The Gut Microbiome and Symptom Burden After Kidney Transplantation: An Overview and Research Opportunities.

Many kidney transplant recipients continue to experience high symptom burden despite restoration of kidney function. High symptom burden is a significant driver of quality of life. In the post-transplant setting, high symptom burden has been linked to negative outcomes including medication non-adherence, allograft rejection, graft loss, and even mortality. Symbiotic bacteria (microbiota) in the human gastrointestinal tract critically interact with the immune, endocrine, and neurological systems to maintain homeostasis of the host. The gut microbiome has been proposed as an underlying mechanism mediating symptoms in several chronic medical conditions including irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia, and psychoneurological disorders via the gut-brain-microbiota axis, a bidirectional signaling pathway between the enteric and central nervous system. Post-transplant exposure to antibiotics, antivirals, and immunosuppressant medications results in significant alterations in gut microbiota community composition and function, which in turn alter these commensal microorganisms' protective effects. This overview will discuss the current state of the science on the effects of the gut microbiome on symptom burden in kidney transplantation and future directions to guide this field of study.

Cancer control collaborations between China and African countries.

Over the past decade, China has emerged as Africa's largest trade partner and source of foreign direct investment, with public health ranked as a top priority in China-Africa collaborations. During the same period, cancer has emerged as a leading cause of death in Africa, with more than 700 000 deaths per year and projections of more than 1 million deaths per year by 2030. In this Review, we explore the effects of increasing China-Africa collaborations on cancer control in Africa. We review the published literature on health-care assistance, research, education and training, and infrastructure and present the results of an institutional review board-approved survey of African oncology health-care professionals and institutional leaders that assessed their perception of the effects of China-Africa collaborations. From peer-reviewed articles and grey literature, we found that the number of China-Africa collaborations have grown substantially over the past decade in different areas, especially in patient care and infrastructure. Research publications have also surged in quantity in the past decade compared with previous years. However, the survey results suggest research collaborations remain infrequent and that medical professionals in African cancer centres rarely participate in direct research collaborations with Chinese institutions. The Review also highlights the challenges and benefits of increasing China-Africa collaborations. Challenges include insufficient monitoring and evaluation of the projects in Africa and poor coordination and alignment of the various initiatives. The benefits of these collaborations for Africa include improved health outcomes, strengthened health systems, and socioeconomic development. Benefits are also apparent for China, such as securing energy and resource supplies, expanded trade and investment opportunities, and improved diplomatic relations. Overall, China-Africa collaborations are increasing and having a substantial effect in both China and the African continent. Recommendations to minimise the challenges and maximise the benefits for more positive consequences on cancer control in Africa are discussed.

Patient reported outcomes following whole brain radiotherapy in patients with brain metastases in NSIA-LUTH Cancer Center.

BACKGROUND: Brain metastases (BM) are a common complication in advanced cancer patients, and extremely challenging to treat. Consequently, whole brain radiotherapy (WBRT) remains the standard palliative intervention for patients with BM. The present study set to evaluate the clinical benefits of WBRT by assessing the quality of life (QoL) in WBRT-treated patients with BM, in Nigeria. METHODS: This was a prospective, longitudinal, hospital-based single-centre study. Consecutive sampling methodology was used to recruit 52 patients with BM undergoing WBRT. Patients were followed up on days 7, 30, 90 and 180 after WBRT. The EORTC QLQ-C15-PAL and EORTC QLQ-BN20 were employed to report patients' responses. The likert scale responses were linearly converted into 0 - 100 scores, and the descriptive analysis was conducted using IBM SPSS Statistics 29.0, at 95% confidence interval, using the two-tailed t-test for continuous variables or the chi-square test for categorical values. The overall survival was calculated with the Kaplan Maier method and the difference tested with Log-rank method, considering the interval from the baseline until death or end of the study. RESULTS: The study cohort was predominantly females (82.7%), and accordingly, 65.4% of the respondents had a breast primary tumor. A goodness-of-fit test yielded non-significant Chi square Pearson (p = 0.325) and Deviance (p = 1.000) residuals, indicating the best fit. The median overall survival was 180 days (~ 6 months). A total of 20 patients (38%) that survived up to 180 days reported alleviated symptoms and better functioning. A significant improvement in physical functioning (p < 0.001) and emotional functioning (p = 0.031) was reported at 180 days post WBRT, compared to baseline. CONCLUSIONS: WBRT is an effective palliative intervention in patients with BM, resulting in improved QoL. More than 50% of patients that survived ~ 3 months reported alleviation of pain, and 38% of patients that survived for ~ 6 months reported a significantly improved functioning. This demonstrated the clinical benefits of WBRT in palliative care and will add to the body of data on the use of WBRT, from Africa.

