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Abstract Background Adaptive designs (ADs) are intended to make clinical trials more flexible, offering efficiency and potentially cost-saving benefits. Despite a large number of statistical methods in the literature on different adaptations to trials, the characteristics, advantages and limitations of such designs remain unfamiliar to large parts of the clinical and research community. This systematic review provides an overview of the use of ADs in published clinical trials (Part I). A follow-up (Part II) will compare the application of AD in trials in adult and pediatric studies, to provide real-world examples and recommendations for the child health community. Methods Published studies from 2010 to April 2020 were searched in the following databases: MEDLINE (Ovid), Embase (Ovid), and International Pharmaceutical Abstracts (Ovid). Clinical trial protocols, reports, and a secondary analyses using AD were included. We excluded trial registrations and interventions other than drugs or vaccines to align with regulatory guidance. Data from the published literature on study characteristics, types of adaptations, statistical analysis, stopping boundaries, logistical challenges, operational considerations and ethical considerations were extracted and summarized herein. Results Out of 23,886 retrieved studies, 317 publications of adaptive trials, 267 (84.2%) trial reports, and 50 (15.8%) study protocols), were included. The most frequent disease was oncology (168/317, 53%). Most trials included only adult participants (265, 83.9%),16 trials (5.4%) were limited to only children and 28 (8.9%) were for both children and adults, 8 trials did not report the ages of the included populations. Some studies reported using more than one adaptation (there were 390 reported adaptations in 317 clinical trial reports). Most trials were early in drug development (phase I, II (276/317, 87%). Dose-finding designs were used in the highest proportion of the included trials (121/317, 38.2 %). Adaptive randomization (53/317, 16.7%), with drop-the-losers (or pick-the-winner) designs specifically reported in 29 trials (9.1%) and seamless phase 2-3 design was reported in 27 trials (8.5%). Continual reassessment methods (60/317, 18.9%) and group sequential design (47/317, 14.8%) were also reported. Approximately two-thirds of trials used frequentist statistical methods (203/309, 64%), while Bayesian methods were reported in 24% (75/309) of included trials. Conclusion This review provides a comprehensive report of methodological features in adaptive clinical trials reported between 2010 and 2020. Adaptation details were not uniformly reported, creating limitations in interpretation and generalizability. Nevertheless, implementation of existing reporting guidelines on ADs and the development of novel educational strategies that address the scientific, operational challenges and ethical considerations can help in the clinical trial community to decide on when and how to implement ADs in clinical trials. Study protocol registration https://doi.org/10.1186/s13063-018-2934-7 .

Background Success of psychosocial interventions in reducing aggressive challenging behaviour is likely to be related not only to mechanistic aspects but also to therapeutic and system factors. The study aims to examine the facilitators and barriers that influence whether psychosocial interventions for aggressive challenging behaviour in adults with intellectual disabilities lead to positive change. We conducted 42 semi-structured interviews with adults with intellectual disabilities who display aggressive challenging behaviour, family/paid carers, and professionals engaged in or delivering a psychosocial intervention across the UK. Data were analysed thematically using a framework approach. Stakeholders considered therapeutic and supportive relationships and personalised care as facilitating factors in addressing aggressive challenging behaviour. The operational structure of community intellectual disability services and conflicting expectations of professionals and carers were the main contextual barriers that impeded the implementation of psychosocial interventions in adults with intellectual disabilities. Findings highlight the valued components that maximise positive change in adults with intellectual disabilities who display aggressive challenging behaviour. Several operational adjustments including referral criteria, roles of professionals and workforce issues need to be addressed in services to maximise the implementation of psychosocial interventions leading to reduction in aggressive challenging behaviour in this population.

