Unleashing the Cytokine Storm: A Case of Macrophage Activation Syndrome in Systemic Lupus Erythematosus.

Macrophage activation syndrome (MAS), synonymous with secondary hemophagocytic lymphohistiocytosis (HLH), is a rare and critical complication of rheumatologic disease stemming from the unregulated activation and rapid multiplication of macrophages and T lymphocytes. While it primarily manifests in children diagnosed with systemic juvenile idiopathic arthritis (sJIA), it can arise less frequently in other rheumatologic conditions. Here, we outline the clinical course, treatment, and outcome of MAS diagnosed in an 18-year-old female previously diagnosed with SLE who exhibited a unique clinical presentation.

A nanoscale photonic thermal transistor for sub-second heat flow switching.

Control of heat flow is critical for thermal logic devices and thermal management and has been explored theoretically. However, experimental progress on active control of heat flow has been limited. Here, we describe a nanoscale radiative thermal transistor that comprises of a hot source and a cold drain (both are ~250 nm-thick silicon nitride membranes), which are analogous to the source and drain electrodes of a transistor. The source and drain are in close proximity to a vanadium oxide (VOx)-based planar gate electrode, whose dielectric properties can be adjusted by changing its temperature. We demonstrate that when the gate is located close ( < ~1 µm) to the source-drain device and undergoes a metal-insulator transition, the radiative heat transfer between the source and drain can be changed by a factor of three. More importantly, our nanomembrane-based thermal transistor features fast switching times ( ~ 500 ms as opposed to minutes for past three-terminal thermal transistors) due to its small thermal mass. Our experiments are supported by detailed calculations that highlight the mechanism of thermal modulation. We anticipate that the advances reported here will open new opportunities for designing thermal circuits or thermal logic devices for advanced thermal management.

How substituents tune quantum interference in meta-OPE3 molecular junctions to control thermoelectric transport.

Quantum interference (QI) can strongly affect electric and thermoelectric properties of molecular junctions (MJs). So far, however, a limited number of experimental studies have explored the influence of QI on thermoelectric transport in MJs. To address this open point, we synthesized derivatives of meta-OPE3 with an electron-withdrawing nitro (-NO2) substituent or an electron-donating N,N-dimethyl amine (-NMe2) substituent, attached at two different positions of the central phenylene ring, and systematically studied the electrical conductance and thermopower of the corresponding gold-molecule-gold junctions. We show that (i) the electrical conductance of MJs depends weakly on the polarity of the substituents but strongly on the substitution position and (ii) MJs with the N,N-dimethyl amine group feature a higher thermopower than MJs with the nitro group. We also present calculations based on first principles, which explain these trends and show that the transport properties are highly sensitive to microscopic details in junctions, exhibiting destructive QI features.

Comparison of Efficacy and Safety of a Bevacizumab Biosimilar, in Combination with Chemotherapies, in Nonresectable Metastatic Colorectal Cancer and in Advanced Nonsquamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study.

