Due to the clear depiction of facial aesthetics and other craniofacial parameters, portraiture photography (PP) is becoming more and more necessary in modern clinical practice. The studies chosen for this review's inclusion looked at how PP affected the orthodontic treatment and diagnostic procedure on the subjects who were watched in the studies. Studies published within the last decade precisely from 2013 were searched for across major online databases after devising a proper search strategy. Multiple reviewers created a specific data extraction form that was used for the investigation, followed by the evaluation of bias and the variables found in each of the chosen papers. This form was meant for the assessment for various variables encountered in this study. According to the meta-analysis, using PP was related with a statistically significant decrease in the risk of orthodontic treatment and diagnostic modalities, with odds ratios (OR) of 0.52 with a 95% confidence interval (CI) of , and a relative risk (RR) of 0.66 with a CI of . In orthodontics, PP is an important tool that offers useful data for diagnosis, treatment planning, and tracking treatment success. To validate the results of studies like ours, a sizable evidence sample is required due to the limited number of trials that have been performed in this area. Portraiture photography (PP) is the art of capturing images of people, with a focus on their facial expressions, personality traits, and physical features . PP can One of the key elements of PP is lighting. Photographers use various lighting techniques to highlight the subject's best features and create a mood or atmosphere in the portrait . For exaPP typically involves the use of digital cameras, specialized lighting equipment, and a standardized photographic protocol to capture standardized images of the patient's face and teeth from different angles . These pIn orthodontic diagnosis, PP can provide essential information about the size, shape, and position of teeth and jaws, as well as any asymmetries or abnormalities in facial features . PP can Despite the potential benefits of PP in orthodontic practice, there is limited consensus on its efficacy and impact on treatment outcomes. Several studies have examined the use of PP in orthodontic diagnosis and treatment planning, but the results have been inconsistent, and there is a need for a comprehensive review of the available literature -10. TherThis systematic review and meta-analysis intended to assess how PP affected orthodontic treatment and diagnostic procedures and its impact in the field of orthodontics.This article was previously posted to the medRxiv preprint server on April 27, 2020.MethodsSearch Strategy InitiationIn accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, registration was completed prior to the commencement of the study Figure  11]. Th. Th11]. Using this PICOS strategy, the research question for this systematic review and meta-analysis was: In patients undergoing orthodontic treatment, what is the impact of PP compared to no PP or alternative methods of dental photography on treatment planning, patient education, and treatment outcomes? This review included randomized controlled trials and observational studies that assess the use of PP in orthodontic treatment and would focus on the impact of this intervention on key outcomes such as treatment planning, patient education, and treatment outcomes.Search Strategy ImplementationThe following search strategy was used across four online databases to identify relevant articles for our investigation using Medical Subject Headings (MeSH) keywords and a combination of Boolean operators:PubMed- (((((((((((((("Photography"[Mesh]) OR "Portraits as Topic"[Mesh]) OR "Dental Photography"[Mesh]) OR "Orthodontics"[Mesh]) OR "Dentistry"[Mesh]) OR "Dental Care"[Mesh]) OR "Orthodontic Appliances"[Mesh]) OR "Orthodontic Brackets"[Mesh]) OR "Orthodontic Wires"[Mesh]) OR "Orthodontic Records"[Mesh]) OR "Orthodontic Models"[Mesh]) AND (("Treatment Outcome"[Mesh]) OR "Patient Education as Topic"[Mesh])) AND (((((((("Humans"[Mesh]) AND "English"[lang]) AND ("2019/03/15"[PDat] : "2023/03/15"[PDat])) AND "Randomized Controlled Trials as Topic"[Mesh]) OR "Observational Study"[ptyp]) OR "Cohort Studies"[Mesh]) OR "Case-Control Studies"[Mesh]) OR "Cross-Sectional Studies"[Mesh]))Google Scholar-  AND  AND (treatment outcomes OR patient education) AND Web of Science- TS= AND TS= AND TS=(treatment outcomes OR patient education) AND  OR PT= OR PT=(cohort study) OR PT=(case-control study) OR PT=)Scopus- TITLE-ABS-KEY AND TITLE-ABS-KEY AND TITLE-ABS-KEY(treatment outcomes OR patient education) AND (DOCTYPE(ar) OR DOCTYPE(cr) OR DOCTYPE(arcp) OR DOCTYPE(co) OR DOCTYPE(sc))Inclusion Criteria for the ReviewTo identify relevant studies for the systematic review and meta-analysis on the impact of PP on orthodontic treatment, a set of inclusion criteria were established. Only studies published from 2013 to the present were considered for inclusion in the analysis. This was done to ensure that the findings of the review were based on current research and reflected the most recent advances in orthodontic treatment. Studies that assessed the impact of PP on orthodontic treatment outcomes, patient education, or treatment planning were included. Only randomized controlled trials or observational studies were considered, as they provide the highest level of evidence in the medical literature. Studies that included a comparison group without the use of PP or with alternative methods of dental photography were also included in the analysis. Finally, only studies that reported quantitative data were considered for inclusion, as this allowed for the most accurate assessment of the impact of PP on orthodontic treatment.Reviewer EvaluationTo ensure the accuracy and completeness of the data extracted for the systematic review and meta-analysis on the impact of PP on orthodontic treatment, multiple reviewers were involved in the data selection process. After conducting the initial search across multiple databases, the reviewers independently screened the titles and abstracts of the identified studies against the established inclusion and exclusion criteria. Any discrepancies between the reviewers were resolved through discussion and consensus. Following the title and abstract screening, the full texts of the selected studies were obtained and reviewed by the reviewers. A data extraction form was used to collect the relevant information from each study. The variables that were assessed included study design, sample size, intervention type, comparator type, outcome measures, and results. The reviewers independently extracted the data from each study, and any discrepancies were resolved through discussion and consensus.After the data extraction process was completed, the extracted data were cross-checked for accuracy and completeness. Any errors or missing data were identified and resolved through discussion and consensus between the reviewers. The extracted data were then compiled and analysed using appropriate statistical methods to assess the impact of PP on orthodontic treatment outcomes.Bias AssessmentTo ensure the validity and reliability of the systematic review and meta-analysis on the impact of PP on orthodontic treatment, the reviewers used two tools for bias assessment. The first tool was the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI) Risk of Bias tool Figure , which wThe second tool used was the AXIS tool Figure , which wThe reviewers selected these tools because they are widely recognized as valid and reliable tools for assessing bias in research studies and systematic reviews. By using these tools, the reviewers were able to ensure that the findings of the review were based on high-quality research and that the review process itself was conducted in a rigorous and systematic manner. Ultimately, this helped to enhance the validity and reliability of the review and to ensure that the findings were useful and informative for clinicians and researchers working in the field of orthodontic treatment.Protocol for StatisticsIn order to conduct the meta-analysis for the systematic review on the impact of PP on orthodontic treatment, the reviewers used the RevMan 5 software. This software allowed the reviewers to analyze and synthesize the data from the selected studies using a random effects model. The software generated odds ratio (OR) and relative risk (RR) forest plots to depict the impact of PP on orthodontic treatment and diagnostic modalities in the total sample size of the selected studies.The OR and RR forest plots generated by the RevMan 5 software provided a visual representation of the data and allowed the reviewers to easily compare the results of the selected studies. The random effects model used in the analysis helped to account for the variability between the studies and to estimate the true effect size of PP on orthodontic treatment outcomes. Overall, the RevMan 5 software played a critical role in the meta-analysis process by allowing the reviewers to analyze and synthesize the data from the selected studies in a systematic and rigorous manner. The OR and RR forest plots generated by the software provided a clear and concise summary of the results of the analysis, which helped to inform the conclusions of the systematic review on the impact of PP on orthodontic treatment.ResultsThe procedure followed in our investigation involved a methodical and exacting strategy to finding pertinent studies and putting the evidence together. The study was able to find high-quality evidence that could be used to support the research question and objectives by using a clear set of inclusion and exclusion criteria and a structured strategy to data selection. The deductive approach taken in this research was intended to reduce bias and make sure that the data presented were solid and trustworthy. 