High frequency of transient congenital hypothyroidism among infants referred for suspected congenital hypothyroidism from the Turkish National screening program: thyroxine dose may guide the prediction of transients.

PURPOSE: We aimed to determine the frequency of transient congenital hypothyroidism (TCH) in 17 participating centers in Türkiye, evaluate the etiological distribution in permanent congenital hypothyroidism (PCH) cases, and investigate the role of laboratory and clinical findings in predicting TCH. METHODS: This retrospective observational multicenter study included patients from 17 pediatric endocrinology centers identified by "National Newborn Screening Program" (NNSP) who were born in 2015 and followed for 6 years. Demographic, clinical, and laboratory information of the cases were compiled through the database http://cedd.saglik-network.org (CEDD-NET). RESULTS: Of the 239 cases initially treated for CH, 128 (53.6%) were determined as transient in whom a trial of levothyroxine (LT4) withdrawal was performed at a median age of 36 (34-38) months. Among the patients with PCH (n = 111), thyroid dysgenesis was diagnosed in 39.6% (n = 44). The predictive factors for TCH were: LT4 dose at the withdrawal of treatment, and initial newborn blood screening (NBS)-TSH level. Based on the receiver operating characteristic (ROC) curve analysis to predict optimal cut-offs for TCH predictors, LT4 dose < 2.0 µg/kg/day at treatment discontinuation was predictive for TCH and was associated with 94.5% specificity and 55.7% sensitivity, with an area under the curve (AUC) of 0.802. The initial NBS-TSH level value < 45 µIU/mL was predictive for TCH with 93.1% specificity and 45.5% sensitivity, with an AUC of 0.641. In patients with eutopic thyroid gland only LT4 dose < 1.1 µg/kg/day at withdrawal time was predictive for TCH with 84.7% sensitivity and 40.4% specificity, with an AUC of 0.750. CONCLUSION: According to our national follow-up data, the frequency of TCH was 53.6%. We determined the LT4 dose < 2.0 µg/kg/day at discontinuation of treatment and the initial NBS-TSH level < 45 µIU/mL as the best cut-off limits to predict TCH.

Evaluating the interactive impact of acculturative stress and anxiety sensitivity on behavioral health outcomes among Latinx during a period of high COVID-19 impact.

As a multi-systemic disease, COVID-19 infection engendered a rise in co-occurring mental and physical health symptoms, particularly affecting the Latinx population. The current work sought to evaluate the main and interactive influence of acculturative stress and anxiety sensitivity in terms of mental and physical health symptoms among 181 Latinx persons (30.4% female, Mage = 34.1 years, SD = 8.20). Data were collected during a period of high COVID-19 impact (2020-2021) and analyses included five separate, two-step hierarchical regressions that were conducted for each of the criterion variables: (1) fear of coronavirus; (2) somatic symptoms; (3) fatigue severity; (4) anxiety symptoms; and (5) depression symptoms. For all analyses, step 1 covariates included years living in the U.S. COVID-19 impact, gender identity, education, and work life distress and home life distress. Results revealed an interactive effect of anxiety sensitivity and acculturative stress on COVID-19 fear, unique main effects for both anxiety sensitivity and acculturative stress on COVID-19 related fear and somatic symptoms, and main effects for anxiety sensitivity alone in relation to fatigue severity, anxiety, and depression. Overall, this study represents an initial investigation of the associations between acculturative stress, anxiety sensitivity, and a range of salient COVID-19 related outcomes among Latinx persons.

The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.

OBJECTIVE: Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233Δ). APPROACH AND RESULTS: Physiological studies of isolated aortae and mesenteric arteries from F233Δ mice revealed an unexpected defect in responsiveness to phenylephrine, an α1 adrenergic receptor agonist. In vivo, F233Δ mice displayed a blunted response to infusion of phenylephrine, and they were found to have elevated catecholamine levels and elevated vascular α1 adrenergic receptor gene expression. Telemetry studies showed that the F233Δ mice were tachycardic and hypotensive at baseline, consistent with diminished vascular tone. In biochemical studies, ZDHHC21 was shown to palmitoylate the α1D adrenoceptor and to interact with it in a molecular complex, thus suggesting a possible molecular mechanism by which the receptor can be regulated by ZDHHC21. CONCLUSIONS: Together, the data support a model in which ZDHHC21 F233Δ diminishes the function of vascular α1 adrenergic receptors, leading to reduced vascular tone, which manifests in vivo as hypotension and tachycardia. This is to our knowledge the first demonstration of a ZDHHC isoform affecting vascular function in vivo and identifies a novel molecular mode of regulation of vascular tone and blood pressure.

