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| 2. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 3. |
- Khare, Shweta, et al.
(författare)
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Antibiotic Prescribing by Informal Healthcare Providers for Common Illnesses : A Repeated Cross-Sectional Study in Rural India
- 2019
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Ingår i: Antibiotics. - : MDPI. - 0066-4774 .- 2079-6382. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Informal healthcare providers (IHCPs) are predominant healthcare providers in rural India, who prescribe without formal training. Antibiotic prescription by IHCPs could provide crucial information for controlling antibiotic resistance. The aim of this study is to determine the practices and seasonal changes in antibiotic prescribing for common illnesses by IHCPs. A repeated cross-sectional study was conducted over 18 months, covering different seasons in the rural demographic surveillance site, at Ujjain, India. Prescriptions given to outpatients by 12 IHCPs were collected. In total, 15,322 prescriptions for 323 different complaint combinations were analyzed, of which 11,336 (74%) included antibiotics. The results showed that 14,620 (95%) of antibiotics prescribed were broad spectrum and the most commonly prescribed were fluoroquinolones (4771,31%), followed by penicillin with an extended spectrum (4119,27%) and third-generation cephalosporin (3069,20%). Antibiotics were prescribed more frequently in oral and dental problems (1126,88%), fever (3569,87%), and upper respiratory tract infections (3273, 81%); more during the monsoon season (2350,76%); and more frequently to children (3340,81%) than to adults (7996,71%). The study concludes that antibiotics were the more commonly prescribed drugs compared to other medications for common illnesses, most of which are broad-spectrum antibiotics, a situation that warrants further investigations followed by immediate and coordinated efforts to reduce unnecessary antibiotic prescriptions by IHCPs.
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| 4. |
- Khare, Shweta, et al.
(författare)
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Determinants and pathways of healthcare-seeking behaviours in under-5 children for common childhood illnesses and antibiotic prescribing : a cohort study in rural India
- 2021
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To explore the healthcare-seeking pathways, antibiotic prescribing and determine the sociodemographic factors associated with healthcare-seeking behaviour (HSB) of caregivers for common illnesses in under-5 (U-5) children in rural Ujjain, India.Study design Prospective cohort study.Study setting and study sample The cohort included 270 U-5 children from selected six villages in rural demographic surveillance site, of the R.D. Gardi Medical College, Ujjain, Madhya Pradesh, India. A community-based cohort was visited two times weekly for over 113 weeks (August 2014 to October 2016) to record the HSB of caregivers using HSB diaries. Sociodemographic information was also solicited.Primary and secondary outcome measures Primary outcomes: first point of care, healthcare-seeking pathway and quantify antibiotic prescribing for the common acute illnesses.Secondary outcome HSB risk factors were determined using mixed-effects multinomial logistic regression.Results A total of 60 228 HSB follow-up time points for 270 children were recorded with a total of 2161 acute illness episodes. The most common illnesses found were respiratory tract infections (RTI) (69%) and gastrointestinal tract infections (8%). No healthcare was sought in 33% of illness episodes, mostly for RTIs. The most common healthcare-seeking pathway was to informal healthcare providers (IHCPs, 49% of illness episodes). The adjusted relative risk for obtaining no treatment, home treatment and treatment by IHCPs was higher for RTIs (aRR=11.54, 1.82 and 1.29, respectively), illiterate mothers (aRR=2.86, 2.38 and 1.93, respectively), and mothers who were homemakers (aRR=2.90, 4.17 and 2.10, respectively). Socioeconomic status was associated with HSB, with the highest aRR for no treatment in the lowest two socioeconomic quintiles (aRR=6.59 and 6.39, respectively). Antibiotics were prescribed in 46% (n=670/1450) illness episodes and the majority (85%, n=572/670) were broad spectrum.Conclusion In our rural cohort for many acute episodes of illnesses, no treatment or home treatment was done, which resulted in overall reduced antibiotic prescribing. The most common healthcare-seeking pathway was to visit IHCPs, which indicates that they are major healthcare providers in rural areas. Most of the antibiotics were prescribed by IHCPs and were commonly prescribed for illnesses where they were not indicated.