Ketamine Compared With Fentanyl for Surgical Abortion: A Randomized Controlled Trial.

OBJECTIVE: To compare patient satisfaction with anesthesia after first-trimester surgical abortion among patients receiving intravenous (IV) ketamine compared with IV fentanyl for procedural sedation. METHODS: This was a randomized noninferiority trial comparing IV ketamine to IV fentanyl for first-trimester surgical abortion up to 13 6/7 weeks of gestation. Patients were randomized to receive either ketamine 200-500 micrograms/kg IV over 2 minutes, repeated every 5 minutes until appropriate analgesia was achieved, or fentanyl 0.5-1 micrograms/kg IV over 2 minutes, repeated every 5 minutes until appropriate analgesia was achieved. All patients received midazolam 2 mg IV. The primary outcome, patient satisfaction, was measured using the Iowa Satisfaction with Anesthesia Scale immediately postprocedure. Secondary outcomes included postoperative pain, additional pain medication necessary during the procedure and on discharge, physician satisfaction, and time to discharge. We calculated a sample size of 84 with a noninferiority margin of 0.6 on the Iowa Satisfaction with Anesthesia Scale with 80% power, one-sided type 1 error of 0.025, and further increased this number to 110 to account for potential dropout. RESULTS: From April to October 2021, 184 patients were screened and 110 were randomized (57 to ketamine and 53 to fentanyl). Demographics were similar between groups. The primary outcome, patient satisfaction with anesthesia, was noninferior in the ketamine group (mean score 2.4, SD 0.8) as compared with the fentanyl group (mean score 2.2, SD 0.9) with a risk difference of 0.20 (95% CI 0.11-0.52). More hallucinations were reported in the ketamine group. Otherwise, secondary outcomes were similar between the groups. CONCLUSION: Compared with IV fentanyl, IV ketamine is noninferior for patient satisfaction with anesthesia when used for procedural sedation for first-trimester outpatient surgical abortion. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04871425.

Urine drug screening on labor and delivery.

BACKGROUND: Substance use including opioids, methamphetamines, benzodiazepines, and barbiturates during pregnancy is harmful for the pregnant person and the fetus. Routine screening using validated questionnaires is recommended, but often biologic sampling is done instead. There is often bias in urine drug screening on labor and delivery units. OBJECTIVE: This study aimed to compare characteristics of people who did and did not receive urine drug screening during labor and delivery and to examine the relationship of maternal results to neonatal results. STUDY DESIGN: This was a retrospective chart review examining all people in 2017 who delivered in the labor and delivery unit at our institution. We collected urine drug screening result information, maternal demographic data, follow-up after positive maternal tests, and neonatal test results. Individual characteristics and obstetrical outcomes were analyzed. RESULTS: Of 6265 deliveries, 297 urine drug screening tests were ordered. People who were tested identified most commonly as Native Hawaiian or Pacific Islander (P<.0001). The most common indications for ordering tests were a history of substance use and insufficient prenatal care (P<.0001). People who tested positive were more likely to self-identify as White (P=.03) and have history of substance use (P<.0001). Among the positive test results, 24 (24%) were caused by a provider-ordered medication. Self-identification as Native Hawaiian or Pacific Islander was not predictive of a positive result. Of the tested people, 36% (108/297) had a positive result on preliminary testing, and 33% (98/295) on confirmatory testing. CONCLUSION: Native Hawaiians and Pacific Islanders were more likely to undergo testing, whereas White people were more likely to have a positive result. Maternal results were not reliable for predicting neonatal drug test results and vice versa. With rising rates of substance use disorders in the pregnant and reproductive-age population, standardized unbiased race-neutral guidelines for urine drug screening should be implemented using laboratory test results that include preliminary and reflex confirmatory results.

