A survey of awareness, knowledge, attitude, and skills of telemedicine among healthcare professionals in India.

Background: Telemedicine Practice Guidelines were promulgated in India in 2020. There is little information about the awareness, knowledge, attitude and skills (AKAS) of the healthcare professionals regarding telemedicine and its practice guidelines a year after. The aim of the study was to study the awareness, knowledge, attitudes and skills of the healthcare workers of the country about telemedicine especially in the context of telemedicine practice guidelines 2020. Methods: An online survey was conducted over 12 weeks from active healthcare workers in India. A standard AKAS Questionnaire for telemedicine and other close and open ended questions were used. Results: A total of 602 active healthcare workers participated in the study. It was seen that a majority of participants had high scores for awareness, knowledge, and attitude toward telemedicine but a mere 39.53% scored high for skills related to telemedicine. A majority of the respondents had no knowledge of the existence of telemedicine practice guidelines and very few had seen or read them. A majority of the respondents were keen to attend a course or training to enhance their understanding and practice of telemedicine. Conclusion: The results of the study show that the basic awareness and background knowledge regarding telemedicine exists in the healthcare professionals in the country. The requirement is to train and educate them about the skills and provisions of the telemedicine practice guidelines 2020 to ensure optimal use of telemedicine and to avoid medico-legal issues.

Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders.

Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD.

Retrospective study of the efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab/pertuzumab (TCH-P) in nonmetastatic HER2-positive breast cancer.

BACKGROUND: Pertuzumab is FDA approved in the preoperative setting in combination with trastuzumab and chemotherapy, in women with nonmetastatic HER2 + breast cancer. The TRYPHAENA trial (n = 77) reported a pathologic complete response rate (pCR), i.e., ypT0ypN0, of 52 % in patients treated with neoadjuvant (docetaxel, carboplatin, trastuzumab, & pertuzumab) TCH-P. Aside from this study, there is limited information regarding the safety and efficacy of TCH-P in the neoadjuvant setting. Our goal was to evaluate the safety and efficacy of neoadjuvant TCH-P in a non-clinical trial setting. MATERIALS AND METHODS: Cancer data registry was utilized to identify patients with HER2 + nonmetastatic breast cancer that received neoadjuvant TCH-P. pCR was defined as the absence of invasive or noninvasive cancer in breast and lymph nodes, i.e., ypT0ypN0. RESULTS: 70 patients with a median age of 52 years met our inclusion criteria. Clinical staging was I-8.5 %; II-68.5 %; and III-22.8 %. 60 % of patients had hormone receptor (HR)-positive tumors. 23 % (16/71) of patients required dose reduction for rash, diarrhea, neuropathy, or thrombocytopenia. Overall, no patients developed grade 3-4 left ventricular systolic dysfunction(LVSD); an asymptomatic reduction in LVEF of >10 % was observed in three patients. The overall observed pCR rate was 53 %. As expected, the pCR rate was higher in patients with HR-negative breast cancer than for patients with HR+ disease: 69 % (20/29) vs. 42 % (17/41), respectively. The axillary downstaging rate was approximately 53 % (19/36). CONCLUSION: Neoadjuvant TCH-P, in a nonclinical trial setting, was associated with a pCR rate of 53 % similar the reported rate in TRYPHAENA. Toxicity was manageable, with no patients experiencing symptomatic heart failure.

Vocal outcome after endoscopic thyroarytenoid myoneurectomy in patients with adductor spasmodic dysphonia.