Differences in maternal responsive and directive behavior during free play with and without aided AAC.

Maternal directive and responsive behaviors were compared for 25 mothers and children with complex communication needs using two types of toys (familiar and unfamiliar toys). Each type of toy play was conducted with and without a single message speech-generating communication device (SGD) programmed to say "more." Rate percentages of coded intervals for maternal directive and responsive behaviors were analyzed using repeated measures ANOVAs. Results indicated that mothers used significantly more responsive behaviors when playing with their own familiar toys than with unfamiliar toys, but no differences in directiveness between types of play. Mothers showed no differences in responsivity or directiveness when the SGD was added to play interactions, indicating that the SGD did not introduce task features that detracted from the mothers' existing levels of responsivity with their children. Clinical implications are discussed.

Mastery motivation in children with complex communication needs: longitudinal data analysis.

This study compared longitudinal changes in mastery motivation during parent-child free play for 37 children with complex communication needs. Mastery motivation manifests as a willingness to work hard at tasks that are challenging, which is an important quality to overcoming the challenges involved in successful expressive communication using AAC. Unprompted parent-child play episodes were identified in three assessment sessions over an 18-month period and coded for nine categories of mastery motivation in social and object play. All of the object-oriented mastery motivation categories and one social mastery motivation category showed an influence of motor skills after controlling for receptive language. Object play elicited significantly more of all of the object-focused mastery motivation categories than social play, and social play elicited more of one type of social-focused mastery motivation behavior than object play. Mastery motivation variables did not differ significantly over time for children. Potential physical and interpersonal influences on mastery motivation for parents and children with complex communication needs are discussed, including broadening the procedures and definitions of mastery motivation beyond object-oriented measurements for children with complex communication needs.

Low-Dose Vasopressin and Analogues to Treat Intraoperative Refractory Hypotension in Patients Prescribed Angiotensin-Converting Enzyme Inhibitors Undergoing General Anesthesia: A Systematic Review.

This review assessed the utility of vasopressin and vasopressin analogues for the treatment of refractory hypotension associated with angiotensin-converting enzyme (ACE) inhibitors in the perioperative setting. A systematic review of the literature was conducted using MEDLINE, Embase, and ProQuest. Six randomized controlled trials met eligibility criteria. In the perioperative setting, continued use of ACE inhibitors within 24 hours before surgery remains controversial. Authors of the reviewed studies suggested that the morning dose of the ACE inhibitor be held, and those patients experienced decreased catecholamine use postoperatively and shorter duration of decreased mean arterial pressure. No incidence of refractory hypertension from withholding the morning dose of the ACE inhibitor was mentioned. All of the patients receiving vasopressin demonstrated improved hemodynamic stability with small, intermittent doses, without profound ischemic changes. For management (prevention and treatment) of ACE inhibitor-associated hypotension in the perioperative setting, all studies showed statistically significant success with vasopressin or vasopressin analogues for improvement of systemic blood pressures. Before vasopressin is widely accepted as a standard of care, further studies are needed to confirm these findings and assess the general utility of vasopressin in surgical populations for management of ACE inhibitor-associated refractory hypotension.

Link between aortic valve sclerosis and myocardial no-reflow in ST-segment elevation myocardial infarction.

OBJECTIVE: The"no-reflow" phenomenon is associated with a worse prognosis at follow-up for patients with acute ST-segment elevation myocardial infarction (STEMI). Predicting and preventing no-reflow is therefore a crucial step in improving the prognosis of STEMI patients. The purpose of this study was to investigate the association between aortic valve sclerosis (AVS) and myocardial no-reflow in patients with STEMI. PATIENTS AND METHODS: Patients with a first-time diagnosis of STEMI were enrolled consecutively. No-reflow was defined as a final TIMI 3 flow with a myocardial blush of grade < 2, temporary epicardial coronary no-reflow, and distal coronary occlusion. AVS was defined by echocardiography as thickening and calcification of the normal trileaflet aortic valve without obstruction to the left ventricular outflow. RESULTS: No-reflow developed in 41 patients. In univariate analysis, age, male gender, smoking, culprit lesion Syntax score (SX score), and hypertension were significantly associated with no-reflow. Multivariate binary logistic regression analyses demonstrated age [95 % confidence interval (CI), 1.024-1.096; p=0.001), AVS (95 % CI, 1.002-1.100; p=0.039], culprit lesion SX score (95 % CI, 1.08-1.021 p=0.008), and symptom-to-balloon time (95 % CI, 1.020-1.097; p=0.002) as independent determinants of myocardial no-reflow. CONCLUSION: AVS was significantly and independently associated with myocardial no-reflow in STEMI patients.