Transcutaneous Electrical Nerve Stimulation for Post-Cesarean Birth Pain Control: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether transcutaneous electrical nerve stimulation (TENS) reduces opioid use after cesarean birth. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of TENS after cesarean birth, with the primary outcome of opioid use during the first 60 hours postoperatively. Secondary outcomes included pain scores and satisfaction with pain control on each postoperative day, duration of postoperative hospitalization, and adverse effects of TENS. We estimated 60 patients in each arm for 80% power to detect a 25% decrease in opioid use, assuming 10% attrition. To assess for a placebo effect, an additional 60 patients were randomized to no TENS during recruitment for secondary analyses comparing opioid use, pain scores, and pain control satisfaction between no TENS and placebo TENS. Analysis was by intention-to-treat. RESULTS: From January 2020 through March 2021, we enrolled 180 participants-60 per group. Baseline characteristics were similar across groups. Median (interquartile range) opioid consumption in the first 60 hours postoperatively, in morphine milligram equivalents, was 7.5 (0-30) with active TENS and 0 (0-22.5) with placebo TENS (P=.31). There were no significant differences in pain scores, satisfaction with pain control, or postoperative length of stay. In the no TENS group, median (interquartile range) opioid consumption in the first 60 hours postoperatively was 7.5 (0-21.9), similar to that in the placebo group (P=.57). There were also no significant differences in pain scores or pain control satisfaction between participants allocated to no TENS and those allocated to placebo TENS. CONCLUSION: Use of TENS after cesarean birth did not change hospital opioid consumption, pain scores, or length of postoperative stay. There was no evidence for a placebo effect of TENS on opioid use or pain scores. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04399707. FUNDING SOURCE: Cardinal Health.

The role of community and culture in abortion perceptions, decisions, and experiences among Asian Americans.

Introduction: Culture and community can play a role in views, stigma, and access related to abortion. No research to date has documented the influence of culture and community attitudes on Asian American (AA) experiences accessing abortion care in the United States (US). This paper aims to fill gaps in research and understand how cultural and community views influence medication abortion access and experiences among AAs. Methods: We used a community-based participatory research approach, which included collaboration among experts in public health, advocates, practitioners, and community partners to understand abortion knowledge, attitudes, and experiences among AAs. Using a semi-structured interview guide, we interviewed twenty-nine eligible people of reproductive age over 18 that self-identified as Asian American or mixed race including Asian American, Native Hawaiian, and/or Pacific Islander (AANHPI), and had a medication abortion in the US between January 2016 and March 2021. Interviews were analyzed and coded in NVivo 12 using a modified grounded theory approach. Results: Participants described various influences of religion negatively impacting acceptability of abortion among their family and community. Lack of openness around sexual and reproductive health (SRH) topics contributed to stigma and influenced most participants' decision not to disclose their abortion to family members, which resulted in participants feeling isolated throughout their abortion experience. When seeking abortion care, participants preferred to seek care with providers of color, especially if they were AANHPI due to past experiences involving stigma and judgment from White providers. Based on their experiences, respondents recommended ways to improve the abortion experience for AAs in the US including, (1) more culturally aware abortion providers from one's community who better understand their needs; (2) clinics providing abortion services located in or near AA communities with signage in local languages; and (3) tailored mental health resources with culturally aware therapists. Conclusion: This study demonstrates ways in which culture and community opinions toward SRH can influence both the acceptability of abortion and experiences seeking abortion care among AAs. It is important to consider family and community dynamics among AAs to better tailor services and meet the needs of AAs seeking abortion care in the US.

Pharmacy availability of emergency contraception in southwestern Pennsylvania: A simulated patient study.

OBJECTIVE: To assess the availability of oral emergency contraception in southwestern Pennsylvania pharmacies. STUDY DESIGN: We conducted a simulated patient study to assess on-the-shelf availability of levonorgestrel emergency contraception and immediate availability of ulipristal acetate emergency contraception. RESULTS: Only 44% of pharmacies stocked levonorgestrel on-the-shelf and only 5% of pharmacies had ulipristal acetate immediately available. CONCLUSIONS: We found significant barriers to obtaining timely oral emergency contraception in southwestern Pennsylvania. IMPLICATIONS STATEMENT: Timely access to emergency contraception is important for people's ability to determine if, when, how, and under what circumstances to have children. Pharmacies in southwestern Pennsylvania need to expand access to oral emergency contraception.