Spasmodic dysphonia (SD) remains one of the most difficult of laryngeal pathologies to treat. With limited role for speech therapy, various surgical modalities have been tried with various success rates. The objective of the study is to report the results of vocal outcome after thyroarytenoid myoneurectomy in patients of adductor spasmodic dysphonia (ASD). 15 patients of ASD were selected. GRBAS, and voice handicap index (VHI) were used for perceptual evaluation of voice. Thyroarytenoid myoneurectomy was performed by vaporizing the muscular layer of the vocal fold with CO2 laser, at an intensity of 6 W with 1.2 mm diameter in scanner mode. Voice analysis was repeated at 12, 24 and 48 months follow-up. Preoperative GRBAS scores and VHI score of all the patients were poor. At 12 months 12/15 (80 %) patients having strain score of 0. There was marked improvement in VHI scores at 6 months. 10/15 (67 %) patients have been followed up for 24 months. 5/10 (50 %) patients have strain (S) value of 0. VHI scoring of 5/10 (50 %) patients was <30. Two of the four patients completed 48 months follow-up had a strain (S) value of 0, one patient has strain value of 1 and one patient had strain value of 2. 2/4 patients had VHI score of <30; one patient had that of 40. Trans-oral CO2 laser thyroarytenoid myoneurectomy shows significant long-term improvement in voice quality in terms of reduced speech brakes, effort and strain in voice.

Why don't many ENT Surgeons Perform Facial Trauma Surgery.

Introduction: The facial bones are prone to severe injuries due to high exposure and the labile nature of the bones, and they are injured in a significant proportion of trauma patients. Varying from simple, common nasal fractures to communited fractures of the face, management of such injuries can be extremely challenging due to fact that these injuries involve a highly vascular zone with proximity to the airway. In spite of being very well trained in surgeries of face and head neck area, with the exception of nasal bones, not many ENT surgeons in India perform facial bone fracture surgeries. Objective: This questionnaire-based study was planned to explore this key issue to understand as why many ENT surgeons do not perform facial trauma surgeries. Method: A cross-sectional questionnaire-based study was conducted over a period of 2 months Responses were obtained from ENT surgeons across various social groups on a Google Form-based questionnaire. The answers were collected and analysed. Result: A total of 240 valid responses were obtained. Most (56.7%) of the ENT surgeons had more than 15 years of practice. Around half (52%) of surgeons never did facial trauma surgery, and 65% of respondents replied that the main reason for their lack of involvement in facial trauma surgery was that they had no exposure to it during postgraduate training. The majority (65%) also wanted to enter this subspeciality if given a chance. Conclusion: To develop facial trauma management as a subspeciality in ENT, more and more ENT departments in medical colleges should include these surgeries as part of their training programmes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-024-04604-z.

Comparison of Endoscopic Versus Microscopic Tympanoplasty: A Prospective Randomised Study.

Aim: To compare endoscopic versus microscopic method for tympanoplasty in terms of Graft uptake and hearing outcome. Material and methods: A randomized prospective observational study was done. 60 patients who came to ENT outpatient of tertiary care teaching hospital requiring operative intervention for inactive mucosal chronic otitis media. Randomization was done and patients divided into two groups with Group A undergoing endoscopic tympanoplasty and Group B undergoing microscopic tympanoplasty. Post operative graft uptake and hearing improvement were compared between both groups. Intraoperatively visualization of middle ear structures, surgeon's comfort, duration of surgery, post operative pain, giddiness was compared. in both the groups. Results: Total 60 patients got randomly divided in the two groups. There was no difference in terms post op graft success rate and post operative hearing improvement in both the groups Intra operative visualization of middle ear structures better in the endoscopic group and also the surgical time was significantly less in endoscopic group. Conclusion: On comparing endoscopic versus microscopic tympanoplasty in patients of mucosal chronic otitis media, success rate in terms of graft acceptance and hearing improvement was equal between both groups. However, visualisation of middle ear structures was better in endoscopic method. Operating time was shorter in endoscopic tympanoplasty. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-024-04585-z.

Preparation of nose for nasal endoscopy: cotton pledget packing versus topical spray. A prospective randomized blinded study.