Background: Success of psychosocial interventions in reducing aggressive challenging behaviour is likely to be related not only to mechanistic aspects, but also to therapeutic and system factors. The study aims to examine the facilitators and barriers that influence whether psychosocial interventions for aggressive challenging behaviour in adults with intellectual disabilities lead to positive change. Methods: We conducted 42 semi-structured interviews with adults with intellectual disabilities and aggressive challenging behaviour, family/paid carers, and professionals engaged in or delivering a psychosocial intervention across the UK. Data were analysed thematically using a framework approach. Results: Stakeholders considered therapeutic and supportive relationships and personalised care as facilitating factors of psychosocial interventions to address aggressive challenging behaviour. The operational structure of community intellectual disability services and conflicting expectations of professionals and carers were the main contextual barriers that impeded the implementation of psychosocial interventions addressing aggressive challenging behaviour in adults with intellectual disabilities. Conclusions: Findings highlight the valued components that maximise positive change in adults with intellectual disabilities who display aggressive challenging behaviour. Several operational adjustments including referral criteria, roles of professionals and workforce issues need to be addressed in services to maximise the implementation of psychosocial interventions to reduce aggressive challenging behaviour in adults with intellectual disabilities.

Background: The introduction of new visual technologies increases the risk of visually induced motion sickness (VIMS). The aim was to evaluate the 6-item Visually Induced Motion Sickness Susceptibility Questionnaire (VIMSSQ; also known as the VIMSSQ-short) and other predictors for individual susceptibility to VIMS.Methods: Healthy participants (10M + 20F), mean age 22.9 (SD 5.0) years, viewed a 360° panoramic city scene projected in the visual equivalent to the situation of rotating about an axis tilted from the vertical. The scene rotated at 0.2 Hz (72° s−1), with a ‘wobble’ produced by superimposed 18° tilt on the rotational axis, with a field of view of 83.5°. Exposure was 10 min or until moderate nausea was reported. Simulator Sickness Questionnaire (SSQ) was the index of VIMS. Predictors/correlates were VIMSSQ, Motion Sickness Susceptibility Questionnaire (MSSQ), migraine (scale), syncope, Social & Work Impact of Dizziness (SWID), sleep quality/disturbance, personality (“Big Five” TIPI), a prior multisensory Stepping-Vection test, and vection during exposure.Results: The VIMSSQ had good scale reliability (Cronbach’s alpha = 0.84) and correlated significantly with the SSQ (r = 0.58). Higher MSSQ, migraine, syncope, and SWID also correlated significantly with SSQ. Other variables had no significant relationships with SSQ. Regression models showed that the VIMSSQ predicted 34% of the individual variation of VIMS, increasing to 56% as MSSQ, migraine, syncope, and SWID were incorporated as additional predictors.Conclusion: The VIMSSQ is a useful adjunct to the MSSQ in predicting VIMS. Other predictors included migraine, syncope, and SWID. No significant relationship was observed between vection and VIMS.

Plant extract-mediated fabrication of metal nanocomposites is used in cell proliferation inhibition and topical wound treatment, demonstrating significant effectiveness. Salvia hispanica L. (chia) seed extract (CE) is used as the reaction medium for the green fabrication of ecofriendly ZnO(CE) nanoparticles (NPs) and Ag/Ag2O(CE) and ZnO/Ag/Ag2O(CE) nanocomposites. The resultant nanoparticles and nanocomposite materials were characterized using UV–visible, Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), and energy-dispersive X-ray (EDX) techniques. In the context of antioxidant studies, ZnO/Ag/Ag2O(CE) exhibited 57% reducing power and 86% 2,2, diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging. All three materials showed strong antibacterial activity against Staphylococcus aureus (S. aureus), Escherichia coli (E.coli), and Bacillus subtilis (B. subtilis) bacterial strains. Additionally, ZnO(CE), Ag/Ag2O(CE), and ZnO/Ag/Ag2O(CE) also revealed 64.47%, 42.56%, and 75.27% in vitro Michigan Cancer Foundation-7 (MCF7) cancer cell line inhibition, respectively, at a concentration of 100 μg/mL. Selectively, the most effective composite material, ZnO/Ag/Ag2O(CE), was used to evaluate in vivo wound healing potential in rat models. The study revealed 96% wound closure in 10 days, which was quite rapid healing compared to wound healing using clinically available ointment. Therefore, in conclusion, the ZnO/Ag/Ag2O(CE) nanocomposite material could be considered for further testing and formulation as a good anticancer and wound healing agent.

