Clinical research challenges posed by difficult-to-treat depression

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Effect of Swiss Ball Training on Balance and Postural Stability in Stroke Patient

Stroke is sudden loss of neurological function. It is caused by interruption in cerebral blood flow. Objectives: To analyze the difference in the balance and postural stability score pre &post swiss ball training in stroke patients. Study Design: Randomized control trial. Methodology: This study was performed on stroke patients which are selected according to inclusion and exclusion criteria. The patients were allocated randomly into two groups, experimental group with exercises being performed on swiss ball and control group with exercises performed as per conventional methods with no additional intervention. Statistical analysis: SPSS software, v 20 analyzed data. Independent samples t test and paired sample test were applied. Results: The results showed mean difference of Berg Balance Scale at pre-intervention level and post-interventional level was 0.15 and 14.15 with p values 0.653 and 0.000, respectively. The TIS also showed non-significant difference at pre-interventional level as shown by p value 0.170 , which was significant at post interventional level with a p value to be 0.000 . Paired sample statistics showed a significant improvement for both groups at pre-post level of measurement with a p value of 0.000. Conclusion: We concluded that in stroke patients performing exercises on swiss ball showed significant better outcomes as compared to control group in improving balance and postural stability. However, both groups improved significantly when tested at pre-post levels of measurement. Keywords: Swiss Ball, Stroke, Physical Therapy, Exercise Therapy and Balance.

Protective Effect of Chichorium Intybus (Kasni) Roots on Hepatotoxocity Induced By Pyrazinamide in Male Mice

Background: Tuberculosis (TB) is major health issue across the world. Yearly 2 million deaths are reported from this disease. Pakistan has been ranked in the top six countries that are bearing the major brunt of TB. Aim: To observe hepatoprotective role of aqueous extract of kasni (Chichorium intybus) roots on hepatotoxicity caused by Pyrazinamide in male BALB/c mice. Study Design: Randomized control Trial. Methodology: Healthy male albino Balb/C mice, fifty six in number were selected randomly and further grouped into four groups (n=14 mice). Group A labelled as control group and maintained on rodent diet with no medication. Group B was labelled as disease control group and only pyrazinamide was administered to mice in this group in dose (500mg/kg BW). Groups C and D designated as exploratory groups. Both group C & D were administered a combination of Anti TB drug, pyrazinamide along with aqueous extract preparations of Kasni roots in low (200mg/kg) & high doses (400mg/kg) respectively. Baseline blood samples were drawn at day zero. Results: Serum alanine aminotransferase (ALT) and alkaline Phosphatase (ALP) were improved in group C & D given aqueous extract of Chicorium intybus roots. Conclusion: It was concluded that high doses of aqueous extract preparations of kasni (Chichorium intybus) roots showed more improvements of serum markers in drug induced hepatotoxicity than low doses of aqueous preparations. Keywords: Chichorium intybus, Hepatoprotective, Alanine aminotransferase (ALT), Alkaline Phosphatase (ALP),

Chloroquine Induced Oxidative Stress in Male Albino Mice: RCT

Many drugs have been found to induce oxidative stress. Oxidative stress is responsible for a large number of diseases. Chloroquine is one of the drugs, which can induce oxidative stress, when it is given at higher dose. Purpose: To find the effect of chloroquine as stress inducer on albino mice. Study Design: Randomized clinical trial. Methodology: Sixty male albino mice were taken into this randomized controlled study. Those were divided into two groups of 30 each. Group A was the control group while group B mice were given single oral dose of 970 mg/kg of body weight of chloroquine on 9th day of experiment. Terminal intracardiac blood sample was obtained on 17th day of experiment. Statistical analysis: SPSS version 23 was used for data analysis. Results: When results of group B were compared with those of group A, there was highly significant (p= 0.000) rise in serum malondialdehyde level and highly significant (p= 0.000) decrease in serum glutathione peroxidase level. Conclusion: It was concluded that Chloroquine induces oxidative stress when it is given at the dose of 970 mg/kg of body weight in mice. Keywords: Chloroquine, Oxidative Stress and Malondialdehyde.

Master Protocols for Precision Medicine in Oncology: Overcoming Methodology of Randomized Clinical Trials

Randomized clinical trials are considered the milestones of clinical research in oncology, and guided the development and approval of new compounds so far. In the last few years, however, molecular and genomic profiling led to a change of paradigm in therapeutic algorithms of many cancer types, with the spread of different biomarker-driven therapies (or targeted therapies). This scenario of “personalized medicine” revolutionized therapeutic strategies and the methodology of the supporting clinical research. New clinical trial designs are emerging to answer to the unmet clinical needs related to the development of these targeted therapies, overcoming the “classical” structure of randomized studies. Innovative trial designs able to evaluate more than one treatment in the same group of patients or many groups of patients with the same treatment (or both) are emerging as a possible future standard in clinical trial methodology. These are identified as “master protocols”, and include umbrella, basket and platform trials. In this review, we described the main characteristics of these new trial designs, focusing on the opportunities and limitations of their use in the era of personalized medicine.