Ranjith K.The objective of this study was to compare the efficacy, safety, pharmacokinetics, and immunogenicity of a proposed bevacizumab biosimilar (DRL_BZ) with the innovator Avastin (reference medicinal product [RMP]) in patients with nonresectable metastatic colorectal cancer (mCRC) over a period of 9 months and advanced nonsquamous non-small cell lung cancer (NSCLC) over 6 months. The study was planned as a randomized, double-blind trial. In part A, a total of 117 mCRC patients were intended to receive 5 mg/kg of bevacizumab every 2 weeks along with mFOLFOX6 chemotherapy for a maximum of 18 cycles. In part B, 60 NSCLC patients were to receive 15 mg/kg of bevacizumab every 3 weeks along with pemetrexed and carboplatin for the initial four cycles, followed by pemetrexed for another four cycles. The primary endpoint was the progression-free survival rate at 6 months (PFS6) in both subparts. The anticipated sample size was 106 evaluable mCRC patients to achieve 85% statistical power for concluding noninferiority with a margin of half the difference (18.8%) between DRL_BZ and Avastin, along with a pilot study involving 60 evaluable NSCLC patients. Safety comparison included assessing adverse events (AEs), infusion reactions, and lab abnormalities. Immunogenicity comparison involved the incidence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs). Pharmacokinetic comparison was planned after the first and fourth dosing cycles of treatment in 24 NSCLC patients. The PFS6 for mCRC patients treated with DRL_BZ and RMP was 57.8% and 50% respectively, with a difference in efficacy of 7.8 (-8.7, 23.7). The PFS9 was 31.1% and 22.9%, with a difference of 8.2% (-6.9%, 22.9%). The objective response rate (ORR) for DRL_BZ and RMP was 28.8% and 22.4%, while the disease control rate (DCR) was 44.2% and 37.9% respectively. For NSCLC patients, the PFS6 was 44% and 45%, showing a difference of -1.0 (-4.2, 22.1). The ORR was 41.4% and 48.1%, and the DCR was 62.1% and 63%. The frequency, type, and severity of AEs were similar in both indications. Blood levels during the first and fourth dosing cycles exhibited comparable values. All NSCLC patients tested negative for ADA, while no mCRC patients on DRL_BZ tested positive for ADA. Low incidences of ADA (8%) and NAbs (4.0%) were reported in patients on RMP. Overall, the efficacy, safety, immunogenicity, and pharmacokinetic parameters of DRL_BZ and RMP were found to be comparable. Clinical Trial Registration For BZ-01-002: CTRI/2016/01/006481.

Time to therapy and safety of testicular tissue cryopreservation in children undergoing gonadotoxic treatment or hematopoietic stem cell transplant.

BACKGROUND: With the use of multimodal treatments and hematopoietic stem cell transplant, the majority of children diagnosed with malignancies and hematologic diseases are now surviving into adulthood. Due to the gonadotoxic effects and potential for future infertility associated with many of these treatments, fertility counseling with sperm cryopreservation prior to starting therapy is the standard of care for post-pubertal males. Unfortunately, the options are limited for pre-pubertal patients or those unable to provide a specimen. Testicular tissue cryopreservation (TTC) is an investigational method to surgically obtain germ cells from testicular tissue and potentially restore future spermatogenesis. While TTC has been shown to be safe, little is reported on the time to treatment following the procedure to ensure adequate wound healing and avoid delays in definitive therapy. OBJECTIVES: The primary outcome was the time to initiation of treatment following TTC. Secondary outcomes were complication rates, delays in treatment due to TTC, and presence of germ cells. METHODS: We conducted a single-institution retrospective cohort study of patients undergoing TTC between 2017 and 2023. Patients at significant risk for treatment related infertility based on established criteria were eligible for TTC. Patients were excluded if they received their oncology or hematology care elsewhere. All patients were enrolled in an IRB approved research protocol with 75% of the tissue submitted for cryopreservation and 25% for research purposes. Time to therapy was defined as the first receipt of gonadotoxic treatment following TTC. RESULTS: A total of 122 patients (53 = malignant, 69 = non-malignant) underwent TTC with a median age of 5.9 years (IQR 2.3-9.35). Germ cells were identified in 115 (94%) specimens. A total of 109 (89%) patients underwent concomitant procedures. The median time to initiation of therapy was 5 (IQR 1.0-7.0) and 7 days (IQR 6.0-13.0) for malignant and non-malignant disease, respectively. The 30-day surgical complication rate was 2.5% and was similar between malignant vs non-malignant diagnoses (p = 0.58). All surgical complications were managed non-operatively. No patients had a delay in definitive treatment due to concern for wound healing or complications. DISCUSSION: Our surgical complication rates are similar to previous studies and are not affected by the time to treatment following TTC. Limitations of the study are its retrospective design, single institution, and short-term follow up. CONCLUSION: TTC can be performed safely, efficiently, and in conjunction with other necessary procedures without resulting in delays of definitive treatment. TTC affords the opportunity for fertility preservation in children who have no other options.

The Metal-Insulator Transition in Vanadium Oxide Nanofilms Enables Microkelvin-Resolution Thermometry.