562 articles in total were found using the original search methodology. The total number of articles was reduced to eight studies that met our stated inclusion and exclusion criteria after eliminating duplicates and applying inclusion and exclusion criteria based on the research question and goals. These studies were chosen based on the strength of the evidence they provided and their applicability to the research topic.Two of these eight studies-out of the eight-came from India, but they looked at the use of PP in two distinct parts of the nation. From Istanbul, Turkey, the United States, the Netherlands, China, and Ukraine, one research from each was chosen Table .Significant impact of PP on the respective orthodontic treatment/diagnostic modalities were observed in 6 of the investigations, with one of them reporting a slightly female-dominated significance impact. Half of the studies recorded greater than 60% of positive perception observed in the respondents pertaining to the usage of PP in an orthodontic setting, with one study reporting a less than ideal 30% and one study reporting variable percentages according to the different curves of smile aesthetics that were observed in them. In five of the selected studies, PP was utilized in the beginning of the orthodontic treatment plan and with half of the selected studies utilizing PP as a diagnostic tool in order top achieve better efficacy in their respective findings Table .Figure The analysis showed an OR of 0.52 with a 95% confidence interval (CI) of  assuming a research estimate (RE) model, indicating that the use of PP was associated with a statistically significant reduction in the odds of orthodontic treatment and diagnostic modalities. Moreover, the analysis revealed a considerable heterogeneity in the studies, with Tau² estimated at 0.62, and a Chi-square statistic of 42.90, with 7 degrees of freedom (df) (P < 0.00001). The I² value of 84% indicated that a large proportion of the total variation across studies was due to heterogeneity rather than chance. Finally, the test for overall effect showed a Z score of 2.10 (P = 0.04), suggesting that the overall effect size was statistically significant. In summary, the statistical analysis presented in figure Figure The analysis showed an RR of 0.66, with a 95% CI of , indicating that the use of PP, was associated with a statistically significant reduction in the risk of orthodontic treatment and diagnostic modalities. The analysis also revealed a significant heterogeneity in the studies, with Tau² estimated at 0.22 and a Chi-square statistic of 33.43, with 7 df (P < 0.0001). The I² value of 79% indicated that a substantial proportion of the total variation across studies was due to heterogeneity rather than chance. Furthermore, the test for overall effect assuming a random effects model showed a Z score of 2.17 (P = 0.03), suggesting that the overall effect size was statistically significant. In summary, the statistical analysis presented in figure DiscussionThe systematic review conducted in our investigation and the results of the subsequent meta-analysis show that the use of PP as a diagnostic tool and at the beginning of the orthodontic treatment plan is associated with a statistically significant decrease in the risk of orthodontic treatment and diagnostic modalities. The selected studies showed that respondents had a favorable opinion of the use of PP in an orthodontic setting. More than 60% of the studies found that respondents had a positive view of the use of PP in orthodontics, indicating the potential for increased use of PP in clinical practice. The meta-analysis also found that using PP was related to a statistically significant decrease in the risk of orthodontic treatment and diagnostic modalities, with ORs of 0.52 and RR of 0.66. These findings suggest that the use of PP may lead to better treatment outcomes and lower diagnostic modalities in orthodontics.In addition, the study found that PP was used as a diagnostic tool in half of the selected studies and at the beginning of the orthodontic treatment plan in five of the studies that were chosen. This highlights the potential benefits of using PP as an early diagnostic tool in orthodontics, which could lead to more effective treatment planning and better treatment outcomes for patients. So, we believe that the systematic review and meta-analysis on the impact of PP on orthodontic treatment is a significant study that provides valuable insights into the potential benefits of using PP in clinical practice. The study's findings have important implications for orthodontic treatment planning and could lead to improved treatment outcomes for patients.During the planning stage of treatment, clinical photographs enable the orthodontist to closely examine the soft tissue patterns of the current patient. To evaluate the shape and tone of the lips, the smile's arc and aesthetics from different perspectives, and the degree of incisal show when beaming ,22. It cA clearer grasp of the external relationships between the craniofacial structures can be gained from photographic analyses. Since the soft tissue profile is also affected by other variables, such as muscles and adipose tissue, the overall facial analyses cannot be completed using the skeletal analysis alone. Thanks to Proffit, photographic assessment has become a hot topic due to the emergence of the paradigm shift that gives a higher priority to soft tissue structure and its assessment, particularly with regard to changes that occur with aging . The relA lateral facial photograph, or a 90° photo of the right side of the patient's face captured while holding the natural head position, is required by a standard photography protocol . It's crOnly when a diagnostic tool can reliably identify the disease is it deemed successful. The efficacy of lateral photography as a diagnostic tool can only be examined by comparing it to the current standard because malocclusion and facial disharmony are not pathological conditions. Numerous investigations contrasting cephalometric and photographic measurements have been carried out -34. WhilThe systematic review and meta-analysis findings underscore several practical implications of incorporating PP into orthodontic practice. These implications have the potential to positively impact both patients and orthodontists while advancing the field of orthodontics.Benefits for patients include the utilization of PP in orthodontic treatment planning allows orthodontists to create more tailored and effective treatment plans. By analyzing detailed facial features and soft tissue patterns, orthodontists can design treatments that not only align teeth but also enhance facial aesthetics, leading to increased patient satisfaction. PP helps facilitate effective communication between patients and orthodontists. Visualizing the expected treatment outcomes through photographs enables patients to have a clearer understanding of their orthodontic journey, fostering a sense of trust and cooperation. During follow-up visits, PP aids in monitoring treatment progress. Orthodontists can track changes in facial aesthetics and incisal display, ensuring that treatment goals are being met. This proactive approach allows for timely adjustments when necessary, leading to more predictable and satisfactory outcomes for patients .Benefits for orthodontists include PP contributes to more accurate orthodontic diagnoses by providing comprehensive information about facial and dental structures. Orthodontists can assess facial symmetry, lip posture, and smile aesthetics, enabling a more holistic understanding of the patient's condition. With a wealth of visual data at their disposal, orthodontists can devise treatment plans more efficiently and with greater confidence. This efficiency translates into reduced treatment times and better outcomes for patients. PP records offer valuable resources for teaching and research purposes. Orthodontic educators can use standardized photographs to illustrate key concepts to students, while researchers can analyze these records to advance the field's knowledge base -7.Benefits for the field of orthodontics include the integration of PP encourages the development of standardized photography protocols within orthodontics. This standardization promotes consistency and comparability across different clinical settings and research studies, contributing to the advancement of evidence-based practice. As technology and techniques in PP continue to evolve, orthodontics stands to benefit from ongoing advancements. Innovations such as 3D imaging and artificial intelligence may further enhance the diagnostic and treatment planning capabilities of PP in the future .Despite the significant findings reported, this systematic review and meta-analysis on the impact of PP on orthodontic treatment has some limitations. One limitation is the potential for publication bias, as only studies published in English were included. This may have resulted in the exclusion of relevant studies conducted in other languages, which could have affected the overall results of the meta-analysis. Another limitation is the heterogeneity of the selected studies in terms of study design, sample size, and PP techniques used. This could have affected the consistency and generalizability of the study's findings. Additionally, the lack of long-term follow-up data in some of the studies made it difficult to assess the long-term impact of using PP in orthodontics. Furthermore, the quality of the selected studies varied, and some studies had a high risk of bias. The use of the JBI Risk of Bias tool and AXIS tool helped to minimize bias in the selected studies and within the review itself. However, it is still possible that some studies may have been affected by bias, which could have affected the overall results of the meta-analysis. Finally, the study only included studies conducted after 2013, which could have excluded relevant studies conducted before this time period. Therefore, the results of the meta-analysis may not reflect the full range of evidence available on the impact of PP on orthodontic treatment. Summarily speaking, while the study provides valuable insights into the potential benefits of using PP in orthodontics, the limitations outlined above suggest that caution should be exercised when interpreting the results. Further research is needed to confirm the findings of this study and to address the limitations identified.In conclusion, our study underscores the critical role of PP in orthodontics. It serves as a powerful diagnostic and treatment planning tool, enabling clinicians to deliver personalized care and monitor treatment progress effectively. With the advent of digital photography technology, PP has seamlessly integrated into modern medical practice, including orthodontics. However, while our findings are promising, it is imperative that future research endeavors expand the evidence base in this field. We encourage researchers to undertake larger, more comprehensive studies to validate and build upon the insights provided by this research. The path to enhanced orthodontic care and patient outcomes lies in further exploration and application of PP.