Clinical availability of the copper IUD in rural versus urban settings: A simulated patient study.

OBJECTIVE: To assess the proportion of Washington state clinics that offer the copper IUD in rural vs urban settings. STUDY DESIGN: We employed a simulated patient model to survey clinics in the Human Health Resources and Services Administration 340B database to primarily assess the availability of the copper IUD. RESULTS: We successfully surveyed 194/212 (92%) clinics. More urban than rural clinics reported copper IUD availability (76/97 [78%] vs 49/97 [51%]; p < 0.01). CONCLUSIONS: Rural clinics are less likely than urban clinics to have the copper IUD available. IMPLICATIONS: The frequency of unintended pregnancies is high in the United States. We should focus our attention on decreasing barriers to the copper IUD as a long-acting reversible contraceptive, particularly for women living in rural settings.

Buffered lidocaine for paracervical blocks in first-trimester abortions: a randomized controlled trial.

OBJECTIVE: The objective was to evaluate if buffered lidocaine decreases injection pain as compared to plain lidocaine for paracervical blocks during first-trimester outpatient surgical abortions. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled trial among women undergoing outpatient uterine aspiration of a first-trimester pregnancy or an early pregnancy loss. Subjects received a paracervical block with either lidocaine 1% 20 mL or lidocaine 1% 18 mL plus sodium bicarbonate 8.4% 2 mL. The primary outcome was pain from injection of the paracervical block measured on a 100-mm visual analog scale (VAS). Secondary outcomes included pain after cervical dilation, uterine aspiration and overall satisfaction with pain control. Scores were compared using the Mann-Whitney U test. We aimed to detect a 15-mm difference in pain from injection of the paracervical block. RESULTS: From May 2017 to October 2018, 48 women received plain lidocaine and 50 women received buffered lidocaine. Groups were similar in demographics. We found no clinically or statistically meaningful difference in pain when evaluating median VAS scores for paracervical block injection between the buffered and plain lidocaine [30.0 (interquartile range (IQR) 15.3-64.5); 44.5 (IQR 18.3-65), respectively, p = .32]. We found no difference in secondary outcomes between buffered and plain lidocaine. CONCLUSION: Buffered lidocaine for paracervical blocks in first-trimester outpatient surgical abortions does not decrease injection pain as compared to plain lidocaine. IMPLICATIONS STATEMENT: Buffering the paracervical block in first-trimester outpatient surgical abortions does not decrease injection pain as compared to plain lidocaine, nor does it increase patient satisfaction. Eliminating sodium bicarbonate allows for a more cost-effective and readily available solution for paracervical blocks.

Aortic aneurysm and dissection in pregnancy: A case report.

We describe a 24-year-old pregnant woman at 34 weeks of gestation who presented to a community hospital with sharp chest pain radiating to her back. She was found to have a 6 cm ascending aortic aneurysm despite not having any established risk factors. She was transported by air ambulance to a tertiary-care hospital. She delivered a live female neonate via cesarean delivery. Her postpartum course was notable for multiple episodes of chest pain and multiple imaging studies that were read as negative for aortic dissection. Definitive valve surgery was postponed by the cardiothoracic surgeons to allow for recovery from severe preeclampsia, treatment of endometritis, and due to concerns for uterine bleeding while on anticoagulation during cardiopulmonary bypass. She was eventually transferred to another hospital in another state for valve-sparing surgery. During transport, she developed a pulmonary embolism, and after arrival an aortic dissection was confirmed. She received a mechanical aortic valve replacement and the aneurysm was repaired. She returned home and recovered without complication. A gene panel revealed a heterozygous pathogenic variant of the Filamin A gene. Aortic aneurysms during pregnancy are rare, and aortic dissections are more rare. We recommend expeditious surgical treatment, a heightened index of suspicion, and testing for a genetic cause of aneurysm when diagnosed in a pregnant or postpartum woman with no known risk factors.

Methamphetamine Use in Pregnant Women in Hawai'i: A Case Series.