High-resolution thermometry is critical for probing nanoscale energy transport. Here, we demonstrate how high-resolution thermometry can be accomplished using vanadium oxide (VOx), which features a sizable temperature-dependence of its resistance at room temperature and an even stronger dependence at its metal-insulator-transition (MIT) temperature. We microfabricate VOx nanofilm-based electrical resistance thermometers that undergo a metal-insulator-transition at ∼337 K and systematically quantify their temperature-dependent resistance, noise characteristics, and temperature resolution. We show that VOx sensors can achieve, in a bandwidth of ∼16 mHz, a temperature resolution of ∼5 µK at room temperature (∼300 K) and a temperature resolution of ∼1 µK at the MIT (∼337 K) when the amplitude of temperature perturbations is in the microkelvin range, which, in contrast to larger perturbations, is found to avoid hysteric resistance responses. These results demonstrate that VOx-based thermometers offer a ∼10-50-fold improvement in resolution over widely used Pt-based thermometers.

Micro-kelvin temperature-stable system for biocalorimetry applications.

Achieving micro-kelvin (µK) temperature stability is critical for many calorimetric applications. For example, sub-nanowatt resolution biocalorimetry requires stabilization of the temperature of the calorimeter to µK levels. Here, we describe how µK temperature stability can be accomplished in a prototypical calorimetric system consisting of two nested shields and a suspended capillary tube, which is well suited for biocalorimetry applications. Specifically, we show that by employing nested shields with µTorr-levels of vacuum in the space between them as well as precise feedback control of the temperature of the shields (performed using high-resolution temperature sensors), the effect of ambient temperature fluctuations on the inner shield and the capillary tube can be attenuated by ∼100 dB. We also show that this attenuation is key to achieving temperature stabilities within ±1 and ±3 µK (amplitude of oscillations) for the inner shield and the capillary tube sensor, respectively, measured in a bandwidth of 1 mHz over a period of 10 h at room temperature (∼20.9 ± 0.2 °C). We expect that the methods described here will play a key role in advancing biocalorimetry.

Efficacy, Safety, Pharmacokinetics, and Immunogenicity of DRL-Trastuzumab Versus Herceptin in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Randomized Controlled Trial.

PURPOSE: Dr Reddy's Laboratories Trastuzumab (DRL_TZ) is a biosimilar to Herceptin under development. The present study was conducted to evaluate efficacy, safety, pharmacokinetics (PKs), and immunogenicity of DRL_TZ in comparison with the reference medicinal product (RMP) along with concomitant weekly paclitaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). METHODS: This was a randomized, double-blind study in female patients with HER2-positive MBC, randomly assigned in a 1:1 ratio to receive either DRL_TZ or the RMP, that is, an innovator product sourced from the European region, along with additional chemotherapy, as first-line treatment for up to 24 weeks. The primary end point was the best overall response rate (ORR) as per RECIST 1.1 criteria. Progression-free survival rate at 6 months (PFS6), safety, immunogenicity, and PK parameters were assessed as secondary end points. RESULTS: A total of 164 patients were randomly assigned to receive either DRL_TZ or the RMP. Best ORR in the per-protocol population was comparable, 91.9% (93.3% CI, 83.2 to 96.3) versus 82.1% (93.3% CI, 72.0 to 89.1) in DRL_TZ and RMP arms, respectively; the difference between the arms was 9.8% with a 93.3% CI of -1.3 to 20.8. The PFS6 rate, safety, PK profile, and antidrug antibody incidence were comparable. An additional 44 patients were recruited in the postrandomization phase, in an open-label manner, and started on DRL_TZ to generate more data on efficacy, safety, and immunogenicity. The additional data with DRL_TZ, when pooled, were similar to the RMP data. CONCLUSION: DRL_TZ was found to have similar efficacy and comparable safety, PK, and immunogenicity profiles as the RMP.

Transcription factor Tcf21 modulates urinary bladder size and differentiation.

Urinary bladder organogenesis requires coordinated cell growth, specification, and patterning of both mesenchymal and epithelial compartments. Tcf21, a gene that encodes a helix-loop-helix transcription factor, is specifically expressed in the mesenchyme of the bladder during development. Here we show that Tcf21 is required for normal development of the bladder. We found that the bladders of mice lacking Tcf21 were notably hypoplastic and that the Tcf21 mutant mesenchyme showed increased apoptosis. There was also a marked delay in the formation of visceral smooth muscle, accompanied by a defect in myocardin (Myocd) expression. Interestingly, there was also a marked delay in the formation of the basal cell layer of the urothelium, distinguished by diminished expression of Krt5 and Krt14. Our findings suggest that Tcf21 regulates the survival and differentiation of mesenchyme cell-autonomously and the maturation of the adjacent urothelium non-cell-autonomously during bladder development.