During nasal endoscopy it is essential to have proper visualization of structures with minimal discomfort to patient and surgeon. For this it is essential that the nose is well prepared before the procedure. The main objective of the study is to compare and evaluate the efficacy of cotton pledget packing versus topical sprays in preparation of nose for nasal endoscopy. The method includes prospective randomized blinded study on 100 patients. Patients were randomly divided in two groups. In first group the nose was packed with 4% lignocaine with xylometazoline nasal drops and in the other group it was prepared with 10% lignocaine topical spray and xylometazoline nose drops. Following the procedure, patient and the surgeon were asked a pre-formed questionnaire to know their experience during endoscopy. It was observed the packing group required more preparatory time as compared to the spray group. The group which was packed had less discomfort, less pain while endoscopy. The visualization of structures was significantly better in the packed group. Eight patients in the packed group did have some mucosal bleed during the process of packing which was not seen in the spray group. Both methods of preparation have merits and demerits but in terms of discomfort, pain during procedure and visualization of structure, packing of nasal cavity with 4% lignocaine and xylometazoline drops is better than spraying of nose with 10% lignocaine and xylometazoline drops.

Use of Silicon T-Tube for Subglottic Stenosis and Tracheal Stenosis.

Introduction: The management of subglottic and tracheal stenosis is challenging for any ENT surgeon. The treatment choice depends on the site, severity of stenosis, patient symptoms, and surgeon preferences. The various options for the management include endoscopic balloon dilatation, various types of laryngotracheoplasty, resection anastomosis, and insertion of a silicon T-tube. Compared to the above, silicon T-tube stenting is a better alternative, as it is a onetime procedure, easy to perform with fewer chances of complications. Shiann Yann lee technique is a form of laryngotracheoplasty with long-term stenting using silicon T-tube. This article analyzed our silicon T-Tube insertion result in patients with subglottic and tracheal stenosis using this technique. Materials and Methods: In this retrospective study, we included a total of 21 patients with subglottic and tracheal stenosis who underwent silicon T-Tube insertion. Data regarding the site of stenosis, procedure, complications, and outcome were analyzed. Results: Out of 21 patients, nine patients had subglottic stenosis (42.8%), 8 had cervical tracheal stenosis (38.09%), 3 had thoracic tracheal stenosis (14.28%), and 1 (4.7%) had combined subglottic and cervical tracheal stenosis. Out of 21 patients,7 (33.3%) have undergone successful removal of silicon T-Tube so far, one death due to medical reasons, and 13 patients (61.9%) are still on Silicon tube on regular follow-up. They are comfortable with the tube in situ. Conclusions: Silicon T-Tube for benign acquired laryngotracheal stenosis with Shiann Yann Lee's technique is effective, safe with less complication, and good acceptability and tolerance by the patient.

Measurement of Nasal Mucociliary Clearance in Indian Adults: Normative Data.

Nasal mucociliary clearance (NMC) plays an important role in removal of inhaled particles. The aim of this study was to assess the normal nasal mucociliary clearance time in Indian adult population in age group 18-60 years. A cross sectional, descriptive, observational study was performed. Two hundred participants in the age group 18-60 years were included in this study. Saccharin transit test was performed in these subjects. Saccharin particle was placed 0.5 cm away from the inferior turbinate from its anterior part. The participants were asked to inform the appearance of sweet taste. Duration between placement of particle and the appearance of taste was noted in minutes. Mean saccharin transit time was 9.44?2.73 minutes. There was no statistically significant difference in saccharin transit time between males & females. Nasal mucociliary clearance time between < 40 years & ≥40 years was compared and there was no significant difference between the 2 groups. The normal mucociliary clearance value in healthy adult Indian population-based on saccharin transit time is 9.44 ± 2.73 min. The earliest change in respiratory defense mechanism is change in nasal mucociliary clearance time and saccharin test is a simple, easy test to detect this. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-03915-x.

Epleys Versus Semonts Manoeuvre in Posterior Canal Benign Paroxysmal Positional Vertigo.