Background: A substantial proportion of patients with treatment resistant schizophrenia do not respond well or partially to clozapine, with a subset that does not tolerate an adequate trial of clozapine. Electroconvulsive therapy (ECT) is regarded as one of the augmenting options, but there is a lack of high-quality evidence for this practice. This protocol describes a double-blind randomised sham-controlled modified-ECT trial to evaluate its efficacy in patients with clozapine resistant/intolerant schizophrenia. The study also involves multimodal investigations to identify the response predictors and the mechanistic basis of modified ECT in this population.Methods: One hundred consenting schizophrenia patients with resistance/intolerance to clozapine referred by clinicians for ECT would be randomly assigned to receive true ECT or sham ECT at three study centers. Sham ECT would mimic all the procedures of modified ECT including anaesthesia and muscle relaxation, except the electrical stimulation. After a blinded course, non-responders to sham ECT would be offered open-label true ECT. Clinical assessments, neurocognitive assessments and multimodal investigations  would be conducted at baseline and repeated after the end of the trial, as well as open-label ECT course. The trial would evaluate the improvement in positive symptoms  of schizophrenia as the primary outcome measure with prediction of this change by resting-state functional-MRI based brain-connectivity as the second primary objective.Registration: Clinical Trial Registry of India (Reg no:CTRI/2021/05/033775) on 24th May 2021. Clozapine-resistant schizophrenia remains a major challenge in the practice of psychiatry with limited evidence-based interventions  , with a To date, the best available evidence for ECT in a clozapine-resistant population is a randomized, single-blind comparison with clozapine alone, which has shown promising results for the ECT group, with around 50% of the patients responding to ECT  and identify the predictors of response to assist in individualizing treatment. Hence, we plan to conduct a concurrent assessment of neuroplasticity measures along with multilevel neurobiological parameters and clinical symptom scores, which would enable disease modelling; furthermore, combining these measures with carefully controlled non-invasive brain stimulation (NIBS) experiments might unravel mechanistic basis and prognostic biomarkers of ECT in this population.Primary objectives:1. To compare the efficacy of bifrontal modified brief-pulse ECT and sham ECT in clozapine-resistant/intolerant schizophrenia. We hypothesize that true-ECT would demonstrate a greater clinical response than sham-ECT.2. To evaluate the resting state brain connectivity predictors of response to ECT in patients with clozapine-resistant/intolerant schizophrenia. We hypothesize that a differential pre-treatment resting brain functional connectivity signal will identify responders to ECT. Secondary objectives:1. To compare the neurobiological profile of clozapine-resistant/intolerant schizophrenia patients with matched healthy controls using multimodal data .2. To examine the differential effect of true-versus-sham ECT on the neurobiological profile of clozapine-resistant/intolerant schizophrenia patients using multi-modal data  and potential interactions with neuroplasticity gene polymorphisms.3. To evaluate the predictive utility of multi-modal data  in identifying clinical response to ECT in patients with clozapine-resistant/intolerant schizophrenia.We employ a parallel-arm double-blind randomized sham-controlled design with an allocation ratio of 1:1 to determine the differential efficacy of add-on electroconvulsive therapy to sham-electroconvulsive therapy in clozapine-resistant/intolerant schizophrenia.This would be a hospital-based study. The study would be conducted in patients with clozapine-resistant/intolerant schizophrenia at three mental health care and research institutes in India: National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru; Central Institute of Psychiatry (CIP), Ranchi; and Kasturba Medical College (KMC), Manipal. These study centers have been providing clinical services of ECT for more than 3–6 decades. The study would be centrally coordinated at NIMHANS.Clozapine-resistant/intolerant schizophrenia patients who have been recommended and referred for ECT by the treating clinicians and already consented for receiving ECT would be approached for willingness to participate in this research study. Diagnosis made by the clinicians would be confirmed by an independent clinician using the structured clinical interview for DSM-5  disorders, clinician version (SCID-CV) . The antipsychotics should have been provided at a minimum dose equivalent to 600 mg/day of chlorpromazine and/or 15mg/day equivalent of olanzapine calculated based on the classical mean dose method  for minimum three months would be considered clozapine resistant if they continue to have moderate or more severity of psychotic symptoms OR a scoTrue ECT: Thrice-weekly, bifrontal ECT would be provided for a minimum of nine sessions and would be extended till a plateau is achieved in clinical response. ECT would be provided with a NIVIQURE ECT device . Modification would be provided with short general anaesthesia and muscle relaxants . Alternative modification agents would be considered if there are any medical indications. The electrodes would be placed 5 cm above the outer canthus of each eye, along a vertical line perpendicular to an imaginary line connecting the two pupils. ECT would be administered as per the standard procedure by a team of psychiatrist(s), anaesthesiologist, nursing and other paramedical professionals.The seizure threshold would be determined during the first ECT session through titration method. The stimulation would be initiated at 30mC with increments of 30mC until adequate seizure is achieved. The ECT administrator would initiate the stimulation at a higher dose depending on age and co-administration of anticonvulsants. From the subsequent sessions, patients would receive 1.5 times suprathreshold ECT. EEG would be recorded during the ECT with the NIVIQURE ECT–EEG device from left and right frontal pole leads (Fp1 and Fp2), referenced to bilateral mastoid processes. As per current guidelines, seizures would be considered adequate if there is evidence for generalized seizures observed in either the motor system (in the isolated limb) or in the typical morphology of EEG . ECTs maAfter the 9th ECT session, ECT course would be terminated on achieving plateau in clinical response, i.e., if there is no change in the clinical status from the previous session in three consecutive sessions as measured by Sheehan-Clinician Global Improvement Global-21 scale (S-CGI-21) . All these measures would encourage the adherence to the intervention and study retention.Concomitant care. Violation with study guidelines like medication change due to unforeseen situations would be noted down and reported. A change in antipsychotic dose by more than 25% from the dose at the initiation of the intervention, change in antipsychotic medication or initiation of other neuromodulatory interventions would be considered as drop-out. All on-going antipsychotic medication and psychosocial interventions concomitant to the study intervention would be allowed.th session or to the point of premature termination of trial. A comparison of change in Scale for the Assessment of Positive Symptom Scale (SAPS) between the two groups would be the primary outcome measure. Response would be defined as ≥ 40% improvement in SAPS scores . Time to response would be compared between the two groups. Clinical symptoms would be measured by SAPS, Scale for the Assessment of Negative Symptoms (SANS) , BPRS  and AudiSide-effects would be monitored using an ECT-side effect checklist after every ECT. Cognition would be monitored using a weekly Battery for ECT-Related Cognitive Deficits (B4ECT-ReCoDe)  of sham ECT group or patients who opted for premature termination of trial due to lack of response to the intervention in the step-1 will be given the option to receive true ECT, at the same frequency and similar duration as described in the step-1 of the trial. Written informed consent will be obtained separately prior to the initiation of both steps  for three study centers with unequal strata sizes of 60, 20 and 20 would be carried out in Stata ver.15.1 , anaesthesiologist, and paramedical staff would become unblinded thereafter. Paramedical staff in the recovery room would remain blinded to the study arm and would assess the time to reorientation and post ECT adverse effects. Independent assessors would monitor study outcome and they would remain blinded about the study arm till the end of post-RCT assessments. As the risk of unblinding would be high on immediate post-ECT adverse effect evaluation, outcome assessors would remain blinded to the immediate adverse effects. The treating clinical team would also remain blinded to study arm and immediate cognitive/behavioral adverse events till the end of post-RCT assessment. To maintain the rigorous blinding, two independent assessors would rate the safety and outcome measures.ECT related records will be maintained by the ECT administrators who are unblinded to the study. ECT procedure details including the details of seizures will be maintained in the ECT suite securely by the ECT administrators. The device used in this study shows an online digital display and provides a digital copy of the EEG which will again be securely stored by ECT administrator. Adverse outcome assessors maintain the adverse effect assessment records securely under the supervision of the psychiatrist administering ECT. This psychiatrist will decide on intimating the adverse events to the clinical teams without compromising the clinical needs of the patients and maintaining the blinding as much possible.Emergency unblinding. Serious adverse events (SAE) would be reported to the trial management group (TMG) and data and safety monitoring board (DSMB), which would assess for suspected unexpected serious adverse reaction (SUSAR); the patient, caregiver, clinical team and the investigators may be unblinded at their discretion. Otherwise, all participants would be unblinded at the termination of the trial (either after completion of nine sessions or premature termination for any other reason). Assessment of blinding efficacy would be done on patients, adverse event assessors and outcome assessors after the last (scheduled/terminated) blinded intervention session using a 5-point likert scale  would be acquired before and after interventions to identify predictive factors and understand mechanistic basis of the ECT outcome. Clinical and neurobiological evaluations would be repeated even after the end of the open label phase. Also, neuroplasticity gene polymorphisms (brain derived neurotrophic factor [BDNF] and catechol-O-methyltransferase [COMT] genes) will be assessed alongside clinical and neurophysiological data to identify the predictors of clinical response. At least 100 subjects matched (as a group) for age, sex, education, handedness, and socio-economic status would be chosen for the comparative analyses of neurobiological studies. They would undergo a one-time baseline assessment of clinical and neurobiological parameters.MRI studies: MRI data will be acquired with a 3T scanner . Structural MRI, resting-state functional MRI and Diffusion Tensor Imaging will be acquired as per the established protocol  and frequency domain (low and high frequency) measures of HRV . DNA extraction will be carried out using the commercial spin column method . Extracted DNA will be checked for quality assurance and stored at -80°C for later use. PCR amplification for SNP assays of selected functional polymorphic variants of COMT  would be linked using codes to facilitate seamless retrieval of different data types.Anonymized coded data would be used for analysis. The primary outcome would be assessed as the change in SAPS scores from baseline to post-9th session of treatment using a two-sample t-test. The last observation carried forward method would be used to handle the missing data of those participants who had premature termination of the intervention. The percentage of responders between the two groups would be compared using logistic regression with estimates of adjusted odds-ratio . Further, comparison of change in the symptoms scores between the two groups at the end of the interventions would be performed through linear mixed-effects model analysis. The time to response would be compared between the two groups using survival curves. Suitable imputation methods would be used for any missing data at specified time-points. Secondary outcome measures including other psychopathology rating scales, adverse effects and dropout rates would also be compared between the two groups.The pre-processing of neurobiological data (where applicable – MRI/EEG data) will be done according to the internationally accepted processing pipelines. Data analysis will be carried out in two phases – a) association and b) prediction. The first phase will involve exploratory analyses with biographic  and disorder-specific  features that influence MRI, EEG, TMS-derived neuroplasticity metrics, HRV, and gene polymorphism measures. These include traditional biostatistical procedures such as descriptive statistics and hypothesis testing for associations in order to identify any potential biomarkers of clinical response. The second phase of analysis will involve building predictive models that will be validated with an independent dataset. Here, instead of examining which individual measurements correlate with outcome measures, we seek to identify combination features  that can give the best prediction for the clinical outcome of proposed brain stimulation methods. State-of-the-art feature engineering/machine learning methods, such as gradient boosting/deep neural nets, will be used to train the model on a part of the acquired dataset. Lastly, causal models like Bayesian networks or mediational analyses will be explored to uncover potential causal relationships between study variables.Formal committees. The DSMB, an independent advisory body, would evaluate the data during the course of the study contributing to the scientific and ethical integrity of the study. It would periodically review and evaluate clinical efficacy and safety data collected during the study, and assess reports on cumulated SAE. It consists of a biostatistician, psychiatrist, and ethicist with a specialization in psychiatry. The board, based on the DSMB charter, will provide a report of recommendation on the continuation, modification, suspension, or termination of the trial to the study sponsor. The sponsor will submit the report to the ethics committees and the TMG to decide the next course of action.The TMG will comprise a group of investigators from the three collaborating institutes. It will monitor the day-to-day execution of the trial. It would take cognizance of trial participant drop-out in the event of withdrawal of consent, noncompliance with study guidelines, and worsening of symptoms. It would interact with the DSMB and Institute Ethics Committee (IEC). It would review the reports and recommendations of these oversight/monitoring committees and plan appropriate actions. It would decide on trial terminations and