Objective: To study the information, supposition and impression of the general population concerning organ donation and transplantation in Pakistan. Study Design: Cross-sectional analytical survey. Place and Duration of Study: Study was conducted at Tertiary Care Hospital, from Jan to Aug 2020. Methodology: We used the web-based questionnaire, devised from relevant studies and National Health Service (NHS) protocols. The questionnaire comprised of 20 multiple-choice questions (MCQs) in addition to demographic profile,distributed among the general population (n=1000) which assessed basic knowledge regarding organ transplantation and willingness for donation. Results: One thousand participants were enrolled in the study. The age range was 24–61, with a mean age of 36.66±9.00 years.933(93.3%) participants believed organ donation should be mandatory, and 600(60%) expressed willingness to donate or accept organ donation. In addition, 933(93.3%) participants believed in arranging awareness campaigns, and 1000(100%) had an opinion of establishing a convenient donor registration system. Conclusion: There are momentous awareness and willingness for organ donation; therefore, befitting tactics can enhance organ donation in Pakistan, and this issue will no longer be considered a haunted one.

Objective: To analyze the effects of uneventful phacoemulsification surgery on choroidal thickness using spectral domain optical coherence tomography. Study Design: Prospective comparative study. Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi, from Jun 2018 to Jun 2019. Methodology: In this prospective study, 300 eyes of 300 patients undergoing phacoemulsification surgery were included. All patients underwent detailed ophthalmologic examination, including measurement with optical biometry, intraocular pressure and choroid thickness. The choroidal thickness was measured perpendicularly at the fovea using spectral domain optical coherence tomography preoperatively and 1 month postoperatively. Changes in intraocular pressure and choroid thickness after surgery were evaluated. Results: There was a statistically significant increase in the choroid thickness in early postoperative period (p-value

Objective: To evaluate changes in visual acuity and contrast sensitivity in patients with keratoconus after corneal collagen cross-linking. Study Design: Quasi-experimental study. Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan, from May 2019 to Apr 2020. Methodology: A total of 48 eyes of 30 patients with progressive keratoconus were included in this study. Baseline uncorrected distance visual acuity, corrected distance visual acuity and contrast sensitivity were recorded, following which transepithelial corneal collagen cross-linking with topical riboflavin and ultraviolet A light was performed. Uncorrected distance visual acuity, corrected distance visual acuity and contrast sensitivity measurements were repeated and recorded 6-months postoperatively. Results: Mean preoperative uncorrected distance visual acuity was 0.56 ± 0.27 logarithm of the minimum angle of resolution which improved to 0.51 ± 0.26 at 6 months after the procedure (p=0.002). Mean corrected distance visual acuity was 0.30 ± 0.19 preoperatively, improving to 0.24 ± 0.18 (p=0.001) at 6 months after corneal collagen cross-linking, thereby depicting a statistically significant improvement. Treated eyes also showed a significant improvement in contrast sensitivity (p=0.001) of 0.05 ± 0.08 logarithmic units of contrast sensitivity, from a mean preoperative contrast sensitivity of 1.72 ± 0.10 to 1.77 ± 0.09 when evaluated 6 months after corneal collagen cross-linking. Conclusion: Corneal collagen cross-linking is a promising advancement in the treatment of keratoconus. It was found effective in significantly improving visual acuity as well as contrast sensitivity, thus enhancing visual outcomes in keratoconus.

