, highlighting the delicate association between the brain, abdomen, and thorax. Measures should be taken to avoid increases in intra-abdominal pressure in neurocritical patients. When treating intracranial hypertension refractory to conventional measures, abdominal causes and multiple compartment syndrome must be considered. The cranial compartment has physiological interdependence with other body compartments, where one can be modified by variations from another, giving rise to the concept of multiple compartment syndrome. Understanding this relationship is fundamental for a comprehensive approach of the neurocritical patient. To the best of our knowledge, this is the first report of a comatose patient post-traumatic brain injury, who developed medically unresponsive intracranial hypertension secondary to acute mesenteric ischemia, in which surgical resolution of intra-abdominal pathology resulted in intracranial pressure normalization and restitutio ad integrum of neurological status.

Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents.

BACKGROUND: Cardiac arrest (CA) can lead to neuronal degeneration and death through various pathways, including oxidative, inflammatory, and metabolic stress. However, current neuroprotective drug therapies will typically target only one of these pathways, and most single drug attempts to correct the multiple dysregulated metabolic pathways elicited following cardiac arrest have failed to demonstrate clear benefit. Many scientists have opined on the need for novel, multidimensional approaches to the multiple metabolic disturbances after cardiac arrest. In the current study, we have developed a therapeutic cocktail that includes ten drugs capable of targeting multiple pathways of ischemia-reperfusion injury after CA. We then evaluated its effectiveness in improving neurologically favorable survival through a randomized, blind, and placebo-controlled study in rats subjected to 12 min of asphyxial CA, a severe injury model. RESULTS: 14 rats were given the cocktail and 14 received the vehicle after resuscitation. At 72 h post-resuscitation, the survival rate was 78.6% among cocktail-treated rats, which was significantly higher than the 28.6% survival rate among vehicle-treated rats (log-rank test; p = 0.006). Moreover, in cocktail-treated rats, neurological deficit scores were also improved. These survival and neurological function data suggest that our multi-drug cocktail may be a potential post-CA therapy that deserves clinical translation. CONCLUSIONS: Our findings demonstrate that, with its ability to target multiple damaging pathways, a multi-drug therapeutic cocktail offers promise both as a conceptual advance and as a specific multi-drug formulation capable of combatting neuronal degeneration and death following cardiac arrest. Clinical implementation of this therapy may improve neurologically favorable survival rates and neurological deficits in patients suffering from cardiac arrest.

Homelessness, organ donation, transplantation, and a call for equity in the United States.

While social justice is a pillar that society seeks to uphold, in the area of organ transplantation, social justice, equity, and inclusion fail in the unbefriended and undomiciled population. Due to lack of social support of the homeless population, such status often renders these individuals ineligible to be organ recipients. Though it can be argued that organ donation by an unbefriended, undomciled patient benefits the greater good, there is clear inequity in the fact that homeless individuals are denied transplants due to inadequate social support. To illustrate such social breakdown, we describe two unbefriended, undomiciled patients brought to our hospitals by emergency services with diagnoses of intracerebral haemorrhage that progressed to brain death. This proposal represents a call to action to remediate the broken system: how the inherent inequity in organ donation by unbefriended, undomiciled patients would be ethically optimized if social support systems were implemented to allow for their candidacy for organ transplantation.

Plasmodium sporozoite search strategy to locate hotspots of blood vessel invasion.

Plasmodium sporozoites actively migrate in the dermis and enter blood vessels to infect the liver. Despite their importance for malaria infection, little is known about these cutaneous processes. We combine intravital imaging in a rodent malaria model and statistical methods to unveil the parasite strategy to reach the bloodstream. We determine that sporozoites display a high-motility mode with a superdiffusive Lévy-like pattern known to optimize the location of scarce targets. When encountering blood vessels, sporozoites frequently switch to a subdiffusive low-motility behavior associated with probing for intravasation hotspots, marked by the presence of pericytes. Hence, sporozoites present anomalous diffusive motility, alternating between superdiffusive tissue exploration and subdiffusive local vessel exploitation, thus optimizing the sequential tasks of seeking blood vessels and pericyte-associated sites of privileged intravasation.

External Stenting (Exostenting) to Correct Vascular Torsion and Angulation.