Introduction: Benign paroxysmal positional vertigo (BPPV), the most common vestibular disorder is characterized by short-lived episodes of rotatory vertigo in association with rapid changes in head position. Diagnosis of BPPV is clinical. The principle of treatment of BPPV involves maneuvers comprising of head movements, in order to bring the free debris from the semicircular canal back to the utricle. In this study we tried to evaluate and compare Epleys and the Semonts manoeuvre in the treatment of Benign paroxysmal positional vertigo of the posterior semicircular canal in terms of subjective and objective improvement. Materials and methods: Study Design: This prospective randomized study included 200 vertigo patients attending ENT OPD of tertiary care centre with Dix Hallpike positive status. (September 2017 -August 2019). Objective improvement was compared in terms of Dix Hallpike positivity between both groups on weekly follow up for four weeks. Subjective improvement was compared in both the groups by dizziness Handicapp index ( DHI) on follow-ups. Results: Total 200 patients formed part of study, with 100 in each group. On comparing Dix Hallpike positivity between both groups on weekly follow ups there was no significant difference between both the groups. DHI, compared between both groups showed that Semonts Maneouver was significantly better. Conclusion: In patients of BPPV both Epleys and Semonts are equally effective objectively. However the subjective improvement was better in patients on whom Semonts manoeuvre was performed. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-03624-5.

Outcome of Tracheostomy in COVID-19 Patients.

Introduction: Since the start of the COVID-19 pandemic 2019, quite a few patients became critical and needed ICU admission with ventilator assistance. Tracheostomy, which was initially performed late during the course of patient on ventilator, has now been considered a procedure that can be performed relatively early as this leads to early weaning of patients and overcomes the shortage of critical beds. Objective: This study aims to focus on the outcomes of tracheotomised COVID-19 patients in terms of survival and any tracheostomy related morbidity. Methods: A prospective study was performed on COVID-19 patients undergoing tracheostomy at this tertiary care teaching hospital, which also was a dedicated centre for treating COVID-19 patients. The duration of this study was from April 2020 to September 2021. Following tracheostomy, all patients were followed up regularly and clinical changes were recorded. Points that were specifically noted were timing of the tracheostomy, change in ventilator settings, tracheostomy related complications, requirement of oxygen, days needed to wean the patient, decanulation, and, if death, the cause of death. Results: A total of 136 surgical open tracheostomies were performed on COVID-19 patients over the study period. The mean duration of intubation (timing of tracheostomy) was 12 days. A total of 73 out of 136 (53.6%) patients survived. 51 patients (37.5%) got decannulated during the course of the hospital stay. 9 patients were decanulated during the follow up visits and 13 patients were lost to follow up. 63 out of 136 (46.3%) patients died due to COVID pneumonia. Most of the patients who died had gone into multi-organ failure. Air leak syndromes (pneumothorax and pneumomediastinum) were common findings. 10 patients already had surgical emphysema before taking up for tracheostomy and 6 developed 2-3 days after tracheostomy. The most common complication was bleeding, which was seen in 28 out of 136 patients. The Median weaning of period of patients who survived was 5 days. Conclusion: Performing tracheostomy early in COVID-19 patients helps in early weaning of the patient from the ventilator and makes nursing care easier and increases the availability of ICU beds. The mortality rate was 46% amongst the 136 tracheostomies done in COVID-19 patients. Local site bleeding was the most common complication and surgical emphysema was also seen more than routine tracheostomies. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03248-1.

Prevalence of Laryngopharyngeal Reflux Disease in Indian Population.

Laryngopharyngeal Reflux Disease (LPRD) is form of extra-oesophageal reflux due to the backflow of gastric contents into the upper aero digestive tract leading to throat symptoms. World over, the prevalence rate of LPRD, ranges from 5 to 30%. The aim of this study was to find the prevalence rate of LPRD in Indian population. This was an observational study whereby the RSI questionnaire was circulated amongst the population and records collected. All subjects who had RSI score more than 13 were considered to be suffering from LPRD. 2300 responses were collected from almost all strata of population. Out of 2300 people who responded 253 had RSI score > 13, and were considered as suffering from LPRD. Thus the prevalence rate of LPRD in population was 11%. The prevalence rate of LPRD in females was 11.2% and in males was 10.6%. The difference in prevalence among both the genders was not significant.The most common symptom of LPR reported by subjects was heartburn followed by clearing of throat and excess throat mucous. The prevalence of LPRD in Indian population as assessed by RSI score > 13 was 11%. The prevalence is same in males and females.