One and done: Feasibility and Safety of Primary Ureteroscopy in a Pediatric Population.

BACKGROUND: Pediatric urolithiasis has been increasing at rate of 4-10 % annually in the United States, most notably within adolescents and females. A significant number of patients will require surgical management of their stones. Primary ureteroscopy (URS) affords the opportunity to treat stones under a single anesthetic with lower re-treatment rates or anatomical and stone characteristic limitations compared to shockwave lithotripsy. Previous studies evaluating primary URS have been largely underpowered, are limited by stone location, and/or are not representative of the stone population in the United States. OBJECTIVES: Primary study outcomes were the success of primary URS and patient characteristics associated with success. Secondary outcomes were the stone-free rate (SFR), 30-day emergency department (ED) visits, 30-day readmissions, and complications. METHODS: We performed a retrospective cohort study of patients less than 18 years of age from 2011 to 2023 who underwent primary URS. Patients were excluded if a ureteral stent was placed prior to URS or diagnostic URS was performed. A successful primary URS was considered if access to the ureter was obtained and treatment of the stone(s) completed. In failed primary URS, a ureteral stent was placed for staged management. RESULTS: A total of 196 patients were included and primary URS was performed or attempted on 224 renal units. The median age was 15.8 (IQR 13.4-16.9) years and median follow up 8.4 (IQR 1.1-24.6) months. The success rate of primary URS was 79 %. No significant characteristics were appreciated for successful primary URS based on: overall age, <14 vs > 14 years of age, sex, body mass index, history of stones, history of endourologic procedures, preoperative alpha blockade, location of stone(s), multiple stones, type of URS, or acute treatment. In successful primary URS, the SFR was 88 % with stone size (p = 0.0001) the only predictor of having residual stones. The 30-day ED rate was 21.4 %, 30-day unplanned readmission rate was 12.5 %, and complication rate was 7.5 %. No long-term complications were appreciated. DISCUSSION: Our success of primary URS compares favorably to previously published literature. Our SFR rate, 30-day ED visits, 30-day unplanned readmission, and complication rates are similar to other studies. Limitations of the study are its retrospective design, selection bias, and intermediate follow-up. CONCLUSIONS: Primary URS can be completed safely in the majority of pediatric patients without any patient characteristics associated with success. We advocate for primary URS when possible due to the excellent SFR and potential of treating stones under a single anesthetic.

An Insidious Case of Severe Acquired Factor VIII Inhibitor.

Acquired hemophilia occurs when neutralizing antibodies inhibit the activity of coagulation factors, commonly occurring with factor VIII. Most cases are idiopathic; however, autoimmune diseases, certain medications, and malignancies can predispose patients to the development of these inhibitors. Moreover, the initial presentation of the disease is more often catastrophic bleeding, with ecchymosis or mucosal bleeding being less common. This case report outlines an incidental finding of a severe factor VIII inhibitor (with 0% activity) with non-catastrophic bleeding at presentation in the setting of potential lymphoma. Subsequently, the patient was treated with recombinant factor VIIa and immunosuppression with steroids. The case sheds light on the benign presentation of a rapidly fatal disease, thus necessitating urgent and rapid identification. Given the insidious presentation, further research is required on the various factor inhibitors to reduce health costs and improve mortality.

Surface Phonon Polariton-Mediated Near-Field Radiative Heat Transfer at Cryogenic Temperatures.