Organ transplantation can be associated with vascular torsions and angulations of both recipient and donor vessels. Such kinks and/or torsions of vessels can compromise the vascular integrity, obstruct inflow and/or outflow, and result in loss of the organ and/or body parts. On many occasions, mild angulations and torsions can be successfully addressed by repositioning the organ. In cases where the abnormal findings persist, maneuvers such as placing a fat pad to create a smoother curve, or even opening the peritoneum (in the case of kidney transplants) to allow for a better positioning of the organ, are associated with successful outcomes. When such torsions/angulations persist despite these approaches, further innovative tactics are required. In the current report, we propose a technique that involves longitudinally opening of a synthetic graft that is rigid enough to maintain its shape, such as a ringed polytetrafluoroethylene graft, and placing it as an external stent around the angulated/torsioned vessel. This maneuver will correct the underlying vascular compromise without having to perform any further invasive interventions, such as reimplanting the organ or resecting part of the involved vessel. Although primarily illustrated for application by describing an instance in which exostenting was applied during kidney transplantation, our approach could be applied to any vessel under many circumstances where angulations/twists are encountered. In this report, we describe the use of an external stent, also called exostenting, to correct a severe torsion/angulation of the external iliac artery in a kidney transplant recipient where all other measures were unsuccessful.

Sensory appeal and puffing intensity of e-cigarette use: Influence of nicotine salts versus free-base nicotine in e-liquids.

BACKGROUND: In the US, nicotine salts (with protonated nicotine instead of free-based nicotine) have been reported to lower the harshness and bitterness of e-cigarette aerosols, making it easier to inhale high levels of nicotine. This study aimed to determine whether nicotine salts also increase sensory appeal at lower concentrations (< 20mg/mL). Moreover, and novel, inhalation intensity of both types of e-liquids was compared. METHODS: In a randomized, double-blinded, within-participants design, healthy adults who use e-cigarettes (n=68) vaped tobacco-flavored e-liquids containing 12mg/mL of free-based nicotine or nicotine salt ad libitum, using their own device, during two online sessions (June-July 2021, Utrecht, The Netherlands). The sensory parameters perceived liking, nicotine intensity, harshness, and pleasantness were rated on a 100-unit visual analog scale. The intensity of use was determined by the recorded puff number, duration and interval. RESULTS: Test scores on appeal, harshness and puffing behavior parameters showed no significant differences between the nicotine salt and the free-base condition. The average inhalation time was 2.5seconds. Additional analyses found no significant effect of liquid order, age, gender, smoking status, vaping frequency and familiarity with nicotine salts. Significant positive correlations were found between the sensory parameters except for harshness. CONCLUSIONS: Contrary to a previous study that used higher nicotine concentrations and standardized puffing conditions in a laboratory setting, we did not observe the effects of nicotine salts on sensory appeal in our real-life study paradigm. Moreover, we did not see effects on study parameters related to puffing intensity.

The Role of the Fusarium oxysporum FTF2 Transcription Factor in Host Colonization and Virulence in Common Bean Plants (Phaseolus vulgaris L.).

The FTF (Fusarium Transcription Factor) gene family is composed of two members (FTF1 and FTF2) with high-sequence homology that encode transcription factors involved in the modulation of virulence in the F. oxysporum species complex (FOSC). While FTF1 is a multicopy gene exclusive of highly virulent strains of FOSC and is located in the accessory genome, FTF2 is a single-copy gene, located in the core genome, and well-conserved in all filamentous ascomycete fungi, except yeast. The involvement of FTF1 in the colonization of the vascular system and regulation of the expression of SIX effectors has been stablished. To address the role of FTF2, we generated and characterized mutants defective in FTF2 in a F. oxysporum f. sp. phaseoli weakly virulent strain and analyzed them together with the equivalent mutants formerly obtained in a highly virulent strain. The results obtained highlight a role for FTF2 as a negative regulator of the production of macroconidia and demonstrate that it is required for full virulence and the positive regulation of SIX effectors. In addition, gene expression analyses provided compelling evidence that FTF2 is involved in the regulation of hydrophobins likely required for plant colonization.

What Does It Take to Solve the 3D Ising Model? Minimal Necessary Conditions for a Valid Solution.

An exact solution of the Ising model on the simple cubic lattice is one of the long-standing open problems in rigorous statistical mechanics. Indeed, it is generally believed that settling it would constitute a methodological breakthrough, fomenting great prospects for further application, similarly to what happened when Lars Onsager solved the two-dimensional model eighty years ago. Hence, there have been many attempts to find analytic expressions for the exact partition function Z, but all such attempts have failed due to unavoidable conceptual or mathematical obstructions. Given the importance of this simple yet paradigmatic model, here we set out clear-cut criteria for any claimed exact expression for Z to be minimally plausible. Specifically, we present six necessary-but not sufficient-conditions that Z must satisfy. These criteria will allow very quick plausibility checks of future claims. As illustrative examples, we discuss previous mistaken "solutions", unveiling their shortcomings.

An Automation System Equivalent to the Douglas Bag Technique Enables Continuous and Repeat Metabolic Measurements in Patients Undergoing Mechanical Ventilation.