any trial modifications of the study procedures. It would also oversee the submission of modification, premature termination (if any), and final (completed) trial summary report to the IEC, trial registries, and funding agency.The data management committee comprises the principal investigators of the three institutes. It would be dedicated to reviewing the data archival, management, and sharing. It would execute the periodic data auditing and audit of the research practices related to the studies. It would ensure anonymization and de-identification of data. It would monitor the storage of data in the encrypted data storage servers. It would oversee the sharing of de-identified data upon reasonable requests from collaborators or the research community. Public access would be granted as per the policy of DBT-Wellcome trust India Alliance and international good research practices in strict compliance with the ethics guidelines for biomedical research in India.We plan to conduct an interim analysis of the data after 20 patients in each group have been randomized. This will be shared with the DSMB and if it observes that there is a clear disadvantage to the sham-ECT patients then this would be brought to the notice of the ethics committee. A decision to continue the trial would be revised to avoid exposure of more patients to a less effective treatment by TMG. If a clear level of adversity from ECT proves to be above a predefined threshold that is clinically significant as deemed by DSMB and TMG, the trial would be discontinued to prevent any undue harm to patients in consultation with the ethics committee.All participants would be assessed daily for clinical changes. S-CGI-21 would be applied a day after each ECT session. Patients will be closely monitored for any adverse effects using checklists and tests as described previously. SAE would be reported to the TMG and DSMB, which would assess for SUSAR. In an unlikely event of a harm attributable to participation in research procedures, financial compensation would be provided as per the provisions of the National Ethical Guidelines for Biomedical and Health Research involving Human Participants by Indian Council of Medical Research 2017 .In the event of withdrawal of consent, non-compliance with study guidelines, and worsening of symptoms, the concerned participant will be dropped from the trial. The best practiced standard care at the respective institutes would be provided by the treating teams of the patients even after the trial.Periodic auditing of data and the research practices will be conducted by trial management group and data management committee. They would ensure the quality of research and patient advocacy.Ethics approval. Requisite clearances have been obtained from the IECs of all three institutes , as well as from an ethics committee not affiliated to any of the three institutes . The trial is registered in Clinical Trial Registry of India .Protocol modification. Upon interim analysis or during the course of the study, any modification made to the study protocol will be reflected in the trial registry (CTRI), and will be intimated to the Institute Ethics Committee, India Alliance CPH Committee (Funding Agency) andWellcome Open Research (where the study protocol has been published).Informed consent. Trained health professionals will obtain consent from the participants  trial summary report will be submitted to the funding agency for perusal. De-identified data would be shared with the research community and public access would be granted as per the policy of DBT- Wellcome trust India Alliance  and inteEncrypted data storage servers would host the multi-modal clinical and neurobiological, including genetic data of all participants. The findings of the research would be disseminated primarily through publication in peer-reviewed journals. Prior to the publication, research data may be presented at national and international scientific fora. The study result and interpretation as a report would be shared with all major stakeholders. The team will engage in regular interaction with all stakeholders  for dissemination of knowledge gathered from the trial.Publications from the trial will acknowledge that the work has been carried out by all participating institutes . The authorship will be in strict adherence to the ethical and research publication guidelines . The Heads of the institutes of the three institutes are the sponsors. The funders and sponsors would support the project through expert suggestions through the technical committees but would not be involved in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. The investigators hold the final authority on taking these decisions. Schizophrenia accounts for a large proportion of patients receiving ECT, which is up to 85% of all cases posted for ECT in Russia  or shift to right unilateral placement if there is increased side effect burden but overall improvement? Will benzodiazepines and antiepileptic mood stabilisers be held during ECT? There is limited description of biomarker collection protocols and the burden on participants and feasibility of these protocols additional to that of the main study is not clear.Is the study design appropriate for the research question?PartlyIs the rationale for, and objectives of, the study clearly described?PartlyAre sufficient details of the methods provided to allow replication by others?PartlyAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Treatment resistant schizophrenia, clozapine, electrophysiological biomarkers, TMSI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. I have read the revised version of the manuscript. Most of the concerns and suggestions that I had raised have been addressed satisfactorily. I do not have any further comments and I would like to formally approve the article.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Electroconvulsive Therapy.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This is an important and ambitious placebo controlled trial for the use of ECT augmentation in patients with highly treatment (clozapine) resistant schizophrenia. A previous reviewer has given an excellent review and I shall only add 3 additional thoughts. The evidence of a real effect of ECT in this population, while not as robust as in depression, is far from absent. The Phutane et al. and Bansod et al. papers show differential effect of varying ECT modalities in schizophrenia , suggesting a real effect of ECT rather than placebo. This should be addressed directly in the background and justification for the current study. The second and major concern I have is the blinding procedure as blinding of assessors will be key. The description of blinding / masking is quite brief and considering the complexity of the intervention over 3 sites, I am doubtful if full blinding can be maintained. A simple example of a problem would be the presence of absence of EEG tracings in the case file. It is likely that EEG tracings are printed out and attached to the patient file or electronic medical record. Other details like duration of motor EEG are often recorded in routine clinical practice. If these are missing, it is hard to truly blind the assessors. See the McManus paper for a detailed description of these challenges. Unless these are robustly addressed, the results of this study will be subject to challenge. The last concern is the key outcome of interest (SAPS) is not used for inclusion and rather a general screening questionnaire (BPRS) is used to assess symptom severity for trial inclusion. While there may be good reasons for this, it introduces complexity and scope for bias where patients score highly on the general screening questionnaire but perhaps not as high on the outcome questionnaire due to greater specificity of the outcome scales, or vice versa. The outcome scale should be used for the intake assessment as well to reduce any bias in the recruitment process.Is the study design appropriate for the research question?PartlyIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesReviewer Expertise:Electroconvulsive TherapyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. st century and raises the ethical issue of delaying or temporarily denying an active treatment arm.This is a study that is ambitious in its scope of determining two specific matters 1) whether ECT is an augmenter of clozapine-resistant/intolerant schizophrenia at least in terms of positive symptoms and 2) whether neurobiological biomarkers, comprehensively assessed in this study, could predict ECT responders. The use of sham ECT is novel in the 21 Most of the specific comments below are minor except for a more nuanced discussion on the ethics of sham-ECT treatment in schizophrenia.Background and Rationale…" Suggest taking out "very young". This may not be the case in clozapine-resistant schizophrenia where there could be a greater age-spread with this condition.The sentence, "Most people with this condition, the majority of whom are very young, requires clarification as to why the authors came to this conclusion. In the same sentence, the Petrides et al 2015 study is not non-blinded but single-blinded. The raters were masked/single-blinded as mentioned earlier by the authors. The sentence should reflect this accurately.The sentence in paragraph 3 In the last paragraph, please expand the acronym NIBS.Objective, Hypothesis and Methods The background and rationale are well written and highlight the limitations of high-quality research of ECT in combination with antipsychotics/clozapine in treatment-resistant/intolerant schizophrenia. The authors have made a compelling argument of the need for a sham treatment arm for ECT based on eliminating placebo effects. The reviewer suggests bringing in the ethical dilemma of sham-controlled arm at the outset, which would then be systematically addressed in the methods. The objectives are clearly stated. The primary objective on clinical positive symptoms efficacy with or without ECT is clear. The definitions of clozapine-resistant and intolerant schizophrenia patients are meticulous and exhaustive setting a high bar in research of this area. The methods are clear and meticulously stated with conservative power analysis for the primary outcome. There is a vigorous approach to blinding and sham-ECT delivery. The neurobiological assessments are comprehensive and cutting-edge in ECT research with schizophrenia. This is to be specially commended. It is highly likely that this study will significantly value add to the literature on brain mechanisms during ECT in schizophrenia.) is different from the third secondary objective of determining predictive utility of a wide range of biomarkers to ECT response.Please clarify whether the second primary objective .“The seizure threshold would be determined during the first ECT session through titration method”. Please clarify if there are additional criteria viz., EEG/Motor seizure length/quality to determine a threshold seizure. It would be appropriate to be specific.On Page 6, ”. Is this justified or necessary since the primary outcome is determined at the 9th ECT session? Would this take away decision-making about termination on routine clinical grounds by the respective treating teams? Please clarify.On Page 6, “After the 9th ECT session, ECT course would be terminated on achieving plateau in clinical response, i.e., if there is no change in the clinical status from the previous session in three consecutive sessions as measured by Sheehan-Clinician Global Improvement Global-21 scale (S-CGI-21) all the symptom assessments, after baseline assessments, are uniformly conducted at the same time point, 24 hours after each ECT, to avoid rater-bias of guessing the treatment arm related to the immediate cognitive effects of post-true ECT effects. The sentence should be modified to reflect this.Page 7, "Clinical symptoms would be measured by SAPS, Scale for the Assessment of Negative Symptoms (SANS) , BPRS  at baseline and every week till the end of the intervention. S-CGI-21 would be assessed after 24 hours of each ECT (true or sham ECT) session."It is suggested that suggests using an additional specific scale to measure auditory hallucinations (as a secondary outcome measure) specifically since ECT may have a differential impact on this measure. Treatment-resistant auditory hallucinations may be more susceptible to brain stimulation in comparison to treatment-resistant delusions or treatment-resistant formal thought disorder. This may be particularly important in this sham control trial where the sham treatment ends at 9 sessions to target specific sensitive parts of a heterogenous condition of schizophrenia. This is likely to provide valuable clues to future approaches in studies of ECT in schizophrenia. This will also add further novelty to this study.Page 7, "Clinical symptoms would be measured by SAPS, Scale for the Assessment of Negative Symptoms (SANS) , BPRS  at baseline and every week till the end of the intervention." The reviewerPage 7, "Functional abilities will be assessed using Groningen Social Disability Schedule (GSDS) and social and occupational functioning scale (SOFAS)  at baseline and after each step of intervention." The reviewer is not able to understand the relevance of both these scales, especially the SOFAS, while the study is entirely conducted in an inpatient population. It is expected that self-care and family interactions may improve during the intervention but to report on wider social and occupational functioning is stretching things too far. Suggest using just one of these two scales.On Page 11, under "Informed consent", while the UBACC is used to assess a patient’s decision-making capacity, did the participants and their families additionally receive a participant information sheet that highlights in layman's terms the study and its risks and benefits? The use of the UBACC is an important addition to ensure an easy-to-use screening tool for decision-making capacity in research. Unfortunately, the study is limited in considering only patients who have a capacity to give consent thus eliminating an arguably larger number of more severely unwell patients. This is understandable and appropriate due to the sham-arm.Discussionno evidence for the role of ECT in the treatment of schizophrenia. With this in mind, a major limitation here is an absence of a contrarian discussion on the ethics of sham-ECT trials. A delay of true-ECT treatment for nearly 3 weeks (9 sessions) and subjecting a patient to repeated administration of IV anaesthesia/muscle relaxant without electrical stimulation in 50% of the participants is ethically troublesome. What would be the answer given while obtaining consent when a patient/family asks: 'What is my benefit in participating in the trial if I receive a 'sham- treatment'?'. At the very least, these matters should be acknowledged. The discussion centres around justifying the use of sham-ECT study in determining the ECT-specific effects rather than placebo or other effects. This is an important research question, which will hopefully be addressed in this study. However, ECT has been used continuously for the treatment of schizophrenia for over 80 years. An absence of evidence through a randomized sham-controlled trial does not necessarily mean that there isIs the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Electroconvulsive Therapy.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.