Methamphetamine use is widespread among pregnant and reproductive-aged women in Hawai'i. Women who use methamphetamine require comprehensive care that is gender specific and tailored to their needs. In Hawai'i, more services are needed to solve this serious public health problem. The authors present three cases of methamphetamine use with negative maternal and fetal outcomes. The first case describes a pregnant woman with daily methamphetamine use who experienced cardiac arrest with subsequent preterm delivery and maternal death due to global anoxic brain injury. The second case describes a pregnant woman with daily methamphetamine use which exacerbated her chronic hypertension and led to intrauterine fetal demise. The third case describes a pregnant woman with current methamphetamine use who experienced preeclampsia and a cerebrovascular accident necessitating preterm delivery. Methamphetamine remains a serious public health concern for the United States and especially in the state of Hawai'i.

Over-The-Counter Availability of Levonorgestrel Emergency Contraception in Pharmacies on Oahu.

Since the United States Food and Drug Administration's approval of over-the-counter levonorgestrel emergency contraception, access to this time-sensitive medication has improved. However, multiple barriers, including the cost of the medication and pharmacy availability, still exist. The objective of this study was to determine the over-the-counter availability of levonorgestrel emergency contraception in pharmacies on Oahu, Hawaii. We conducted a cross-sectional population-based study using in-person simulated patient encounters at all pharmacies on Oahu. Out of 109 chain pharmacies and 13 independent pharmacies, 102 (84%) pharmacies had levonorgestrel emergency contraception available over the counter. Of pharmacies in which it was available, 12.7% required an employee to unlock the medication, 37.3% required the medication to be unlocked at the register, 29.4% were packaged in a large plastic box, and 3.9% were packaged in a blister pack. Levonorgestrel emergency contraception is widely available as an over-the-counter medication in pharmacies on Oahu, yet there are packaging and display practices that make it less accessible. Many of these practices could be improved with pharmacy education or changes in store policies. Systems-based interventions are needed to improve the access to levonorgestrel emergency contraception as an over-the-counter medication.

Shingles in Pregnancy: An Elusive Case of Left Upper Quadrant Abdominal Pain.

Pregnancy can complicate the presentation and workup of abdominal pain. A healthy 21-year-old gravida-3 para-1 woman at 34 weeks of gestation presented for severe pain localized to her abdominal left upper quadrant (LUQ. Physical exam was unremarkable except for localized pain on palpation, and she was discharged with acetaminophen and cyclobenzaprine for presumed musculoskeletal pain. The next day, she returned for worsening pain. An extensive workup including labs, electrocardiogram, chest x-ray, and abdominal computed tomography was unremarkable, and she was discharged with hydrocodone/acetaminophen. Later that evening, after two discharges, the patient presented for increased pain with new onset of vesicles in her left T6 dermatome. She was diagnosed with shingles, started on valacyclovir and gabapentin, and eventually went on to deliver a healthy infant. Shingles classically presents as excruciating pain followed by the eruption of vesicles. This case is important because it reviews the significance of shingles in pregnancy and is one of the first reports to extensively discuss the differential and workup of LUQ abdominal pain in pregnancy. Abdominal pain is a relatively common complaint during pregnancy, and a methodical approach should be taken when evaluating LUQ in pregnancy. Shingles could be considered in the differential diagnosis of pain of unclear origin.

Clinical outcomes in outpatient respiratory syncytial virus infection in immunocompromised children.

BACKGROUND: Immunocompromised patients are at high risk for morbidity and mortality due to respiratory syncytial virus (RSV) infection. Increasingly, pediatric patients with malignancy or undergoing transplantation are managed primarily as outpatients. Data regarding the clinical presentation and outcomes of RSV in the outpatient pediatric immunocompromised population are limited. METHODS: We performed a retrospective cohort study of children with hematologic malignancy or hematopoietic or solid organ transplant with laboratory-confirmed RSV infection diagnosed as outpatients at an academic medical center between 2008 and 2013. RESULTS: Of 54 patients with RSV detected while outpatients, 15 (28%) were hospitalized, 7 (13%) received ribavirin, and one (2%) received intravenous immunoglobulin. One (2%) patient was critically ill, but there were no deaths due to RSV infection. Fever (P < 0·01) was associated with increased risk of hospitalization. CONCLUSIONS: Most immunocompromised children with RSV detected while outpatients did not require hospitalization or receive antiviral treatment. Potential studies of RSV therapies should consider inclusion of patients in an ambulatory setting.

