Real-world total cost of care by line of therapy in relapsed/refractory diffuse large B-cell lymphoma.

AIMS: There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While total cost of care (TCC) by the number of lines of therapy (LoTs) has been evaluated, more recent cost estimates using real-world data are needed. This analysis assessed real-world TCC of R/R DLBCL therapies by LoT using the IQVIA PharMetrics Plus database (1 January 2015-31 December 2021), in US patients aged ≥18 years treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an R-CHOP-like regimen as first-line therapy. METHODS: Treatment costs and resources in the R/R setting were assessed by LoT. A sensitivity analysis identified any potential confounding of the results caused by the impact of the COVID-19 pandemic on healthcare utilization and costs. Overall, 310 patients receiving a second- or later-line treatment were included; baseline characteristics were similar across LoTs. Inpatient costs represented the highest percentage of total costs, followed by outpatient and pharmacy costs. RESULTS: Mean TCC per-patient-per-month generally increased by LoT ($40,604, $48,630, and $59,499 for second-, third- and fourth-line treatments, respectively). Costs were highest for fourth-line treatment for all healthcare resource utilization categories. Sensitivity analysis findings were consistent with the overall analysis, indicating results were not confounded by the COVID-19 pandemic. LIMITATIONS: There was potential misclassification of LoT; claims data were processed through an algorithm, possibly introducing errors. A low number of patients met the inclusion criteria. Patients who switched insurance plans, had insurance terminated, or whose enrollment period met the end of data availability may have had truncated follow-up, potentially resulting in underestimated costs. CONCLUSION: Total healthcare costs increased with each additional LoT in the R/R DLBCL setting. Further improvements of first-line treatments that reduce the need for subsequent LoTs would potentially lessen the economic burden of DLBCL.

Correction: Challenging drug-resistant TB treatment journey for children, adolescents and their care-givers: A qualitative study.

[This corrects the article DOI: 10.1371/journal.pone.0248408.].

US cost-effectiveness analysis of polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma.

AIMS: We evaluated the pharmacoeconomic value of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) in previously untreated diffuse large B-cell lymphoma (DLBCL) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MATERIALS AND METHODS: A 3-state partitioned survival model was used to estimate life years (LYs), quality-adjusted LYs (QALYs), and cost impacts of Pola-R-CHP versus R-CHOP. Analyses utilized mixture-cure survival modelling, assessed a lifetime horizon, discounted all outcomes at 3% per year, and examined both payer and societal perspectives. Progression-free survival, overall survival (OS), drug utilization, treatment duration, adverse reactions, and subsequent treatment inputs were based on data from the POLARIX study (NCT03274492). Costs included drug acquisition/administration, adverse reaction management, routine care, subsequent treatments, end-of-life care, and work productivity. RESULTS: Incremental cost-effectiveness ratios of Pola-R-CHP versus R-CHOP were $70,719/QALY gained and $88,855/QALY gained from societal and payer perspectives, respectively. The $32,824 higher total cost of Pola-R-CHP versus R-CHOP was largely due to higher drug costs ($122,525 vs $27,694), with cost offsets including subsequent treatment (-$52,765), routine care (-$1,781), end-of-life care (-$383), and work productivity (-$8,418). Pola-R-CHP resulted in an increase of 0.47 LYs and 0.46 QALYs versus R-CHOP. Pola-R-CHP was cost-effective in 60.9% and 58.0% of simulations at a willingness-to-pay threshold of $150,000/QALY gained from societal and payer perspectives, respectively. LIMITATIONS: There was uncertainty around the OS extrapolation in the model, and costs were derived from different sources. Recommended prophylactic medications were not included; prophylactic use of granulocyte colony-stimulating factor for all patients was assumed to be equal across treatment arms in POLARIX. Work productivity loss was estimated from a general population and was not specific to patients with DLBCL. CONCLUSION: Pola-R-CHP was projected to be cost-effective versus R-CHOP in previously untreated DLBCL, suggesting that Pola-R-CHP represents good value relative to R-CHOP in this setting.