Amaranthus spinosus L. is an annual weed species with high invasive potential worldwide, and it can affect animal behavior and well-being due to the presence of sharp spines. We used GPS tracking collars to monitor cattle activity and spatial distribution in a grazing system with different levels of weed encroachment. Animals in weed-infested paddocks had reduced resting time and increased grazing time, distance traveled, and rate of travel compared to animals in weed-free paddocks. The spatial distribution of the cattle was greater in weed-free paddocks than in weed-strips or weed-infested areas. Pasture weed encroachment affects cattle behavior and their spatial distribution across the pasture. Increasing animal activity can result in lower animal performance due to greater energy expenditure and impacts on animal welfare. Understanding the impact of pasture weed encroachment on animal behavior is especially important for increasing livestock productivity and sustainability while maintaining animal welfare.Pasture weed encroachment is a major challenge in livestock production based on grazing systems. p < 0.05) compared to animals in weed-free paddocks. The spatial distribution of the animals was consistently greater in weed-free paddocks than in weed-strips or weed-infested areas. The effects of weed encroachment on animal activities were minimized after weed senescence at the end of the growing season. Pasture weed encroachment affected cattle behavior and their spatial distribution across the pasture, potentially impacting animal welfare. Further long-term studies are encouraged to evaluate the impacts of weed encroachment on animal performance and to quantify the effects of behavioral changes on animal energy balance.Weed encroachment on grasslands can negatively affect herbage allowance and animal behavior, impacting livestock production. We used low-cost GPS collars fitted to twenty-four Angus crossbred steers to evaluate the effects of different levels of weed encroachment on animal activities and spatial distribution. The experiment was established with a randomized complete block design, with three treatments and four blocks. The treatments were paddocks free of weeds (weed-free), paddocks with weeds established in alternated strips (weed-strips), and paddocks with weeds spread throughout the entire area (weed-infested). Animals in weed-infested paddocks had reduced resting time and increased grazing time, distance traveled, and rate of travel ( It is estimated that agricultural production needs to increase by approximately 50% by 2050 to meet the world food demand due to global population growth and rising income . LivestoUsing herbicides is the most common and effective method of weed control . HoweverAmaranthus accounts for approximately 70 species across the globe [Amaranthus spinosus L.) is an annual small-seeded, broadleaf weed species with extended germination, fast growth, high seed production, and high invasive potential. It is widely found in grasslands [The genus he globe . Spiny passlands . Furtherasslands . Typicalasslands ,13. Spinasslands , althougIn addition to the demand for increasing livestock production efficiency, there is growing global concern regarding animal welfare in livestock production systems. In Florida (USA), spiny pigweed usually encroaches on paddocks spontaneously during the warm season (spring–summer). More investigation into the impact of weed encroachment on animal behavior is required in order to better explain the animal performance responses. Several studies have demonstrated the effects of weed encroachment on forage responses ,7,14,15,Advances in precision livestock farming technologies allow the use of global positioning systems (GPS) to monitor animal behavior on grazing systems remotely in near real-time. Using low-cost GPS and geographic information systems (GIS) enables the monitoring of the spatial variability of animal distribution over time in grazing areas . UnderstFreedom to express normal behavior is one of the five defining principles of animal welfare . TherefoCynodon dactylon (L.) Pers.) pastures on animal behavior. Therefore, this study aimed to evaluate the effect of pasture weed encroachment on animal behavior through GPS collars, which registered signals every second for a lengthy period of time. We hypothesized that animals would avoid weed-infested areas in the paddock and increase their daily activity as weed encroachment increased.Most studies using GPS collars to track livestock behavior have been set to collect GPS signals every 5 to 15 min during short periods ,24, prevCynodon dactylon (L.) Pers.). Climatic data for the experimental period were collected at the Florida Automated Weather Network (FAWN). The monthly accumulated rainfall, temperature , and temperature–humidity index (THI) for both experimental years (2021 and 2022) are reported in This study was carried out at the University of Florida, Institute of Food and Agricultural Sciences (UF/IFAS), North Florida Research and Education Center, Marianna, FL, USA, during the summers (June to September) of 2021 and 2022. Twelve paddocks  of common bermudagrass, approximately 1.3 ha each in area, were established . The treatments were paddocks free of weeds (weed-free), paddocks with weeds established in alternated strips (weed-strip), and paddocks with weeds spread throughout the entire area  in the uncontrolled (weed-infested) and alternated strip paddocks in May 2020. All of the seeds were collected at the research station during the summer of 2020. In 2021, we sprayed Corteva AgriscienceTM DuraCorTM herbicide  and used 2.5 mL/L of non-ionic surfactant  to set the treatments. The herbicide was applied only for the weed-free and weed-strip treatments. Thus, for the “weed-free” treatment, the whole area was sprayed with the herbicide at the beginning of the experiment (early June). Similarly, the spiny pigweed strips were established using the same herbicide, with the strips’ coordinates previously inserted into the system of the sprayer tractor. The “weed-infested” treatment paddocks were not sprayed with any herbicide. The treatments were designed to create different levels of weed encroachment in the pasture. The same spraying protocol was repeated in early June of 2022 for the second year of evaluations.To establish the treatments, spiny pigweed seeds were drilled (1.1 kg haBos spp.) per paddock were considered testers and remained on the respective treatments throughout each cycle of study (summer 2021/2022). The initial mean BWs of the tester steers (n = 24) were 358 ± 22 and 387 ± 29 kg for 2021 and 2022, respectively. All of the paddocks were continuously stocked under variable stocking rates using “put-and-take” animals to adjust the herbage allowance. The target herbage allowance was 2 kg DM of bermudagrass herbage mass per kg BW for all treatments. The put-and-take animals were extra animals added to or removed from each paddock every cycle (21 d), according to the measured bermudagrass herbage mass (HM), to maintain the same herbage allowance for all the treatments during the entire experimental period. We used a high herbage allowance threshold to guarantee enough fodder for the animals and avoid possible issues with toxicity in weed-infested paddocks. The bermudagrass HM was quantified every 21 d using double sampling [2) and then dried at 55 °C for 72 h to determine the actual herbage mass. A calibration equation for the disk was developed every 21 d, with the measured HM regressed on the disk settling height. For the weed-infested treatment, thirty bermudagrass disk heights were collected, and botanical composition was measured after clipping eight representative points at ground level in each paddock. Both species were dried to determine the actual herbage mass of each. The herbage mass of bermudagrass in weed-infested areas was then determined by calculating the average of both methods (double sampling and destructive method). For the weed-strip treatment, sixty bermudagrass disk heights were measured. Thirty disk measurements were taken in the striped area encroached upon by spiny pigweed, and the other thirty were taken in the bermudagrass strip. Botanical composition was measured after clipping four representative points at ground level in the spiny pigweed strips only. The material was then dried to assess the actual mass of the herbage from both species in the spiny pigweed strip. Similarly to the weed-infested treatment, the herbage mass of bermudagrass was determined by calculating the average of both methods (the double sampling and destructive methods). This approach of averaging both methods was adopted in order to consider the bermudagrass growing beneath the spiny pigweed cluster. To determine the spiny pigweed mass in the weed-strip treatment paddocks, the herbage mass obtained by the destructive method was adjusted for the spiny pigweed area in the paddock  approved the experimental protocols (IACUC202200000506). Two crossbred Angus steers . The anTwo tester steers from each paddock were fitted with GPS collars, for a total of twenty-four tester animals distributed among the treatments . The GPS collars used in this study were constructed as described by  using th® (v. 3.22.14) software and created shapefiles of each paddock boundary for the study area. The paddock boundaries were defined using a georeferenced Google Earth image and fence posts as ground control points. All of the GPS coordinates registered out of the respective paddock boundary, including data registered along the pathway from the pen to the paddock, were filtered and excluded. We did not filter inaccurate locations inside the respective paddocks, since the inaccuracy was the same for all treatments. Filtering inaccurate locations could result in the loss of many locations, with a low error in return for a slight improvement in location precision [The devices were set to record positions (latitude/longitude) every second for twenty-one days. This period was chosen according to the device’s battery lifespan and the schedule of forage and animal evaluations during the trial. The animals were monitored for four sequential periods of 21 d in 2021 and five periods (21 d) in 2022, totaling 84 days of monitoring in 2021 and 105 days in 2022. The evaluation periods are described in recision .® (R version 4.3.0). The distance between two sequential positions was calculated using the Pythagorean theorem, then summed for 24 h periods to estimate the distance traveled per day by each animal (m/day). The rate of travel (m/min) was calculated using the ratio between the traveled distance and time spent to change the location point. The daily distance traveled and rate of travel were calculated using R Studio®  programming. The data from each paddock were averaged across the two animals (testers).To calculate the distance between two sequential points and to handle data on GIS, latitude and longitude coordinates were converted to the Universal Transverse Mercator (UTM) coordinate system using the GSTAT, SP, and RGDAL packages in R Studio®  programming to calculate the percentage of time spent on each activity daily. The data were averaged across the two animals from each paddock.To estimate the daily patterns of animal activity, including grazing time, resting time, and traveling time, we used the rate of travel pattern validated by Augustine , adapted® v. 3.22.14) to generate an additional shapefile for each spot of interest . The geographic coordinates of each corner of the artificial shades, water troughs, and weed strips had previously been taken by a conventional GPS using a smartphone (Coordinates-GPS Formatter app V. 7.8.0). To minimize the inaccuracy of the smartphone GPS, we rasterized the vector points and used a georeferenced Google Earth image and the “georeferencer” tool in QGIS® software to adjust the shade and water trough areas. To consider the shade projection, the area around the water troughs, and the remaining inaccuracy of the smartphone–GPS system, we generated a new shapefile for shade and water troughs with a round buffer of 10 m from the original coordinate using the geoprocessing “buffer” tool of the software QGIS®. To