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| 5. |
- Lundgren, Jens D, et al.
(författare)
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Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.
- 2023
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Ingår i: NEJM evidence. - : Massachusetts Medical Society. - 2766-5526. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain.The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021.Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference).Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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- Sharma, Janpriy, et al.
(författare)
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Avenues of decarbonisation in the dynamics of processed food supply chains : Towards responsible production consumption
- 2024
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Ingår i: Heliyon. - : Cell Press. - 2405-8440. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Nowadays, the demand for processed food items is surging. To fulfil the enhanced demand, a significant impact is laid on the environment, which enhances the carbon footprint being generated. Hence, to overcome this, the avenues of decarbonisation need to be explored. The presented work is aimed at promoting the decarbonisation of the existing practices within the processed food supply chains. It finds strong compliance with the sustainable development goal (SDG-12), focusing on responsible production-consumption mechanisms. For the same, key enactors of decarbonisation are identified and mapped with the practices at various stages of food supply chains, i.e. upstream, downstream, and other allied practices. Based upon these enactors, a relational, hierarchical framework is developed to provide a comprehensive perspective on complex intricacies. This framework is analysed with an innovative approach which comprises the fundamentals of Interval-Valued Intuitionistic Hesitant Fuzzy Set with the Entropy measures. It results in the outranking of the enactors relative to its importance in the decarbonisation of processed food supply chains. Furthermore, the empirical findings are validated by the sensitivity analysis to felicitate robust decision-making. The outcomes of the presented work provide a roadmap and stepped approach to achieve the decarbonisation goals and make productionconsumption mechanisms sustainable. It finds implications in the development of the framework, policy formulation, and decisional attributes for the decarbonisation of food supply chains. It focuses on the adoption of strategies that align with global efforts to mitigate climate change and promote a sustainable future.
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| 7. |
- Singh, Neha, et al.
(författare)
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Downregulation of tumor suppressor gene PML in uterine cervical carcinogenesis : impact of human papillomavirus infection (HPV)
- 2013
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Ingår i: Gynecologic Oncology. - : Elsevier. - 0090-8258 .- 1095-6859. ; 128:3, s. 420-6
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Cervical cancer is a leading gynecological cancer in Indian women and is caused due to infection with high risk human pappilloma virus (HR-HPV) 16 and 18. It has been well documented that PML (promyelocytic leukemia) enhances viral infectivity and plays a crucial role in antiviral response mechanisms. The aim of the present study was to evaluate the role of PML gene with context to HPV infection in cervical carcinogenesis.METHODS: The expression pattern of PML was analyzed by western blotting and immunohistochemistry in a total of 170 fresh surgically resected cervical tissue specimens comprising precancer (n=12), cancer (n=118) and normal controls (n=40) recruited from PGIMER, Chandigarh, India. HPV status was analyzed by L1 consensus PCR followed by type specific PCR for HR-HPV types 16 and 18 and low risk types 6 and 11.RESULTS: A significant downregulation of PML protein was observed in the majority of cervical cancer and precancer cases 68% (89/130) compared to normal controls. The loss of expression pattern of PML gene was significantly increased with severity of disease both clinically and pathologically (p<0.001). HPV infection was detected in the majority of cancer cases 96% (113/118) and in 83% (10/12) of precancer lesions whereas no infection could be detected in normal controls. Interestingly, all the 68% (89/130) cervical cancer cases that showed downregulation of PML were HPV infected (p=0.0001).CONCLUSION: Taken together, these observations suggest that the downregulation of PML gene and its synergism with HPV infection may play an important role and may serve as a new marker for early diagnosis and therapeutic intervention for cervical carcinogenesis.
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