Cost of Disease Progression in Diffuse Large B-Cell Lymphoma After Frontline Treatment With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

BACKGROUND: In recent years, novel agents have become available to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL); the impact of such agents on treatment costs has not been formally studied. We present results from 2 independent, retrospective, real-world cohort analyses to determine the cost of disease progression after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MATERIALS AND METHODS: Analyses were conducted using the IQVIA PharMetricsⓇ Plus claims database and the Surveillance, Epidemiology, and End Results registry-Medicare-linked database (SEER-Medicare) and included patients ≥18 years and ≥66 years, respectively. "No progression" was defined as no second-line therapy for ≥2 years after the end of first-line R-CHOP and "treated progression" as initiating a second-line therapy within 2 years following the end of first-line R-CHOP. Analyses were adjusted for baseline covariates, and per-patient-per-month (PPPM) costs were compared between progressors and nonprogressors. RESULTS: The IQVIA PharMetrics Plus analysis (January 1, 2010-June 30, 2018) included 871 patients (nonprogressors, n = 725; progressors, n = 146), including 10 patients who received chimeric antigen receptor T-cell therapy (CAR-T). Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,554 vs. $1561, P < .001). The SEER-Medicare analysis (January 1, 2010-December 31, 2017) included 4099 patients (nonprogressors, n = 3389; progressors, n = 710), including 12 patients receiving CAR-T. Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,928 vs. $2902, P < .001). CONCLUSION: Treated progression of DLBCL increases adjusted PPPM costs by over $8000 compared with no progression.

Nurse-led initiation of hepatitis C care in rural Cambodia.

Objective: To determine whether a nurse-led model of care for patients with hepatitis C virus (HCV) infections can provide safe and effective diagnosis and treatment in a resource-poor setting in rural Cambodia. Methods: The nurse-led initiation pilot project was implemented by Médecins Sans Frontières in collaboration with the Cambodian health ministry in two operational districts in Battambang Province between 1 June and 30 September 2020. Nursing staff at 27 rural health centres were trained to identify signs of decompensated liver cirrhosis and to provide HCV treatment. Patients without decompensated cirrhosis or another comorbidity were initiated at health centres onto combined treatment with sofosbuvir, 400 mg/day, and daclatasvir, 60 mg/day, orally for 12 weeks. Treatment adherence and effectiveness were assessed during follow-up. Findings: Of 10 960 individuals screened, 547 had HCV viraemia (i.e. viral load ≥ 1000 IU/mL). Of the 547, 329 were eligible for treatment initiation at health centres through the pilot project. All 329 (100%) completed treatment and 310 (94%; 95% confidence interval: 91-96) achieved a sustained virological response 12 weeks post-treatment. Depending on patient subgroups, this response varied from 89% to 100%. Only two adverse events were recorded; both were determined as unrelated to treatment. Conclusion: The safety and effectiveness of direct-acting antiviral medication has previously been demonstrated. Models of HCV care now need to enable greater access for patients. The nurse-led initiation pilot project provides a model for use in other resource-poor settings to scale up national programmes.

The challenge of antibiotic resistance in post-war Mosul, Iraq: an analysis of 20 months of microbiological samples from a tertiary orthopaedic care centre.

OBJECTIVES: Iraq has suffered unrest and conflicts in the past decades, leaving behind a weakened healthcare system. In 2018, Médecins Sans Frontières (MSF) opened a tertiary orthopaedic care centre in Mosul providing reconstructive surgery with access to microbiological analysis. METHODS: A retrospective cross-sectional analysis of microbiological and clinical data of patients admitted between April 2018 and December 2019. RESULTS: There were 174 patients who were included in this study; there were more males than females (135 to 38, respectively), and the mean age was 32.6 y. Of the 174 patients, the majority had more than one bacterial isolate detected (n = 122, 70.1%); 141 (81.0%) had at least one multidrug-resistant (MDR) isolate detected during their hospital stay. Staphylococcus aureus (n = 197, 48.2%) was the most common organism isolated. Overall, most isolates detected were MDR (n = 352, 86%), mostly methicillin-resistant S. aureus (n = 186, 52.8%) or extended-spectrum beta-lactamase-producing Enterobacterales (n = 117, 33.2%). Among patients admitted to the operating department (n = 111, 63.7%), 81.1% (n = 90) were admitted for violent trauma injuries. Patients who had more than one procedure performed per surgery had significantly increased odds of having at least one MDR organism isolated (OR 8.66, CI 1.10-68.20, P = 0.03). CONCLUSION: This study describes a high prevalence of antibiotic resistance in patients with trauma-related wounds in Mosul, Iraq. It highlights the importance of microbiological analysis and ongoing surveillance to provide optimal treatment. Additionally, it underscores the importance of infection prevention and control measures as well as antibiotic stewardship.

Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study.

BACKGROUND: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. METHODS: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. INTERPRETATION: A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. FUNDING: Janssen Research & Development and Legend Biotech.

Challenging drug-resistant TB treatment journey for children, adolescents and their care-givers: A qualitative study.