Objective: To compare optical biometry and A-scan for calculating intraocular lens power in patients with nuclear cataract at tertiary care eye hospital. Study Design: Cross sectional comparative study. Place and Duration of Study: Armed Forces Institute of Ophthalmology, Pak Emirates Military Hospital, Rawalpindi, from Jul to Dec 2018. Methodology: In this study 70 eyes of 70 patients planned for cataract surgery by phacoemulsification underwent both optical biometry with intraocular lens master and ultrasound biometry applanation by A scan after informed consent. Intraocular lens power calculated by these two methods of biometry was compared. Phacoemulsification surgery was performed through a 2.3 mm superior temporal clear corneal incision. All patients underwent in the bag implantation of the same intraocular lens type. Results: The mean age of the patients was 62.89 ± 6.69 years. A significant (p-value65 years. Conclusion: Optical biometry was found efficient and safe method for calculation of intraocular lens power. Optical biometry is noncontact method having very less chance of infection and suitable for most of the eye types.

Objective: To compare I–Gel versus endotracheal tube effects on hemodynamic stability and intraocular pressure in patients undergoing elective ophthalmological surgeries. Study Design: Quasi-experimental study. Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi Pakistan, from Nov 2019 to Oct 2020. Methodology: A total of 108 patients undergoing elective ophthalmological surgeries under general anesthesia from both genders, age range between 18-45 years, American Society of Anesthesiologists status I or II were included. General anesthesia given following standard procedures and monitoring. Heart rate, Systolic & Diastolic blood pressure monitored and intraocular pressure measured in each eye with Reichert ton open at baseline, upon insertion of airway device and 5 minutes after insertion. Results: Total 108 patients enrolled in the study with a mean age of 37.74 ± 6.0 years and age-range of 18-45. Heart rate at Insertion in I-Gel group was 78.14 ± 3.41 beats per minute whereas in intubated group was 97.20 ± 2.84 beats per minute, mean systolic blood pressure at insertion in group A and B was 115.28 ± 5.3 and 130.44 ± 2.81mm of Hg respectively. Intraocular pressure at insertion right eye in group A and B was 12.04 ± 0.48 and 17.98 ± 0.42 mm of Hg respectively. Intraocular pressure at insertion left eye in group A was 12.12 ± 0.45 whereas in group B was 17.95 ± 0.38mm of Hg (p-value=0.001). Conclusion: I–Gel provides better hemodynamic profile and intraocular pressure stability when compared with endotracheal tube.

Objective: To assess frequency of Hepatitis B and C infection in patients undergoing cataract surgery. Study Design: Cross sectional study. Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi, from Jan 2018 to Jan 2020. Methodology: Pre operatively patients were subjected to detail ocular examination for cataract evaluation. Patient under 20 years of age, complicated cataract, uveitis, retinal detachment, previous history of ocular surgery or neurosurgery, treatment with systemic medication causing ocular side effects were excluded from study. Preoperatively hepatitis B and C screening was performed for all enrolled patients. The findings were recorded on data sheets and analyzed through statistical software system (SPSS) version 20. Results: Out of 4671 patients, 35 (0.74%) were positive for hepatitis B surface antigen (HBsAg) and 146 (3.1%) were positive for hepatitis C antibody (HCVAb). Eight (22.8%) females and 27 (77.17%) males were positive for HBsAg. Fifty seven (39.04%) females and 88 (60.96%) males were found to be HCVAb positive. It clearly shows higher prevalence of hepatitis in males. Twenty three (65%) of patient with hepatitis B virus and 80 (54.8%) of patients with hepatitis C virus had nuclear sclerosis cataract as compared to 51% of non-infected patients. Conclusion: Screening of hepatitis B and C is mandatory in order to prevent health care associated hepatitis infection. There has been a role of inflammation due to hepatitis in development of cataract. Further studies may elaborate it vividly.