estimate the percentage of daily time spent near shade or water, we used the spatial analyst tools in the same mapping program to calculate the percentage of GPS points inside of each buffered area (shade or water) through the intersection between the filtered GPS points and the respective area of interest. For weed-strip treatments, the same approach was adopted to estimate the percentage of time spent by grazing animals in the bermudagrass strips or spiny pigweed strips. Data were averaged across five evaluation periods and two years of study for each treatment. ® v. 3.22.14).To estimate the daily time spent (%) by the animals in areas of water and shade, as well as the time spent in each strip (bermudagrass × spiny pigweed) in the weed-strip treatment paddocks, we used the vector tools of the referred GIS software (QGIS®. This interpolation method created a density map of an input vector layer (GPS points) using the Kernel density estimation. The density was calculated based on the number of points in a location, with larger numbers of clustered points resulting in larger values. Because of the high requirement for computing resources and the hard work necessary to process the big data within a reasonable amount of time, we randomly selected one paddock from each treatment in each study year to generate heatmaps and characterize the pattern of animal distribution. To estimate the livestock site preferences, we calculated the Landscape Preference Index (LPI) using the ratio of the proportion of time spent in the area of interest to the proportion of the area of interest compared to the entire available area, as described in Handcock [To track the animal spatial distribution and identify the animals’ site preferences, we generated a heatmap based on the filtered GPS data using the Kernel density method of the software QGISHandcock .p < 0.05.We computed daily means for each collared steer and then calculated the average for each paddock  in each treatment. The statistical model used for the analyses was: p > 0.05). There were no differences in bermudagrass HM, ADG, stocking rate, or herbage allowance among treatments , with a peak of HM in the second evaluation period and lower HM observed for the first and last periods of evaluation , with animals in weed-infested paddocks increasing their daily walking by approximately 26% compared to animals grazing in weed-free paddocks . There was a significant effect of pasture weed encroachment on the daily distance traveled by the animals (paddocks . Similarpaddocks .p > 0.05). However, the evaluation period significantly affected the travel rate of grazing steers , while increasing the grazing time (p < 0.05) compared either with weed-strips or weed-free paddocks , with no interaction between the level of weed encroachment and the evaluation period (p > 0.05). Overall, animals presented longer resting times in the last evaluation period compared to the other four  in the time spent in shady or water trough areas by grazing animals according to the different levels of pasture weed encroachment. However, there was a tendency to spend less time by water trough areas in weed-infested paddocks  and in water trough areas for 2.6 h (11%). There were no significant differences  demonstrated the same pattern of animal distribution according to the treatment and period of evaluation. During the first three periods of evaluation, the animals in paddocks encroached by weeds (weed-strips or weed-infested) were concentrated in the hotspots mentioned above and moved mainly through the edges of the paddock, with this behavior being more evident for weed-infested paddocks and in 2021. The animals spread out across the paddock area from the third evaluation period onwards, progressively occupying larger paddock areas . The greThe absence of effects of weed encroachment on bermudagrass herbage allowance can be explained by the bermudagrass growth beneath the spiny pigweed clusters, which was associated with the low grazing intensity used in this trial to avoid animal injuries or toxicity issues with the weeds. The aim of this study was to evaluate the impacts of pasture weed encroachment on animal behavior, assuming that behavioral changes could impact long-term animal performance. We set all the treatments with the same herbage allowance to control the effect of herbage allowance on animal behavior. Thus, the same animal performance observed among treatments in this study was also expected due to the same herbage allowance and the brief period of evaluation for inferences in terms of animal performance. Our findings suggest that the animals were able to adapt to weed-infested areas by changing their activity patterns, possibly to intensify their forage searching. It is possible that the period of study was too short to detect the impact of increasing animal activity on energy expenditure and, consequently, animal performance, although we did not evaluate the animal energy balance. Also, it is possible that reducing the herbage allowance by increasing the stocking rate could result in greater differences among the treatments, since the animals would face more challenges in terms of browsing forage, and the competition would increase. Additionally, we did not offer any supplement besides mineral mixture to the animals, which prevented greater ADG that could provide evidence for differences among the treatments. The average daily distance traveled which was estimated in this study (~5 km) is similar to the one observed by Johnson . It was The greater daily travel distances observed for grazing animals in weed-infested areas compared to areas with lower levels of weed encroachment or weed-free areas may be justified by the challenge animals face finding fodder in weed-infested areas. According to Owen-Smith , extendeGrazing animals in weed-infested paddocks also presented a greater average rate of travel. Animals traveled longer distances and moved faster through different grazing stations in weed-infested paddocks as a possible adaptation in order to maintain the same dry matter intake in a similar period. Spine pigweed clusters might have restricted the forage access in some spots, mainly access to the forage growing beneath the weed cluster, due to the spines. This explanation is supported by the effect of the evaluation period on the rate of travel. The travel rate significantly decreased in the last period of evaluation (late summer), when the spiny pigweed was becoming senescent and had a lower HM. The pattern of the rate of travel from the second to the last evaluation periods followed a similar pattern to spiny pigweed HM. These findings suggest that the animals remained for longer in the same grazing station because access to the forage was growing easier. Accordingly, the greater resting time and reduced grazing time in the last period of evaluation also demonstrate the effect of spiny pigweed HM on daily animal activities. The greater grazing time and reduced resting time in weed-infested paddocks compared to weed-free areas supports the notion that the animals changed their normal behavior and daily patterns of activities to adapt to the weed encroachment in the pasture. The same herbage allowance observed among treatments associated with the controlled effect of climatic factors on animal behavior, since all animals were under the same climatic conditions, demonstrate that the observed behavioral changes were an effect of the weed encroachment levels. In addition, the THI observed during the period of study (74–79) is considered to have had a light impact on heat stress for beef cattle , suggestWe estimated animals resting for, on average, 87.2% of the day, with daily grazing time and traveling time averaging approximately 7.6% and 5.2%, respectively. Although our estimates were calculated based on the speed ranges previously validated by Augustine  and adapDespite the possible inaccuracy of GPS collars in terms of estimating resting and grazing time, it is a crucial tool for monitoring changes in animal behavior in response to any challenge, such as weed encroachment in pastures. In weed-infested pastures, the focus should be on identifying changes in resting time and grazing time patterns according to the level of encroachment to detect the opportune moment for management interventions such as herbicide spraying or moving animals to another pasture area. In our view, this makes the device’s precision more important than its accuracy, since changes in the typical pattern of activity indicate the change in animal behavior regardless of the time spent in each activity. The GPS device showed applicability to monitoring animal behavior changes in response to pasture weed encroachment, but further studies are needed in order to calibrate a site-specific speed threshold to accurately estimate animals’ activities in grazing systems using low-cost devices without motion sensors.Although the estimated time spent by shady areas and water trough areas accounted for only approximately 33% of the day , shady oThe changes in the animals’ movement patterns throughout the evaluation periods in weed-infested and weed-strip paddocks suggest that the animals were avoiding weed patches and traveling mainly through the edges of the paddocks during the peak of the spiny pigweed development (periods 1 to 3), possibly because of the weed spines and the difficulty of walking and accessing the forage. This behavior was more evident with higher levels of weed encroachment (weed-infested paddocks). The greater time spent by animals in bermudagrass strips compared to spiny pigweed strips  supportsAnimals increased their spatial distribution over the paddock from the third period onwards in response to the spiny pigweed’s senescence. Spiny pigweed is an annual weed that usually reduces in biomass in mid-to-late summer, as was demonstrated in our study . The greThe more homogeneous spatial distribution of the animals during the five periods in weed-free paddocks compared to paddocks encroached upon by weeds, as observed in our study, demonstrates that pasture weed control can have additional benefits for the ecosystem. A greater spatial distribution of animals could play an important role in excreta distribution of livestock throughout the pasture, and could avoid excessive deposition of excreta in specific areas . The decThis is the first study to evaluate the effects of pasture weed encroachment on animal activity and site preferences. Our findings have demonstrated the effect of weed encroachment on animal behavior and the importance of weed control in grazing systems. GPS tracking collars could possibly detect changes in livestock spatial distribution and daily activities according to the level of weed encroachment in the pasture, allowing for the detection of potential challenges to animal welfare in grazing systems and supporting decision making for management interventions, such as weed control. We emphasize that the GPS collars were used to monitor the effect of weeds on animal behavior on a high temporal scale, without human interference in animal activities. However, we did not evaluate the long-term effect of increasing animal activity on energy balance. Further effort should be devoted to evaluating the economic viability of GPS collars for cattle tracking, determining the most suitable number of tracked animals for herd monitoring, and estimating the impact of energy expenditure on increasing activity in long-term animal performance.Pasture weed encroachment affects animal behavior and spatial distribution in grazing systems. Animals in weed-infested pastures tend to reduce their resting time and increase their grazing time, distance traveled, and rate of travel as a possible adaptation to weed encroachment. GPS tracking collars are alternative tools used to monitor animal behavior grazing systems in order to provide near real-time information to support decision making for management interventions. Further long-term studies are encouraged to evaluate the impacts of weed encroachment on animal performance, quantify the impacts of behavioral changes on animal energy balance, and determine the economic threshold for weed control in grazing systems.