The role of physical activity, body mass index and maturity status in body-related perceptions and self-esteem of adolescents.

BACKGROUND: Adolescence represents a transitional period which is marked by physical, social and psychological changes. Changes in body shape and physical activity especially alter and shape the psychological well-being of adolescents. AIM: The purpose of this study was to determine the role of physical activity level, body mass index and maturity status in body-related perception and self-esteem of 11-18 years old adolescents. SUBJECTS AND METHODS: A total of 1012 adolescents participated in this study. The "Social Physique Anxiety Scale", "Body Image Satisfaction Scale", "Physical Self-Perception Profile for Children" and "Rosenberg Self-Esteem Inventory" were administered. Physical activity level and body mass index were assessed using the "Physical Activity Questionnaire" and "Bioelectrical Impedance Analyzer", respectively. RESULTS: Regression analysis indicated that body mass index was the only predictor of perceived body attractiveness, social physique anxiety, body image satisfaction and self-esteem for female adolescents. For male adolescents, both physical activity and body mass index were correlated with perceived body attractiveness and social physique anxiety. Pubertal status were not correlated with self-esteem and body-related perceptions for both males and females adolescents. CONCLUSION: In summary, body mass index and physical activity plays an important role in body-related perceptions and self-esteem of adolescents.

Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats.

BACKGROUND AND AIM: The lymphatic network plays a major role in maintaining tissue fluid homoeostasis. Therefore several pathological conditions associated with oedema formation result in deficient lymphatic function. However, the role of the lymphatic system in the pathogenesis of ascites and oedema formation in cirrhosis has not been fully clarified. The aim of this study was to investigate whether the inability of the lymphatic system to drain tissue exudate contributes to the oedema observed in cirrhosis. METHODS: Cirrhosis was induced in rats by CCl(4) inhalation. Lymphatic drainage was evaluated using fluorescent lymphangiography. Expression of endothelial nitric oxide synthase (eNOS) was measured in primary lymphatic endothelial cells (LyECs). Inhibition of eNOS activity in cirrhotic rats with ascites (CH) was carried out by L-N(G)-methyl-L-arginine (L-NMMA) treatment (0.5 mg/kg/day). RESULTS: The (CH) rats had impaired lymphatic drainage in the splanchnic and peripheral regions compared with the control (CT) rats. LyECs isolated from the CH rats showed a significant increase in eNOS and nitric oxide (NO) production. In addition, the lymphatic vessels of the CH rats showed a significant reduction in smooth muscle cell (SMC) coverage compared with the CT rats. CH rats treated with L-NMMA for 7 days showed a significant improvement in lymphatic drainage and a significant reduction in ascites volume, which were associated with increased plasma volume. This beneficial effect of L-NMMA inhibition was also associated with a significant increase in lymphatic SMC coverage. CONCLUSIONS: The upregulation of eNOS in the LyECs of CH rats causes long-term lymphatic remodelling, which is characterised by a loss of SMC lymphatic coverage. The amelioration of this lymphatic abnormality by chronic eNOS inhibition results in improved lymphatic drainage and reduced ascites.

Exquisite sensitivity to subsecond, picomolar nitric oxide transients conferred on cells by guanylyl cyclase-coupled receptors.

