Dicyanorhodanine-Pyrrole Conjugates for Visible Light-Driven Quantitative Photoswitching in Solution and the Solid State.

Small molecule photoswitches capable of toggling between two distinct molecular states in response to light are versatile tools to monitor biological processes, control photochemistry, and design smart materials. In this work, six novel dicyanorhodanine-based pyrrole-containing photoswitches are reported. The molecular design avails both the Z and E isomers from synthesis, where each can be isolated using chromatographic techniques. Inter- and intramolecular hydrogen bonding (H-bonding) interactions available to the E and Z isomers, respectively, uniquely impart thermal stability to each isomer over long time periods. Photoisomerization could be assessed by solution NMR and UV-vis spectroscopic techniques along with complementary ground- and excited-state computational studies, which show good agreement. Quantitative E → Z isomerization occurs upon 523 nm irradiation of the parent compound (where R = H) in solution, whereas Z → E isomerization using 404 nm irradiation offers a photostationary state (PSS) ratio of 84/16 (E/Z). Extending the π-conjugation of the pyrrole unit (where R = p-C6H4-OMe) pushes the maximum absorption to the yellow-orange region of the visible spectrum and allows bidirectional quantitative isomerization with 404 and 595 nm excitation. Comparator molecules have been prepared to report how the presence or absence of H-bonding affects the photoswitching behavior. Finally, studies of the photoswitches in neat films and photoinactive polymer matrices reveal distinctive structural and optical properties of the Z and E isomers and ultimately afford reversible photoswitching to spectrally unique PSSs using visible light sources including the Sun.

Hybrid Email and Outpatient Clinics to Optimize Maintenance Therapy in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia treatment includes an outpatient (OP)-based 2-year maintenance therapy (MT). Over an 8-year period, patients were transited from only OP to a hybrid e-clinic/OP-clinic model. Electronic and patient-held medical records of acute lymphoblastic leukemia patients 1 to 18 years old during MT were used to analyze demographics, drug doses, treatment response and cost. A survey evaluated family satisfaction with the hybrid service. Four hundred and seventy-eight children, all with at least 1 year of MT from March 13, 2014 to March 24, 2022 were grouped into 4 treatment eras, representing the transition from all OP (era 1) to the current hybrid MT practice (era 4). Cohort demographics were similar across all eras. With transition to era 4, OP visits decreased to a third (16 to 18/48 visits). Practice optimization in era 2 resulted in higher MT dose intensity in subsequent eras (era 1: median 82% [interquartile range, 63 to 97]; era 2: 93% [73 to 108]; era 3: 88% [68 to 106]; era 4: 90% [74 to 114], P <0·0001), with no differences in absolute neutrophil count or neutropenia-related toxicity ( P =0.8). The hybrid service reduced MT expenses by ~50% and families (133/156, 85%) reported being very satisfied. Our experience indicates that a hybrid model is feasible, effective and less burdensome for patients and families.

Comparative treatment costs of risk-stratified therapy for childhood acute lymphoblastic leukemia in India.

BACKGROUND: To evaluate the treatment cost and cost effectiveness of a risk-stratified therapy to treat pediatric acute lymphoblastic leukemia (ALL) in India. METHODS: The cost of total treatment duration was calculated for a retrospective cohort of ALL children treated at a tertiary care facility. Children were risk stratified into standard (SR), intermediate (IR) and high (HR) for B-cell precursor ALL, and T-ALL. Cost of therapy was obtained from the hospital electronic billing systems and details of outpatient (OP) and inpatient (IP) from electronic medical records. Cost effectiveness was calculated in disability-adjusted life years. RESULTS: One hundred and forty five patients, SR (50), IR (36), HR (39), and T-ALL (20) were analyzed. Median cost of the entire treatment for SR, IR, HR, and T-ALL was found to be $3900, $5500, $7400, and $8700, respectively, with chemotherapy contributing to 25%-35% of total cost. Out-patient costs were significantly lower for SR (p < 0.0001). OP costs were higher than in-patient costs for SR and IR, while in-patient costs were higher in T-ALL. Costs for non-therapy admissions were significantly higher in HR and T-ALL (p < 0.0001), representing over 50% of costs of in-patient therapy. HR and T-ALL also had longer durations of non-therapy admissions. Based on WHO-CHOICE guidelines, the risk-stratified approach was very cost effective for all categories of patients. CONCLUSIONS: Risk-stratified approach to treat childhood ALL is very cost-effective for all categories in our setting. The cost for SR and IR patients is significantly reduced through decreased IP admissions for both, chemotherapy and non-chemotherapy reasons.

Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01): a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India.

BACKGROUND: In the west, survival following treatment of childhood acute lymphoblastic leukaemia (ALL) approaches 90%. Outcomes in India do not exceed 70%. To address this disparity, the Indian Collaborative Childhood Leukaemia group (ICiCLe) developed in 2013 a contemporary treatment protocol for uniform risk-stratified management of first presentation ALL based on cytogenetics and minimal residual disease levels (MRD). A multicentre randomised clinical trial opened in 2016 (ICiCLe-ALL-14) and examines the benefit of randomised interventions to decrease toxicity and improve outcomes. METHODS: Patients 1-18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (< 10 years) B cell precursor ALL (BCP-ALL) patients with low presentation leucocyte count (< 50 × 109/L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. Patients with T-lineage ALL constitute the fourth risk group. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. Treatment intensity varies by risk group. Clinical data management is based on a web-based remote data capture system. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young non-high-risk BCP-ALL. The second randomisation examines the survival benefit of substituting doxorubicin with mitoxantrone in delayed intensification for all patients. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation. DISCUSSION: ICiCLe-ALL-14 is the first multicentre randomised childhood cancer clinical trial in India. The pre-trial phase allowed standardisation of risk-stratification diagnostics and established the feasibility of collaborative practice, uniform treatment, patient enrolment and data capture. Pre-trial observations confirm the impact of risk-stratified therapy in reducing treatment-related deaths and costs. Uniform practice across centres allows patients to access care locally, potentially decreasing financial hardship and dislocation. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI) CTRI/2015/12/006434 . Registered on 11 December 2015.

Chemical Composition, Antibacterial Activity, and Antibiotic Potentiation of Boswellia sacra Flueck. Oleoresin Extracts from the Dhofar Region of Oman.

The emergence of MDR bacterial pathogens has directed antibiotic discovery research towards alternative therapies and traditional medicines. Boswellia sacra oleoresin (frankincense) was used to treat bacterial infections in traditional Arabian and Asian healing systems for at least 1000 years. Despite this, B. sacra extracts have not been rigorously tested for inhibitory activity against gastrointestinal pathogens or bacterial triggers of autoimmune diseases. Solvent extracts were prepared from Boswellia sacra oleoresins obtained from three regions near Salalah, Oman. MIC values were quantified against gastrointestinal pathogens and bacterial triggers of selected autoimmune diseases by disc diffusion and broth dilution methods. The antibacterial activity was also evaluated in combination with conventional antibiotics, and the class of interaction was determined by ΣFIC analysis. Isobolograms were used to determine the optimal ratios for synergistic combinations. Toxicity was evaluated by ALA and HDF cell viability bioassays. The phytochemical composition of the volatile components of all extracts was identified by nontargeted GC-MS headspace analysis. All methanolic extracts inhibited the growth of all of the bacteria tested, although the extracts prepared using Najdi oleoresin were generally more potent than the Sahli and Houjari extracts. Combinations of the methanolic B. sacra extracts and conventional antibiotics were significantly more effective in inhibiting the growth of several bacterial pathogens. In total, there were 38 synergistic and 166 additive combinations. Approximately half of the synergistic combinations contained tetracycline. All B. sacra extracts were nontoxic in the ALA and HDF cell viability assays. Nonbiased GC-MS headspace analysis of the methanolic extracts putatively identified a high diversity of monoterpenoids, with particularly high abundances of α-pinene. The antibacterial activity and lack of toxicity of the B. sacra extracts indicate their potential in the treatment and prevention of gastrointestinal and autoimmune diseases. Furthermore, the extracts potentiated the activity of several conventional antibiotics, indicating that they may contain resistance-modifying compounds.