Enabling digital pathology in the diagnostic setting: navigating through the implementation journey in an academic medical centre.

AIMS: As digital pathology (DP) and whole slide imaging (WSI) technology advance and mature, there is an increasing drive to incorporate DP into the diagnostic environment. However, integration of DP into the diagnostic laboratory is a non-trivial task and filled with unexpected challenges unlike standalone implementations. We share our journey of implementing DP in the diagnostic laboratory setting, highlighting seven key guiding principles that drive the progression through implementation into deployment and beyond. METHODS: The DP implementation with laboratory information system integration was completed in 8 months, including validation of the solution for diagnostic use in accordance with College of American Pathologists guidelines. We also conducted prospective validation via paired delivery of glass slides and WSI to our pathologists postdeployment. RESULTS: Common themes in our guiding principles included emphasis on workflow and being comprehensive in the approach, looking beyond pathologist user champions and expanding into an extended project team involving laboratory technicians, clerical/data room staff and archival staff. Concordance between glass slides and WSI ranged from 93% to 100% among various applications on validation. We also provided equal opportunities for every pathologist throughout the department to be competent and confident with DP through prospective validation, with overall concordance of 96% compared with glass slides, allowing appreciation of the advantages and limitations of WSI, hence enabling the use of DP as a useful diagnostic modality. CONCLUSIONS: Smooth integration of DP into the diagnostic laboratory is possible with careful planning, discipline and a systematic approach adhering to our guiding principles.

Increasing rates of influenza vaccination during pregnancy: a multisite interventional study.

BACKGROUND: Pregnancy is a high-risk indication for influenza vaccination; however, rates of vaccination fall short of Centers for Disease Control and Prevention-recommended guidelines. METHODS: Brief educational sessions with family physicians and obstetricians were undertaken in the fall of 2002. Notes reading "Think Flu Vaccine" were placed on active obstetric charts during the study period. Charts were reviewed at the end of influenza season for documentation of discussion or administration of influenza vaccination. Charts for the same period during the previous 2 years were also reviewed for baseline. RESULTS: Baseline rates of vaccination or discussion averaged 1.5% over the 2000-2002 influenza seasons. After intervention, the 2002-2003 rate of vaccination or discussion demonstrated an almost 15-fold increase to 21.9%. This was greater in family practices (3.2% to 44.9%) versus obstetric practices (1.2% to 19.4%), and in small (3.3% to 46.7%) versus large (1.1% to 16%) practices (all values were P < .001). CONCLUSIONS: Provider education with simple chart prompts seems an effective way to increase rates of physician discussion of influenza vaccination with pregnant women. The increased rates seen in this study across various practice settings also suggest that inclusion of influenza vaccination on standardized prenatal care flowsheets may achieve similar goals with less individualized effort and should be considered.

Influenza vaccination in pregnancy: current practices in a suburban community.

PURPOSE: The Centers for Disease Control (CDC) identify women in their second and third trimesters as a high-risk population warranting influenza vaccination. This study attempted to characterize understanding of these guidelines and obstacles to their implementation in a suburban community. METHODS: Family physicians and obstetricians with admitting privileges to a community-based hospital were surveyed regarding estimated vaccine availability and administration in their practices and regarding knowledge of indications and contraindications to influenza vaccination in pregnancy. RESULTS: Of the 20 obstetricians and 66 family physicians completing the survey, 68.4% of obstetricians and 90.5% of family physicians carried the vaccine in their offices (P =.027). Both obstetricians and family physicians incorrectly perceived multiple factors as contraindications to influenza vaccination in pregnancy. Obstetricians and family physicians reported similar proportions of their pregnant patients received the vaccine (35 versus 40%). CONCLUSIONS: In this study, more family physicians had the influenza vaccine available than obstetricians, but there was no difference in estimated rates of vaccination during pregnancy or in the understanding of its indications and contraindications. Finally, no physicians in our community reported providing influenza vaccination in pregnancy at recommended frequencies. Further research is needed to clarify methods of improving vaccination rates in both family practice and obstetric settings.