Our Experience of Tracheostomy in COVID-19 Patients.

Tracheostomy in patients with COVID-19 requires significant decision making and procedural planning. Use of tracheostomy can facilitate weaning from ventilation and potentially increase the availability of much needed intensive care unit (ICU) beds, however this being a high aerosol generating procedure it does put the health care worker to risk of transmission. Here we present our experience and protocols for performing tracheostomy in COVID-19 positive patients. Eleven tracheostomies were performed in COIVD-19 patients over a period of 2 months (May-June 2020) at this tertiary care hospital dedicated to manage COVID patients. All patients underwent open surgical tracheostomy, the specific indication, preoperative protocols, surgical steps and precautions taken have been discussed. Tracheostomy was done not before 10 days after initiation of mechanical ventilation. Patient's cardiovascular vitals should show recovery with some spontaneous effort. There should be reduction in need for FiO2 and ventilator requirements. Of total 11 tracheostomies performed only one patient had post procedure bleeding which was controlled conservatively. We have summarized our experience in performing tracheostomies in 11 such patients. Our guidelines and recommendations on tracheostomy during the COVID-19 pandemic are presented in this study. We suggest tracheostomies to be done after 10 days of intubation with precautions and given indications with the idea of early weaning off of patient from ventilator and more availability of ICU beds which is already overwhelmed by patient load.

Effect of Smoking on Nasal Mucociliary Clearance.

Nasal mucociliary clearance (NMC) system is an important defence mechanism in respiratory tract. The contents present in the smoke are found to be toxic to cilia in vitro. Our study aims at evaluating the NMC in smokers so as to know effect of tobacco smoke on ciliary function and also comparing it with non smokers. We also studied effect of duration, intensity and pattern of smoking on the NMC. A total of 60 participants in the age group 21-40 years (30 smokers and 30 non smokers) were included in the study. Saccharin test was performed in all participants. A 0.5 mm diameter particle of saccharin was placed 1 cm from the anterior end of the inferior nasal turbinate. The time duration was noted for the first appearance of sweet taste. The mean NMC in smoker group was 16.53 min and in nonsmoker group was 9.28 min On comparison it was found that NMC time in smoker group was significantly higher than nonsmoker group p < 0.001 also a positive correlation noted between pack years of smoking and NMC. Saccharin test is a simple test to assess NMC. The prolonged NMC in smokers may be due to reduced ciliary activity or due to changes in viscoelastic properties.

A Proposed Grading System and Experience of COVID-19 Associated Rhino Orbito Cerebral Mucormycosis from an Indian Tertiary Care Center.

Mucormycosis is an opportunistic fungal infection. India faced an unprecedented increase in patients with post coronavirus disease 2019 (COVID-19) associated rhino-orbito-cerebral mucormycosis (ROCM). This study proposes a grading system which correlates the extent of the disease with the management plan. An observational study was conducted January 2021-June 2021. We identified 65 patients. Eleven patients had mild disease, 27 patients had moderate, 16 patients were severe and 11 patients were graded as very severe. The management was planned based on this grading system. Early diagnosis, aggressive surgical debridement and antifungal drug therapy is the key to improve survival in ROCM. Procedures such as endoscopic orbital clearance, sublabial maxillectomy, and modified endoscopic Denkers (MED) approach facilitate access and surgical debridement. The new grading system proposed assists in planning the approach and extent of surgical debridement.

Role of transoral CO(2) laser surgery for severe pediatric laryngomalacia.