Recent experiments, at room temperature, have shown that near-field radiative heat transfer (NFRHT) via surface phonon polaritons (SPhPs) exceeds the blackbody limit by several orders of magnitude. Yet, SPhP-mediated NFRHT at cryogenic temperatures remains experimentally unexplored. Here, we probe thermal transport in nanoscale gaps between a silica sphere and a planar silica surface from 77-300 K. These experiments reveal that cryogenic NFRHT has strong contributions from SPhPs and does not follow the T^{3} temperature (T) dependence of far-field thermal radiation. Our modeling based on fluctuational electrodynamics shows that the temperature dependence of NFRHT can be related to the confinement of heat transfer to two narrow frequency ranges and is well accounted for by a simple analytical model. These advances enable detailed NFRHT studies at cryogenic temperatures that are relevant to thermal management and solid-state cooling applications.

Pyridoxine Deficiency and Neurologic Dysfunction: An Unlikely Association.

Pyridoxine deficiency is a prevalent condition in the United States that primarily affects patients with alcohol use disorder. The presentation of this condition is very nonspecific and commonly presents with a constellation of symptoms including peripheral neuropathy, stomatitis, dermatitis, confusion, depression, encephalopathy, and seizures. Over half of these patients have associated alcohol use disorder, which causes pyridoxine deficiency due to the breakdown of pyridoxal phosphate during ethanol metabolism in the liver. As an important cofactor in the synthesis of γ-aminobutyric acid (GABA), deficient levels of pyridoxine may lower the seizure threshold due to reduced GABA-mediated inhibition. This case details a 57-year-old male with chronic alcoholism and a history of seizures who developed episodes of myoclonic jerks, tremors, anxiety, and neuropathy whose symptoms persisted even while on anti-epileptic medication. He was found to have pyridoxine deficiency and had full resolution of symptoms shortly after the administration of vitamin B6 supplementation. Pyridoxine deficiency may lead to severe neurologic disorders such as encephalopathy and seizures. Hence, it is important to consider pyridoxine deficiency in the workup of neurologic complaints, especially in high-risk patients.

Diffuse Large B-cell Lymphoma of the Orbit With Intracranial Extension: A Rare Entity.

Primary diffuse large B-cell lymphoma of the orbit is a rare diagnosis that accounts for less than 1% of all non-Hodgkin's lymphoma (NHL) cases. We present here the case of a middle-aged woman with a past medical history of intellectual delay and hypothyroidism who presented with a large diffusely infiltrating mass of the left orbit. A biopsy of the lesion during the patient's hospitalization confirmed a diagnosis of diffuse, large B-cell lymphoma. Due to extensive local invasion, she was deemed a poor surgical candidate. While inpatient, she was started on systemic chemotherapy and discharged with close follow-up planned with the oncologic and surgical teams.

Role of Tranexamic Acid in Palliative Control of Bleeding in End-Stage Head and Neck Cancer: A Case Report.

Tumor-related bleeding is a common manifestation of end-stage head and neck cancer, and it can have a significant impact on a patient's quality of life. Tranexamic acid is an anti-fibrinolytic agent that has been shown to effectively control bleeding and reduce the need for transfusions in various hemorrhagic conditions. Here, we present the case of a patient with end-stage head and neck cancer experiencing recurrent episodes of bleeding, who was able to successfully achieve hemostasis after being treated with tranexamic acid. This case report highlights the role of tranexamic acid as a palliation agent that can help control the unpleasant bleeding symptoms of end-stage head and neck cancer and provide a better quality of life for patients.

Electrical Conductance and Thermopower of ß-Substituted Porphyrin Molecular Junctions─Synthesis and Transport.

Molecular junctions offer significant potential for enhancing thermoelectric power generation. Quantum interference effects and associated sharp features in electron transmission are expected to enable the tuning and enhancement of thermoelectric properties in molecular junctions. To systematically explore the effect of quantum interferences, we designed and synthesized two new classes of porphyrins, P1 and P2, with two methylthio anchoring groups in the 2,13- and 2,12-positions, respectively, and their Zn complexes, Zn-P1 and Zn-P2. Past theory suggests that P1 and Zn-P1 feature destructive quantum interference in single-molecule junctions with gold electrodes and may thus show high thermopower, while P2 and Zn-P2 do not. Our detailed experimental single-molecule break-junction studies of conductance and thermopower, the latter being the first ever performed on porphyrin molecular junctions, revealed that the electrical conductance of the P1 and Zn-P1 junctions is relatively close, and the same holds for P2 and Zn-P2, while there is a 6 times reduction in the electrical conductance between P1 and P2 type junctions. Further, we observed that the thermopower of P1 junctions is slightly larger than for P2 junctions, while Zn-P1 junctions show the largest thermopower and Zn-P2 junctions show the lowest. We relate the experimental results to quantum transport theory using first-principles approaches. While the conductance of P1 and Zn-P1 junctions is robustly predicted to be larger than those of P2 and Zn-P2, computed thermopowers depend sensitively on the level of theory and the single-molecule junction geometry. However, the predicted large difference in conductance and thermopower values between Zn-P1 and Zn-P2 derivatives, suggested in previous model calculations, is not supported by our experimental and theoretical findings.