BACKGROUND: Childhood multidrug-resistant TB (MDR-TB) still affects around 25000 children every year across the globe. Though the treatment success rates for drug-resistant TB (DR-TB) in children are better than adults, children and adolescents face unique hurdles during DR-TB (MDR-TB, Pre-XDR TB and XDR-TB) treatment. This study aimed to understand the patients, guardians and healthcare providers' perspectives about DR-TB treatment journey of patients and caregivers. METHODS: This is a qualitative study involving in depth-interviews of purposively selected adolescents (n = 6), patients guardians (for children and adolescents, n = 5) and health care providers (n = 8) of Médecins Sans Frontières (MSF) clinic, Mumbai, India. In-depth face to face interviews were conducted in English or Hindi language using interview guides during September-November 2019. The interviews were audio-recorded after consent. Thematic network analysis was used to summarize textual data. ATLAS.ti (version 7) was used for analysis. RESULT: The age of adolescent patients ranged from 15-19 years and four were female. Five guardians (of three child and two adolescent patients) and eight healthcare providers (including clinicians- 2, DOT providers-2, counselors-2 and programme managers-2) were interviewed. The overarching theme of the analysis was: Challenging DR-TB treatment journey which consisted of four sub-themes: 1) physical-trauma, 2) emotional-trauma, 3) unavailable social-support and 4) non-adapted healthcare services. Difficulties in compounding of drugs were noted for children while adolescents shared experiences around disruption in social life due to disease and treatment. Most of the patients and caregivers experienced treatment fatigue and burnout during the DR-TB treatment. Participants during interviews gave recommendations to improve care. DISCUSSION: The TB programmes must consider the patient and family as one unit when designing the package of care for paediatric DR-TB. Child and adolescent friendly services (paediatric-formulations, age-specific counselling tools and regular interaction with patients and caregivers) will help minimizing burnout in patients and caregivers.

One Step Forward: Successful End-of-Treatment Outcomes of Patients With Drug-Resistant Tuberculosis Who Received Concomitant Bedaquiline and Delamanid in Mumbai, India.

BACKGROUND: The Médecins Sans Frontières Clinic in Mumbai, India, has been providing concomitant bedaquiline (BDQ) and delamanid (DLM) in treatment regimen for patients with drug-resistant tuberculosis (DR-TB) and limited therapeutic options, referred from other healthcare institutions, since 2016. The study documents the end-of-treatment outcomes, culture-conversion rates, and serious adverse events (SAEs) during treatment. METHODS: This was a retrospective cohort study based on routinely collected program data. In clinic, treatment regimens are designed based on culture drug sensitivity test patterns and previous drug exposures, and are provided for 20-22 months. BDQ and DLM are extended beyond 24 weeks as off-label use. Patients who initiated DR-TB treatment including BDQ and DLM (concomitantly for at least 4 weeks) during February 2016-February 2018 were included. RESULTS: Of the 70 patients included, the median age was 25 (interquartile range [IQR], 22-32) years and 56% were females. All except 1 were fluoroquinolone resistant. The median duration of exposure to BDQ and DLM was 77 (IQR, 43-96) weeks. Thirty-nine episodes of SAEs were reported among 30 (43%) patients, including 5 instances of QTc prolongation, assessed as possibly related to BDQ and/or DLM. The majority (69%) had culture conversion before 24 weeks of treatment. In 61 (87%), use of BDQ and DLM was extended beyond 24 weeks. Successful end-of-treatment outcomes were reported in 49 (70%) patients. CONCLUSIONS: The successful treatment outcomes of this cohort show that regimens including concomitant BDQ and DLM for longer than 24 weeks are effective and can be safely administered on an ambulatory basis. National TB programs globally should scale up access to life-saving DR-TB regimens with new drugs.

Microbial radiosensitization using combined treatments of essential oils and irradiation- part B: Comparison between gamma-ray and X-ray at different dose rates.