Controversy exists as to the preferred treatment modality for managing refractory pediatric laryngomalacia (LM). Simultaneous bilateral procedures have been associated with supraglottic stenosis. Unilateral operations have a higher rate of secondary intervention. This prospective study was conceptualized to ascertain a preferred approach. A secondary goal was to correlate the surgical outcome with presenting symptoms and signs. Twenty-two children with severe LM met the criteria for enrollment. Bilateral CO(2) laser-assisted supraglottic laryngoplasties were performed in all cases. The procedure mainly consisted of division of the aryepiglottic fold. Nineteen (86%) patients met our defined success criteria. There were no surgical complications. Bilateral supraglottic laryngoplasty has a role in the management of severe refractory LM.

Prevalence of New Onset Anosmia in COVID-19 Patients: Is The Trend Different Between European and Indian Population?

COVID-19 outbreak is major pandemic affecting lakhs of people all across the globe. Along with other nonspecific clinical features, reports mention anosmia to be an important symptom in COVID-19 positive patients. To study the prevalence of anosmia in confirmed COVID-19 patients, in Indian population and to ascertain its significance as a symptom of COVID 19. Study was done at a tertiary care COVID treating hospital. While eliciting detailed history from Covid-19 positive patients, all patients were asked about symptom of anosmia. Same was asked from control group of subjects who were COVID-19 negative. The history of anosmia was also elicited on discharge after the patients tested negative for COVID-19. 74 patients formed part of the study. 11 of 74 (14.8%) patients had anosmia. On using the chi square test for significance the difference was significant (p < .01), suggesting anosmia to be a significant clinical feature in COVID-19 patients. On comparing with world literature it was observed that the prevalence of anosmia is higher in European population as compared to Indian Also the symptom of anosmia improved when the patient recovered from the disease. Prevalence of new onset anosmia in Indian population with COVID-19 is 14.8%. Symptom of anosmia in present times should be considered as a important clinical feature and should raise a suspicion of COVID-19. The prevalence of anosmia in Indian population is much lesser than that reported in European population.

Screening Test for LPRD: History Versus Video Laryngoscopy.

OBJECTIVE: To find a better screening test by correlating between history and video-laryngoscopy in patients with laryngopharyngeal reflux disease. To compare the Reflux Symptom Index (RSI) and the Reflux Finding Score (RFS). METHOD: Patients with the signs and symptoms of LPRD were scored based on RSI. Those with RSI above 13 were included in study and evaluated further by videolaryngoscopy examination and rated according to RFS. The correlation between RSI and RFS was analysed. RESULT: Out of the 107 patients included in study 55% were females. Among these patients positive RFS score (i.e. > 7) was seen in 58.3%. The average RSI was 18.22, and average RFS was 7.45. According to RSI the most common symptom was heartburn/indigestion (44.5%) and from RFS the most common finding was posterior commissure hypertrophy (95%). Correlation between RSI and total RFS was found to be 0.184 with a p value of 0.159 which was not significant. CONCLUSION: LPRD is more common in females and in the middle age group. A correlation of RSI and RFS was not found to be significant suggesting that both should be used for diagnosis of LPRD instead of relying on only one. RFS and RSI are easy, quick and out patient based screening tools and when used together can be more reliable for LPRD diagnosis.

Translational modulation of proteins expressed from bicistronic vectors.

Bicistronic vectors are useful tools for exogenous expression of two gene products from a single promoter element; however, reduced expression of protein from the second cistron compared with the first cistron is a common limitation to this approach. To overcome this limitation, we explored use of dihydrofolate reductase (DHFR) complementary DNA encoded in bicistronic vectors to induce a second protein of interest by methotrexate (MTX) treatment. Previous studies have demonstrated that levels of DHFR protein and DHFR fusion protein can be induced translationally following MTX treatment of cells. We demonstrated that in response to MTX treatment, DHFR partner protein in a bicistronic construct is induced for longer periods of time when compared with endogenous DHFR and DHFR fusion protein, in vitro and in vivo. Using rapamycin pretreatment followed by MTX treatment, we also devised a strategy to modulate levels of two proteins expressed from a bicistronic construct in a cap-independent manner. To our knowledge, this is the first report demonstrating that levels of proteins in DHFR-based bicistronic constructs can be induced and modulated using MTX and rapamycin treatment.