Objective: To evaluate the sensitivity and specificity of bedside tests for prediction of difficult airway scheduled for ophthalmological surgeries under general anesthesia. Methods: This prospective study was carried out at Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan from March 2020 to October 2020. All pediatric and adult patients with American society of anesthesiologist grade I to IV undergoing elective ophthalmological surgeries under general anesthesia were consecutively enrolled. Mallampati grading, sternomental, thyromental distance, and mouth opening used as the predictors tools whereas Cormack and Lehane (CL) classification validated with on table laryngoscopy. Grade I and II were assigned as easy laryngoscopy whereas grade III and IV were declared as difficult intubation. Results: Of 232 patients, difficult intubation was observed in 36 (15.5%). Sensitivity and specificity of thyromental distance was 80.5% and 99.4% respectively. Whereas sensitivity of mouth opening was 66.6% and specificity was 99.4%. In case of sternomental distance, sensitivity and specificity corresponded to 61.6% and 100% respectively. The sensitivity and specificity of Modified Mallampati Grading was 97.2% and 96.4% respectively. The relationship between CL grading and MMC showed that all the patients with CL grade I had Malampati grade I, i.e., 28 (100%), while all patients with CL grade IV had Malampati grade IV, i.e., 7 (100%). Conclusion: Bedside tests prove to be useful parameters for prediction of difficult airway at pre-anesthesia assessment among which Mallampati test is most sensitive and specific, subsequently ensuring availability of difficult intubation equipment, which is a focus of concern in third world countries.

The coronavirus infection 2019 (COVID-19) is a progressing viral pandemic. Adverse impacts related to COVID19 are usually includes sore throat, cough, fever and dyspnea. Anosmia emerged as newer reported symptom however, recognition awaited from the World Health Organization (WHO) and Center for Infection Control and Prevention (CDC). This case series features an instance of isolated abrupt presentation of anosmia as a manifestation of COVID-19 between two young males with parallelism of smoking and modest disease manifestation. Loss of smell is demonstrative of COVID-19 disease and has significant ramifications with regards to healthcare workers working close to infected therefore has increased susceptibility.

Objective: To assess knowledge, opinion and perception of the general population regarding corneal donation and transplantation. Another objective was to investigate desires, fulfilment, battle and results of patient’s experiences of Corneal Transplant Surgeries performed at Tertiary Care Eye Hospital. Study type, settings & duration: A Cross-sectional study conducted at Tertiary Care Eye Hospital over a period of twenty one months from July 2018 till April 2020. Methodology: The format of the questionnaire was based on previously published studies in the field of corneal transplantation. Our study was divided into two parts. The first part was conducted via structured questionnaire distributed among the general population (n =2090) visiting our hospital as patients and attendants which assessed basic knowledge regarding corneal transplantation and willingness for donation. Next step was interviews of operated patients of penetrating keratoplasty (n =30). Results: Total 2090 participants responded to questionnaire in our institution with mean age of sample as 36.66±9.00 years. 1693 (81%) had the opinion that corneal donation will help restoring vision of sufferers whereas 300 (14.3%) considered it unethical. 28 (93.3%) of the patients were in good health and prognosis after surgery whereas 2(6.7%) did not have a good outcome. Vision and quality of life of 29 (96.7%) patients’ improved.30 (100%) supported the idea of corneal donation and transplantation. Conclusion: To conclude a noteworthy population can support corneal donation if the government builds up appropriate channels and facilities to promote corneal donation and eye banks.

PurposeWe wanted to investigate effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) on inflammatory cytokine expression in both activated and non-activated Mφ.Materials and methodsMononuclear cells, isolated from healthy donor buffy coats were cultured for a 6-day differentiation-period. Fully differentiated Mφ were pre-treated with either 25(OH)D3 or 1.25(OH)2D3 for (4, 12 or 24 hours) +/-LPS challenge for 4 hours. Gene expression analyses of VDR, Cyp27b1 and pro-inflammatory markers TNF-α, IL-6, NF-κB, MCP-1, was performed using RT-quantitative PCR. TNF-α protein levels from Mφ culture media were analysed by ELISA.ResultsBoth 25(OH)D3 and 1.25(OH)2D3 significantly inhibited TNF-α expression in both LPS-stimulated and unstimulated Mφ. Also, NF-κB, and to a lesser extend IL-6 and MCP-1 were inhibited. LPS up-regulated Cyp27b1 gene expression which was partly reverted by 1.25(OH)2D3.ConclusionThese data show anti-inflammatory effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) in human macrophages, and support, that means for targeting high dose vitamin D3 to the immune system may have beneficial clinical effect in inflammatory conditions.