Postoperative Pain Relief: The Comparison of Bupivacaine before Incision and Near Closure of Wound

Background: Pain is the most common and most difficult problem faced by patients after operation. Due to inadequate management 30-70% patients suffer from post-operative pain. Acute pain resulting in chronic pain reduces quality of life and creates economic burden. Aim: To compare post-operative pain relief between infiltration of 0.25% bupivacaine into skin and subcutaneous tissue in the line of incision before incision and along edges of wound near completion of procedure. Study design: Randomized control trial Methodology: Sixty four patients were randomly divided into two groups i.e. (0.25% Bupivacaine 6 to 30ml) at the site of incision into skin and subcutaneous tissue Preincision (Group P) and (0.25% Bupivacaine 6 to 30ml) along the edges of wound at near closure of procedure (Group C). Intensity of pain was assessed on visual analogue scale in the recovery room, 3, 6 and 24 hours postoperatively.The time of first dose of rescue analgesia within 24 hours was also noted in both groups. Results: There was no statistically significant difference between two groups regarding age (p-value = 0.324), gender i.e. males (p=0.545) females (p=0.763) and duration of operation (P=Value=0.208). The mean time of rescue analgesia in Group P and Group C in minutes was 318.12±149.47 and 374.84±125.67 respectively (p value =1.5) reflecting no statistically significant difference. Conclusion: Postoperative analgesia and analgesic requirement do not differ significantly whether bupivacaine is infiltrated before incision or just before closure of wound. Keywords: Postoperative pain, bupivacaine, rescue analgesia, Preincision

Prevention of Oculocardiac Reflex by Premedication With Low Dose I/V Ketamine during Strabismus Surgery

Background: OCR commonly occurs during strabismus surgery, producing bradycardia, arrhythmias and even cardiac arrest after manipulation of orbital structures. Ketamine is NMDA receptor antagonist and acts as an analgesic. Aim: To determine the effect of ketamine premedication on prevention of OCR during strabismus surgery. Study design: Randomized control trial Methodology: 60 patients were randomly divided into two groups i.e., Ketamine 0.75mg/kg (Group K) and control (Group C). Group K patients were premedicated with 0.75mg/kg ketamine while Group C patients did not receive any premedication. Heart rate and ECG were observed 30 sec before and continuously after traction on extraocular muscles was applied upto end of surgery for bradycardia and arrhythmias. Percentage change in HR and presence of arrhythmias was documented. All the data was collected using case report form and analyzed using SPSS version 15. Results: In Group C, 15(50%) cases had arrhythmias while in Group K, only 4(13.33%) cases had arrhythmias. Mean HR in Group C was 118.77±6.92/min and in Group K was 101.57±15.65/min. In Group C, oculocardiac reflex was present in 23(76.7%) cases and in Group K, OCR was present in 6 (20%) cases and prevented in 24 (80%) cases. Conclusion: Premedication with 0.75mg/kg IV ketamine significantly reduces the occurrence of oculocardiac reflex during strabismus surgery. Keywords: Ketamine, Oculocardiac Reflex, Premedication, Prevention, Strabismus

Histological Effects of Cotton seed Oil on Ovaries and RTWI among Female Albino Rats: RCT

Background: Concerns over the rising infertility rate among humans is now becoming a global health issue. Aim: To observe the histological changes in ovaries while measuring relative tissue weight indices of all ovaries among different groups receiving cottonseed oil. Study Design: Randomized controlled trial. Methodology: Twenty four adult female albino rats (12 weeks of age) were divided into 04 groups. Group-1 (Control) rats were given orally distilled water @ 400mg (equivalent to 400μl)/kg body weight per day. Group-2, Group-3 & Group-4 rats were given cottonseed oil (treatment groups) @ 400mg (equivalent to 432μl)/kg body weight per day, respectively, for a period of 30 days. Results: Cottonseed oil significantly reduced fertility in terms of follicles and ova in all treatment groups than control having non-significant differences among means of different groups. Conclusion: This study concluded that the crude cottonseed oil significantly affected female rat fertility in terms of reduced number of follicles and ova as shown histologically. However, it did not affect relative tissue weight indices among different groups. Hence, its use in edible products may result in increased women infertility. Keywords: Cottonseed Oil, Relative Tissue Weight Indices and Number of Follicles.

Chloroquine Induced Hepatotoxicity in Male Albino Mice: RCT

Many drugs have been found to induce hepatotoxicity and acute liver failure. Chloroquine is one of those drugs, which can induce hepatotoxicity when it is given at higher dose Purpose: To find the effect of chloroquine on liver function tests (LFTs) Study Design: Randomized clinical trial Methodology: Sixty male albino mice were taken into this randomized controlled study. Those were divided into two groups of 30 each. Group A was the control group while group B mice were given single oral dose of 970 mg/kg of body weight of chloroquine on 9th day of experiment. Terminal intracardiac blood sample was obtained on 17th day of experiment Statistical analysis: SPSS version 23 was used for data analysis Results: When results of group B were compared with those of group A, they depicted highly significant (p=0.000) rise in serum ALP. Serum albumin decreased significantly (p= 0.007). Serum AST increased significantly (p=0.005). Serum ALT, however, did not rise significantly (p=0.285) in group B. Similarly, serum total proteins did not decrease significantly ( p=0.530) in group B Conclusion: It was concluded that chloroquine induced mild hepatotoxicity in male albino mice when a single oral dose of 970 mg/kg of body weight of it is given Key Words: Chloroquine, Hepatotoxicity and Alkaline Phosphatase.