Iodide is secreted into the lumen of the stomach and salivary glands via NIS expressed in the basolateral membrane and then circulates back from the small intestine to the bloodstream via NIS expressed in the apical membrane.Polarized NIS expression in the human body regulates intestinal-bloodstream recirculation of iodide, perhaps prolonging the availability of iodide in the bloodstream. This leads to more efficient iodide trapping by the thyroid gland. Understanding the regulation and manipulating gastrointestinal iodide recirculation could increase radioiodine availability during theranostic NIS applications. Iodine is an essential component of thyroid hormones which, in turn, are key factors for human physiology and development before and after birth. Active iodide transport into thyroid epithelial cells is mediated by the sodium iodide symporter (NIS), a plasma membrane glycoprotein. Diagnosis and therapy of thyroid diseases using radioiodine have been applied since 1940 , but NISA secondary structure model for NIS, with 13 transmembrane segments, has been proposed based on experimental data -8. NIS cThyroid-stimulating hormone (TSH) and iodide are the two main factors regulating iodide transport in the thyroid, which is stimulated by TSH and decreased by iodide. Hence, TSH stimulation and iodide depletion are the two most important modulators routinely used to optimize radioiodine treatment in metastatic thyroid carcinoma ,12,13.NIS gene is one of the most promising candidates for gene therapy applications, both as a therapeutic and a reporter gene  NIS expression is the fact that extrathyroidal tissues are unable to perform iodide organification. Therefore, the accumulation of iodide is the sum of cellular uptake and efflux, largely dependent on the plasma availability (absorption and clearance) of the tracer  imaging and correlate the findings with NIS immunohistochemistry in human tissues that accumulate radioiodine. We were particularly interested in evaluating NIS expression in the human small intestinal epithelium and understanding the possible role of NIS in iodide absorption and recirculation.NIS can be considered a master molecule of iodine metabolism. We studied the polarized NIS expression in tissues that accumulate iodide by using immunohistochemistry and a polyclonal antibody against the C-terminal end of NIS. Notably, NIS is expressed in the basolateral membrane of epithelial cells from salivary glands, thyroid, and stomach, while in the intestinal epithelium, the expression of NIS occurs in the apical membrane. NIS is regulated differently in each of these tissues and is responsible for iodide absorption from the intestine. Some of the absorbed iodide undergoes organification in the thyroid. In the gastrointestinal lumen, iodine is secreted via NIS into the stomach and salivary glands and is again absorbed via NIS in the small intestine. The role of this recirculating mechanism of iodine in the gastrointestinal system remains unclear. Iodine is finally excreted by the kidney via glomerular filtration.In the present study, we performed immunohisto-chemistry of NIS using paraffin-embedded samples.This study was approved in 2020 by the local ethics committee of the National Institute of Oncology in Hungary.Radioiodine distribution in the human body was evaluated using planar whole-body imaging after therapeutic administration of radioiodine-131 in patients who had undergone thyroidectomy for cancer. Post-therapeutic whole-body scan is routinely performed in anterior and posterior images .t < 60 min before any voiding.A whole-body scanner was used to image the distribution of radioiodine-131 across the entire body. In the case of radioiodine-131, a high-energy collimator (up to 450 keV) was used with a scanning speed of 12 cm/min and a window setting of 364 keV ± 15%. Counts were obtained from the regions of interest over the entire body and thyroid in anterior and posterior images. Geometric averages for anterior and posterior counts were used. The counts were calibrated to the counts at time The local Institutional Review Board of the National Institute of Oncology reviewed and approved the immunohistochemistry examination of stored paraffin- embedded tissues. Human NIS (hNIS) polarized expression was studied in iodide accumulating tissues by immunohistochemistry using a polyclonal antibody against the C-terminal end of hNIS ,11, as pRoutine planar imaging during whole-body radioiodine distribution showed an accumulation of iodide (via NIS) in the stomach, salivary glands, and gastrointestinal lumen. Iodine dissolved in the gastric juice progresses to the duodenal lumen and is absorbed via NIS in the small intestine, in a similar process described in rodents. No significant radioiodine accumulation was observed in the distal part of the small intestine or in the colon. In the circulation, iodide is trapped by the thyroid (when this gland is present) or finally excreted by the kidney through glomerular filtration .The results of NIS immunohistochemistry showed the localization of the NIS protein in the basolateral membrane in epithelial cells from salivary glands, thyroid, and stomach and in the apical membrane in epithelial cells from the small intestine .The images showing the distribution of radioiodine correlated well with NIS polarized expression. The NIS expressed in the apical membrane was responsible for iodide absorption from the intestine. In the stomach and salivary glands, iodide was secreted into the lumen by NIS expressed in the basolateral membrane; then, in the small intestine, iodide circulated back to the bloodstream via apical NIS .in vivo distribution of radioiodine in the human body and the polarized NIS expression using immunohistochemistry in iodide accumulating organs. Iodine is a trace mineral in the environment and is ingested by humans via food. Because of its scarcity, iodine must be absorbed through a very specific and efficient mechanism. Iodide anions are quickly filtered from the bloodstream by the kidney and excreted via urine. Iodide is also “trapped” by the thyroid; it is transported by NIS into thyrocytes, where it is covalently bound to the tyrosyl residues of thyroglobulin. NIS is highly specific and efficient in accumulating iodide into thyroid cells, but iodide is also quickly cleared from circulation by glomerular filtration. Thus, it is critical that iodide remains in circulation for a sufficiently long time  cells. Disrupting this basolateral sorting signal results in apical targeting of NIS protein in epithelial cells. This determinant must be recognized by sorting machinery that is cell-specific and characterized by distinct adaptor proteins.Studies of human samples are limited by availability and tissue autodigestion, and thus we could not evaluate Very little is known currently about NIS-expressing tissues regarding the presence, function, and regulation of cell-specific factors that interact with and determine the polarized targeting of NIS in the plasma membrane ,24. In tIn conclusion, iodine and TSH are the two main factors regulating thyroidal iodide transport, in which the transport is stimulated by TSH and decreased by iodine -5. HenceBoth tissue-specific expression and polarized NIS expression determine the distribution of iodide in the human body. As an anion, absorbed iodide is quickly filtered from the circulation by the kidney into the urine. Gastrointestinal recirculation can lead to prolonged plasma retention of iodide, thus resulting in higher iodide availability and accumulation into the thyroid. NIS is the first theranostic molecule ever used, as it is used in thyroid imaging, as a reporter gene in gene therapy, and in radioiodine treatment of metastatic thyroid cancer. Manipulating intestinal recirculation of iodide can optimize radioiodine availability in the bloodstream for NIS-mediated targeted radiotherapy and reporter imaging.