PURPOSE: To develop a system that is equivalent to the gold standard Douglas Bag (DB) technique for measuring oxygen consumption (V̇o2), carbon dioxide generation (V̇co2), and respiratory quotient (RQ) and to validate its use in clinical settings. METHODS: This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Healthy volunteers and patients 18 years or older who received mechanical ventilation were enrolled. FINDINGS: Data from 3 healthy volunteers and 7 patients were analyzed in this study. The interrater reliability between the automation device and DB methods were 0.999, 0.993, and 0.993 for V̇o2, V̇co2, and RQ, respectively. In healthy volunteers, mean (SD) V̇o2, V̇co2, and RQ measured by DB were 411 (100) mL/min, 288 (79) mL/min, and 0.70 (0.03) at high fraction of inspired oxygen (Fio2) and 323 (46) mL/min, 280 (45) mL/min, and 0.85 (0.05) at normal Fio2, respectively. V̇o2 was significantly higher (P < 0.05) and RQ was lower (P < 0.01) in the high Fio2 group as compared to those in the normal Fio2 group. Values measured by the automation system were 227 (31) mL/min, 141 (18) mL/min, and 0.62 (0.04) at high Fio2 and 209 (25) mL/min, 147 (18) mL/min, and 0.70 (0.06) at normal Fio2, respectively. RQ was significantly lower (P < 0.05) in the high Fio2 group as compared to the normal Fio2 group. We also successfully performed continuous and repeat measurements by using the device. The longest measurement reached 12 hours 15 minutes, including 50 cycles of repeat measurements that are equivalent to the DB technique as described above. IMPLICATIONS: We developed an automation system that enables repeat measurements of V̇o2, V̇co2, and RQ, and the accuracy was equivalent to the DB technique. High Fio2 may decrease RQ because of an increase in V̇o2.

Portal and Hepatic Venous Territorial Mapping in Healthy Human Livers: Virtual Three-Dimensional Computed Tomography Size-Shape-Topography Study.

OBJECTIVES: This study aimed to assess portal and hepatic venous volumes as related to the planning of complex liver resections and segmental liver transplant. MATERIALS AND METHODS: We analyzed 3-dimensional computed tomography of portal and hepatic vein territorial maps of 140 potential living related liver donors. Portal and hepatic vein maps were simulated both separately and in overlap (cross-mapping) to calculate inflow and outflow volumes. RESULTS: In total liver volume, the right hemiliver was always dominant (mean 64.7 ± 4.8%) and the right medial sector (mean 36.4 ± 6.8%) and segment 8 (mean 19.1 ± 4.3%) accounted for the largest volumes, whereas the left medial sector(mean 13.5 ± 3.1%) and segment 4A (mean 5.8 ± 1.8%) accounted for the smallest volumes (with exclusion of caudate lobe). The right hepatic vein was dominant for both right hemiliver and right lateral sector and had the largest drainage volume in total liver volume (mean 40.0 ± 11.2%). The left hepatic vein was dominant for both left hemiliver and left lateral sector but had the smallest drainage volume fortotal liver volume (mean 21.3 ± 5.0%). The middle hepatic vein drained 50.2 ± 12.5% of the right medial sector and 75.8 ± 15.4% of the left medial sector. In 67 cases, an accessory vein (inferior hepatic vein) drained 16.5 ± 13.2% ofthe right hemiliver, 31.4 ± 25.1% ofthe right lateral sector, 26.6 ± 23.2% of segment 7, and 37.4 ± 31.3% of segment 6. CONCLUSIONS: The portal and hepatic vein territorial anatomy was characterized by extensive individual variability. An extremely smallremnant volume (<25% of total liver volume) precluded a minority of virtual extended left and a majority of extended right hepatectomies. Left trisectionectomy was associated with risky drainage from the middle hepatic vein, extensive segment 6 remnant congestion volume in 8% of cases, and right lateral sector-favorable inferior hepatic vein large drainage pattern in 13% of livers.

Fock-space approach to stochastic susceptible-infected-recovered models.

We investigate the stochastic susceptible-infected-recovered (SIR) model of infectious disease dynamics in the Fock-space approach. In contrast to conventional SIR models based on ordinary differential equations for the subpopulation sizes of S, I, and R individuals, the stochastic SIR model is driven by a master equation governing the transition probabilities among the system's states defined by SIR occupation numbers. In the Fock-space approach the master equation is recast in the form of a real-valued Schrödinger-type equation with a second quantization Hamiltonian-like operator describing the infection and recovery processes. We find exact analytic expressions for the Hamiltonian eigenvalues for any population size N. We present small- and large-N results for the average numbers of SIR individuals and basic reproduction number. For small N we also obtain the probability distributions of SIR states, epidemic sizes and durations, which cannot be found from deterministic SIR models. Our Fock-space approach to stochastic SIR models introduces a powerful set of tools to calculate central quantities of epidemic processes, especially for relatively small populations where statistical fluctuations not captured by conventional deterministic SIR models play a crucial role.