Stored rice and rice products are prone to contamination by pathogenic fungi and bacteria such as Aspergillus niger, Bacillus cereus, and Paenibacillus amylolyticus. Treatment with antimicrobial essential oils (EOs) and irradiation are options to control spoilage organisms. Microbial samples with or without fumigation with an oregano/thyme EO mixture were irradiated at 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0 and 3.5 kGy for calculation of a D10 value. The relative sensitivity was calculated as the ratio of D10 values for the irradiation plus oregano and thyme EO combination and irradiation alone treatments. In all cases, irradiation plus fumigation with the oregano and thyme EO mixture showed increased efficacy compared with irradiation alone. The relative sensitivity of γ-ray irradiation against A. niger was 1.22, 1.33, and 1.24 for radiation dose rates of 10.445, 4.558, and 0.085 kGy/h, respectively, however against B. cereus it was 1.28, 1.45, and 1.49, and against P. amylolyticus it was 1.35, 1.33, and 1.38, for respective γ-ray irradiation dose rates. The relative sensitivity of X-ray irradiation against A. niger, B. cereus, and P. amylolyticus was 1.63, 1.21, and 1.31, respectively, at the X-ray dose rate of 0.76 kGy/h. The results showed that the relative sensitivity of γ-ray irradiation was higher against the two bacteria than the fungus, whereas X-ray showed higher sensitivity against the fungus than the two bacteria. There was no consistent positive or negative relationship between dose rate and relative sensitivity. The results demonstrated the potential of an oregano and thyme EOs mixture as an antimicrobial agent and its efficacy to increase the radiosensitization of A. niger, B. cereus, and P. amylolyticus during γ-ray or X-ray irradiation treatments.

Potential synergistic antimicrobial efficiency of binary combinations of essential oils against Bacillus cereus and Paenibacillus amylolyticus-Part A.

The checkerboard method was used to study the potential interactions between eight essential oils (Basil, Cinnamon, Eucalyptus, Mandarin, Oregano, Peppermint, Tea tree, and Thyme) when used as antibacterial agents against Bacillus cereus LSPQ 2872 and Paenibacillus amylolyticus ATCC 9995. The minimum inhibitory concentration (MIC) of each essential oil (EO) and the fractional inhibitory concentration (FIC) index for the binary combinations of essential oils (EOs) were determined. According to FIC index values, some of the compound binary combinations showed an additive effect; however, Thyme/Tea tree and Cinnamon/Thyme EOs exhibited a synergistic effect against P. amylolyticus and B. cereus, respectively. Cinnamon/Thyme EOs mixture exhibited no interactive effect against P. amylolyticus, but a synergistic effect against B. cereus. The combination of Oregano/Thyme EOs displayed the best antibacterial activity and showed a synergistic effect against B. cereus and P. amylolyticus bacteria. The Oregano/Thyme EOs mixture has potential application in food preservation to reduce the contamination of B. cereus and P. amylolyticus.

GeneXpert and Community Health Workers Supported Patient Tracing for Tuberculosis Diagnosis in Conflict-Affected Border Areas in India.

Médecins Sans Frontières (MSF) has been providing diagnosis and treatment for patients with tuberculosis (TB) via mobile clinics in conflict-affected border areas of Chhattisgarh, India since 2009. The study objectives were to determine the proportion of patients diagnosed with TB and those who were lost-to-follow-up (LTFU) prior to treatment initiation among patients with presumptive TB between April 2015 and August 2018. The study also compared bacteriological confirmation and pretreatment LTFU during two time periods: a) April 2015-August 2016 and b) April 2017-August 2018 (before and after the introduction of GeneXpert as a first diagnostic test). Community health workers (CHW) supported patient tracing. This study was a retrospective analysis of routine program data. Among 1042 patients with presumptive TB, 376 (36%) were diagnosed with TB. Of presumptive TB patients, the pretreatment LTFU was 7%. Upon comparing the two time-periods, bacteriological confirmation increased from 20% to 33%, while pretreatment LTFU decreased from 11% to 4%. TB diagnosis with GeneXpert as the first diagnostic test and CHW-supported patient tracing in a mobile-clinic model of care shows feasibility for replication in similar conflict-affected, hard to reach areas.

Synergistic Effects of Nanocomposite Films Containing Essential Oil Nanoemulsions in Combination with Ionizing Radiation for Control of Rice Weevil Sitophilus oryzae in Stored Grains.