Cervical dysplasia, also referred to as cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesion (SIL), is the precursor lesion of cervical carcinoma. Therefore, its diagnosis is vital for early detection and inhibiting the development of cervical carcinogenesis. Human papillomavirus (HPV) is the most common aetiology of cervical cancer and this infection mainly affects young women of childbearing age, thus affecting pregnant women as well. It is essential to know how CIN progresses in pregnant patients because the management of pregnant and non-pregnant patients is different (considering the safety of both mother and child in pregnancy). This review intends to highlight the studies which have assessed the rates of progression of CIN diagnosed in pregnancy throughout the antenatal period and the impact of the mode of delivery on CIN outcomes. We searched PubMed/MEDLINE and Google Scholar databases for relevant articles. Many studies indicate that the rate of progression of these lesions is very slow during the tenure of pregnancy; many also report postpartum regression of these lesions. Thus, in most of these patients, management can be safely implemented in the postpartum period while just keeping them under observation in the antenatal period. However, patients with high-grade CIN have a higher chance of developing invasive cancer and, therefore, require careful monitoring. There is a dispute regarding the role of the mode of delivery in determining the fate of cervical dysplasia. While some studies supported vaginal births over caesarean sections, others did not find any difference between the two in defining the outcome of the dysplastic lesions. In 2018, cervical cancer was categorised as the fourth most common cancer prevailing among women worldwide. The estimated age-standardized incidence was 13.1 per 100,000 women with a huge interregional inconsistency. Cervical cancer was also responsible for over 311 million deaths globally during the same year, thus becoming the fourth leading cause of mortality among women. Medium- and low-resource countries face the highest mortality [The commonest aetiology of cervical cancer is high-risk human papillomavirus (HPV) type 16 and 18, which has the highest oncogenic potential . CervicaIn pregnant women, the prevalence of abnormal findings in cervical cytology is about 2-7%, which is almost the same as that of the non-pregnant population . About 1A review article states that the peak incidence of CIN and pregnancy co-existence occurs during the third decade of life . AlthougColposcopy is an essential tool for evaluating cervical dysplasia during pregnancy. The American Society for Colposcopy and Cervical Pathology recommend colposcopy during pregnancy and postpartum in patients with an immediate risk of high-grade CIN of more than 4% . HoweverPatsner et al. conducted a study to analyse the fate of low-grade CIN during pregnancy . It was The supervision of pregnant women with atypical findings in cervical cytology is clinically challenging. While, the health of the mother cannot be compromised, and invasive lesions (if any) must be excluded, the unborn baby also should not be made vulnerable to any preventable risks .Throughout the past few years, there have been many studies pertaining to the outcome and progression of CIN or cervical dysplastic lesions throughout pregnancy, whether they progressed, remained persistent or regressed, and the results obtained are heterogeneous. Also, whether the mode of delivery  affects the outcome of these cervical lesions has been under constant supervision and research. While some authors advocate vaginal delivery as a safer option in pregnant patients with CIN -16, otheThis review will highlight the salient features of some studies that focus on the rate of progression, persistence, or regression of cervical dysplastic lesions diagnosed in pregnancy. It shall also put forward facts that had been inferred about the role of the mode of delivery affecting the outcome of cervical dysplastic lesions in pregnancy.MethodologyPubMed/MEDLINE and Google Scholar databases were searched with the keywords “Cervical dysplasia”, “Pregnancy”, “Progression”, “Mode of delivery” and others. About 100 publications including original research and review articles pertaining to this topic were reviewed.The outcome of cervical premalignant/dysplastic lesions in the antenatal periodThe natural history of CIN in pregnancy has been subject to conflicting reports. Origoni et al. stated that the rate of progression of CIN to invasive cervical cancer is 0.4%, which is extremely low . On the Spontaneous regression in the postpartum period has been reported to be in the range of 16.7-69.3% among pregnant women with high-grade CIN . There iCoppola et al. conducted a retrospective study on pregnant patients diagnosed with high-grade CIN to determine the outcome of the lesions in these patients . The regPalle et al. conducted a retrospective study to assess the fate of CIN during pregnancy . This stKaplan et al. carried out a retrospective study to assess the prognosis and recurrence risk for patients who were diagnosed with CIN in the antepartum period . In thisA retrospective study of abnormal Pap smears of pregnant patients to study the post-partum progression or regression of cervical dysplasia diagnosed during pregnancy observed that there was a low progression rate of cervical dysplasia during pregnancy and regression rates postpartum were high (63-76%) for all the lesions of cervical dysplasia . So, conIn 2006, the American Society of Colposcopy and Cervical Pathology (ASCCP) published revised guidelines for the management of abnormal cervical cytology and histologic lesions in pregnant and non-pregnant women ,27,28. TFader et al. carried out a retrospective study to investigate the fate of dysplastic cervical lesions diagnosed through cytology in pregnant patients in relation to antepartum colposcopy and cervical biopsy . It was Rueckert et al. carried out a case-control study of pregnant women with severe cervical dysplasia as well as non-pregnant controls to relate postpartum regression and progression rates . They suGomez et al. carried out a study to analyse the progression of high-grade CIN through pregnancy as well as the postpartum period . This stSurgical intervention of the cervix during pregnancy has been reported to be associated with preterm births -35. HoweKorenaga and Tewari in their review article recognised cervical cancer as the most common gynaecological malignancy diagnosed in pregnancy . During Pereira et al. in an observational analytical and retrospective study in Brazil did not find significant differences between pregnant and non-pregnant women, with respect to the occurrence of precursor lesions of cervical cancer. Thus pregnant women have the same risk as non-pregnant women in presenting with cervical dysplastic lesions .Another study obtained postpartum CIN regression rates ranging from 37% to 74%, with regression of low-grade CIN in about 80% of cases . CervicaFreudenreich et al. assessed the course of dysplasia during pregnancy (the rate of persistence and remission) and opined that attentive monitoring of CIN during the antenatal period is sufficient and clinically safe . PostponSuchońska et al. conducted a study to assess the natural history of CIN during pregnancy and postpartum period and observed that several CIN cases tend to spontaneously regress following delivery .Stuebs et al. evaluated the progress of untreated high-grade CIN during pregnancy and measured progression, persistence, and regression in the postpartum period . Their sLiterature reveals that pregnancy and postpartum period witness higher remission rates of CIN than non‑pregnant states. Following delivery, a considerably higher rate of spontaneous remission of even high intraepithelial lesions is seen while progression or persistence of CIN is infrequent.The reason for the regression of cervical intraepithelial dysplastic lesions after delivery as observed in many studies may be due to the immunosuppressive effect of sex hormones during pregnancy.. On biopsy, the dysplastic epithelium may be excised in its entirety. In addition, disruption of the epithelial integrity during delivery may trigger a local immune response leading to the loss of dysplastic tissue ,20.The impact of the mode of delivery on the progression of cervical dysplasiaThe association of delivery mode with the progression of CIN in pregnant patients is a hazy field of research to date. A pathophysiological theory was considered that the injury as well as the transitory ischemia of the cervix caused during the final stages of labour lead to a tough inflammatory response, thus promoting repair mechanisms and cervical remodelling through the local build-up of inflammatory cells . AdditioSchuster et al. did not observe any difference in CIN regression rate among the two groups of patients with abnormal cervical cytology diagnosed during pregnancy; the two groups being patients with vaginal delivery and caesarean section, thus indicating that the impact route of delivery does not influence the fate of the dysplastic lesions . On the Adhoot et al. studied whether pregnant women with abnormal cervical cytological findings (dysplasia) in antepartum differ in their postpartum rates of regression, taking into consideration the mode of delivery . The cerOn the other hand, Coppola et al. did not find any such association between mode of delivery and rate of cervical dysplasia . KaneshiBracic et al. conducted a retrospective study to evaluate the fate of CIN in pregnancy and the influence of delivery mode on the outcome . This stKorenaga and Tewari, in their review article, stated that higher regression rates of CIN have been described with vaginal delivery (60-66%) when compared to caesarean (12%), probably through debridement of dysplastic focus by vaginal birth trauma .Douligeris et al. carried out a meta-analysis aimed at assessing the effect of the mode of delivery on the natural evolution of cervical dysplastic lesions in pregnant patients . This stAccording to a study by Stuebs et al., the rate of regression of cervical dysplastic lesions was nearly two times higher for vaginal delivery (27.4%) when compared to caesarean sections (15.2%) . Also, aTherefore, the impact of the mode of delivery in determining the fate of cervical dysplastic lesions is a topic which is still in debate and further studies involving larger cohorts and different topographical locations should be considered before shedding further light into this topic.A cervical Pap smear is compulsory during pregnancy as early as possible . This will help in detecting CIN (if present) early. The treatment for cervical dysplastic lesions diagnosed in pregnancy can be deferred to the post-partum period and this has been found to be safe for both mother and child. These lesions have very low rates of progression and high rates of persistence during pregnancy. Although some studies have also highlighted that cervical dysplastic lesions tend to regress spontaneously after delivery, one should not expect such outcomes from all patients. Thus the patients must be carefully evaluated in the antenatal and postpartum monitoring and careful follow-up are essential. Patients with CIN  who miss their scheduled follow‑up visits are at the highest risk of developing cervical cancer.Although no concrete evidence has been put forward so far regarding a connection with the mode of delivery, few studies opine that vaginal delivery is a safer option for CIN patients as there is disruption of the dysplastic cervical foci during the foetal passage through the vagina. However, there are other studies that do not find any correlation between the mode of delivery and the regression of these lesions. Whether vaginal delivery or caesarean section should be practised in these patients is a question which does not have a definite answer. However, unless a caesarean section is otherwise indicated, it is advisable to go for a vaginal delivery. It is anticipated that the facts put forward in this review will aid future investigators in carrying out further research in this field.