Real-world outcomes of diffuse large B-cell lymphoma in the biosimilar era.

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and the most common type of non-Hodgkin lymphoma (NHL). The clinical use of rituximab has improved the treatment response and survival of patients with DLBCL. The introduction of rituximab biosimilar into healthcare system has helped in providing a cost-effective treatment to B-cell lymphoid malignancies as standard of care and has improved access to patients worldwide. The aim of this study was to observe the real-world effectiveness and safety of Reditux™ and Ristova® in DLBCL patients. Methods: Observational study in adults with DLBCL receiving Reditux™ or Ristova® across 29 centers in India (2015-2022). Effectiveness and safety were assessed up to 2 years after first dose. Results: Out of 1,365 patients considered for analysis, 1,250 (91.6%) were treated with Reditux™ and 115 (8.42%) with Ristova®. At 2 years, progression-free survival (PFS) 69% [hazard ratio (HR), 1.16; 95% CI, 0.80-1.67], overall survival (OS) 78.7% (HR, 1.20; 95% CI, 0.78-1.86), response rates, quality of life (QoL), and overall safety in both the cohorts were comparable. The best overall response rate (BORR) at 6 months was comparable with no statistically significant differences between the Reditux™ and the Ristova® cohorts (89.2% vs. 94.3%). In multivariate analysis, BCL-2 and VAS were significant prognostic factors for PFS. Conclusion: Reditux™ and Ristova® were comparable in real-world setting. Clinical Trial Registration: ISRCTN registry, identifier (ISRCTN13301166).

The Double-Edged Sword: Naloxone-Induced Noncardiogenic Pulmonary Edema.

Naloxone-induced noncardiogenic pulmonary edema (NCPE) is a scarcely reported side effect that can occur after naloxone administration. We present a case of a 46-year-old male who presented to the emergency department for further management of an opioid overdose, who developed acute hypoxic respiratory failure after several doses of naloxone. The rapid deterioration of the patient's respiratory status required increased supplemental oxygen, with plane film radiography suggesting diffuse pulmonary edema. This case emphasizes the importance of understanding the significant side effects of a lifesaving drug and the implications they carry now that naloxone is available without prescription.

Non-Cutaneous Visceral Kaposi's Sarcoma Diagnosis Confounded by Mycobacterium Avium Complex Lymphadenitis.

Kaposi's sarcoma (KS) is an Acquired Immune Deficiency Syndrome (AIDS)-defining illness, with cutaneous KS being a more common presentation. Visceral involvement, particularly in the gastrointestinal (GI) tract, without cutaneous involvement, is rare. Consisting of generally non-specific symptoms, GI-KS can have potentially fatal outcomes, including hemorrhage or perforation, making prompt diagnosis and treatment imperative. Our case describes a 31-year-old male with AIDS who presented with a neck mass and purulent, bloody rectal drainage. The neck mass was biopsied and identified as caseated necrotic cervical lymphadenitis caused by Mycobacterium avium complex (MAC). The patient presented with rectal drainage, and additional abdominal necrotic lymph nodes were discovered on CT. A subsequent colonoscopy was completed, confirming the diagnosis of visceral KS. Delayed diagnosis of visceral KS can lead to an extensive, widespread disease requiring adjuvant and prolonged treatment. Prompt diagnosis can reduce morbidity and mortality. This case aims to shed light on a rare presentation of a common disease state with potentially fatal complications and emphasizes the importance of maintaining a broad differential diagnosis.