The fumigant toxicity of eight individual essential oils (EOs; basil, cinnamon, eucalyptus, mandarin, oregano, peppermint, tea tree, and thyme) and one binary combination (thyme and oregano) for control of the rice weevil, Sitophilus oryzae, were investigated. In bioassays, all individual and combined EOs were toxic to the rice weevil. Eucalyptus EO exhibited the highest toxicity among the individual EO treatments, causing 100% mortality at a minimum concentration of 0.8 µL/mL after 24 hr of exposure. The combination treatment of oregano and thyme EO displayed higher fumigant activity than the individual oregano or thyme treatments. A stable oil-in-water nanoemulsion was evaluated using high-pressure homogenization (microfluidization [MF]) and varying the pressure and number of cycles. The droplet size of the emulsions was found to decrease from 217 to 71 nm and encapsulation efficiency increased from 37% to 84% with increasing MF pressure and number of cycles. The optimum conditions for preparing the mixture of oregano and thyme EO nanoemulsions were evaluated to be homogenization pressure of 103 MPa and three cycles. Incorporating an oregano:thyme nanoemulsion (0.75%) into cellulose nanocrystal (CNC) containing chitosan (CH/CNC), methyl cellulose (MC/CNC), and polylactic acid (PLA/CNC) composite films resulted in extended diffusion matrices causing 32% to 51% rice weevil mortality after 14 days exposure. Irradiation at 200 Gray alone caused 79% mortality and increased to 100% when combined with the bioactive chitosan film containing the oregano:thyme nanoemulsion. PRACTICAL APPLICATION: A binary combination of oregano:thyme has potential as a biopesticide against stored product pests. The encapsulation of EO nanoemulsions into biopolymeric support could be used for bioactive packaging to prevent food spoilage and extend shelf life. Combining bioactive films with irradiation can provide complete control of rice weevil in packaged rice. The system developed in this research may also be extended to explore other food-packaging films with various food models to control different types of stored pests.

Antifungal activities of combined treatments of irradiation and essential oils (EOs) encapsulated chitosan nanocomposite films in in vitro and in situ conditions.

Cellulose nanocrystals (CNCs) reinforced chitosan based antifungal films were prepared by encapsulating essential oils (EOs) nanoemulsion. Vapor phase assays of the chitosan-based nanocomposite films loaded with thyme-oregano, thyme-tea tree and thyme-peppermint EO mixtures showed significant antifungal activity against Aspergillus niger, Aspergillus flavus, Aspergillus parasiticus, and Penicillium chrysogenum, reducing their growth by 51-77%. Combining the bioactive chitosan films loaded with thyme and oregano EOs produced ~2 log reduction in fungal growth in inoculated rice during 8 weeks of storage at 28 °C. The bioactive films showed a slow release (26%) of volatile components over 12 weeks of storage. Sensorial evaluation of rice samples packed with the bioactive films showed no significant change in odor, taste, color and general appreciation compared with untreated rice. Incorporation of cellulose nanocrystals (CNCs) with the chitosan matrix played an important role in stabilizing the physicochemical and release properties of the nanocomposite films. In addition, combining the bioactive chitosan films with a dose of 750 Gy of ionizing radiation showed significantly higher antifungal and mechanical properties than treatment with the bioactive film or irradiation alone.

Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome.

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.

Evidence for synergistic activity of plant-derived essential oils against fungal pathogens of food.

The antifungal activities of eight essential oils (EOs) namely basil, cinnamon, eucalyptus, mandarin, oregano, peppermint, tea tree and thyme were evaluated for their ability to inhibit growth of Aspergillus niger, Aspergillus flavus, Aspergillus parasiticus and Penicillium chrysogenum. The antifungal activity of the EOs was assessed by the minimum inhibitory concentration (MIC) using 96-well microplate analysis. The interactions between different EO combinations were done by the checkerboard technique. The highest antifungal activity was exhibited by oregano and thyme which showed lower MIC values amongst all the tested fungi. The antifungal activity of the other EOs could be appropriately ranked in a descending sequence of cinnamon, peppermint, tea tree and basil. Eucalyptus and mandarin showed the least efficiency as they could not inhibit any of the fungal growth at 10,000 ppm. The interaction between these two EOs also showed no interaction on the tested species. A combined formulation of oregano and thyme resulted in a synergistic effect, showing enhanced efficiency against A. flavus and A. parasiticus and P. chrysogenum. Mixtures of peppermint and tea tree produced synergistic effect against A. niger. Application of a modified Gompertz model considering fungal growth parameters like maximum colony diameter, maximum growth rate and lag time periods, under the various EO treatment scenarios, showed that the model could adequately describe and predict the growth of the tested fungi under these conditions.

World Market Development and Consumer Acceptance of Irradiation Technology.

Food irradiation is an efficient technology that can be used to ensure food safety by eliminating insects and pathogens to prolong the shelf life. The process could be applied to fresh or frozen products without affecting the nutritional value. Presently more than 60 countries have adopted the technology. However, the technology adaptation differs from one country to another and, in some cases, consumers' misunderstanding and lack of acceptance may hinder the technology adaptation process. This review summarizes the development of irradiation treatment worldwide and consumer attitudes towards the introduction of this technology. Also, the wholesomeness, beneficial effects, and regulation of irradiation are assessed.