Nitric oxide (NO) functions as a diffusible transmitter in most tissues of the body and exerts its effects by binding to receptors harboring a guanylyl cyclase transduction domain, resulting in cGMP accumulation in target cells. Despite its widespread importance, very little is known about how this signaling pathway operates at physiological NO concentrations and in real time. To address these deficiencies, we have exploited the properties of a novel cGMP biosensor, named δ-FlincG, expressed in cells containing varying mixtures of NO-activated guanylyl cyclase and cGMP-hydrolyzing phosphodiesterase activity. Responsiveness to NO, signifying a physiologically relevant rise in cGMP to 30 nM or more, was seen at concentrations as low as 1 pM, making cells by far the most sensitive NO detectors yet encountered. Even cells coexpressing phosphodiesterase-5, a cGMP-activated isoform found in many NO target cells, responded to NO in concentrations as low as 10 pM. The dynamics of NO capture and signal transduction was revealed by administering timed puffs of NO from a local pipette. A puff lasting only 100 ms, giving a calculated peak intracellular NO concentration of 23 pM, was detectable. The results could be encapsulated in a quantitative model of cellular NO-cGMP signaling, which recapitulates the NO responsiveness reported previously from crude cGMP measurements on native cells, and which explains how NO is able to exert physiological effects at extremely low concentrations, when only a tiny proportion of its receptors would be occupied.

A Case of Post-Myocardial Infarction Ventricular Septal Rupture Complicated by Postoperative Septal Rupture.

We present the case of a 60-year-old man who presented with a post-myocardial infarction ventricular septal rupture caused by a delayed presentation of myocardial infarction. Despite revascularization, hemodynamic stability, and a 10-day delay until operative management to allow for tissue healing, the patient experienced a fatal recurrent postoperative ventricular septal rupture. (Level of Difficulty: Beginner.).

Overperception of moral outrage in online social networks inflates beliefs about intergroup hostility.

As individuals and political leaders increasingly interact in online social networks, it is important to understand the dynamics of emotion perception online. Here, we propose that social media users overperceive levels of moral outrage felt by individuals and groups, inflating beliefs about intergroup hostility. Using a Twitter field survey, we measured authors' moral outrage in real time and compared authors' reports to observers' judgements of the authors' moral outrage. We find that observers systematically overperceive moral outrage in authors, inferring more intense moral outrage experiences from messages than the authors of those messages actually reported. This effect was stronger in participants who spent more time on social media to learn about politics. Preregistered confirmatory behavioural experiments found that overperception of individuals' moral outrage causes overperception of collective moral outrage and inflates beliefs about hostile communication norms, group affective polarization and ideological extremity. Together, these results highlight how individual-level overperceptions of online moral outrage produce collective overperceptions that have the potential to warp our social knowledge of moral and political attitudes.

Monitoring blood flow alterations in the Tg2576 mouse model of Alzheimer's disease by in vivo magnetic resonance angiography at 17.6 T.

Many neurodegenerative diseases including Alzheimer's disease are linked to abnormalities in the vascular system. In AD, the deposition of amyloid ß (Aß) peptide in the cerebral vessel walls, known as cerebral amyloid angiopathy (CAA) is frequently observed, leading to blood flow abnormalities. Visualization of the changes in vascular structure is important for early diagnosis and treatment. Blood vessels can be imaged non-invasively by magnetic resonance angiography (MRA). In this study we optimized high resolution MRA at 17.6 T to longitudinally monitor morphological changes in cerebral arteries in a Tg2576 mouse model, a widely used model of AD. Our results at 17.6 T show that MRA significantly benefits from the ultra-high magnetic field strength especially to visualize smaller vessels. Visual and quantitative analysis of MRA results revealed severe blood flow defects in large and medium sized arteries in Tg2576 mice. In particular blood flow defects were observed in the middle cerebral artery (MCA) and in the anterior communicating artery (AComA) in Tg2576 mice. Histological data show that Aß levels in the vessel wall may be responsible for impaired cerebral blood flow, thereby contributing to the early progression of AD. To our knowledge this is the first ultra-high field MRA study monitoring blood flow alterations longitudinally in living Tg2576 mice, consequently providing a powerful tool to test new therapeutic intervention related to CAA in a mouse model of AD.

Whole-Foods, Plant-Based Diet Perceptions of Medical Trainees Compared to Their Patients: A Cross-Sectional Pilot Study.

Purpose: To evaluate medical trainees' and patients' perceptions of the utility of a whole-foods, plant-based (WFPB) diet for chronic disease management. Methods: A cross-sectional study using two original survey tools was implemented. Quantitative and qualitative data were collected from trainees and patients to evaluate perceived motivations and barriers to WFPB diet implementation. Results: Two hundred trainees and 52 patients responded to the surveys. Nearly half (48%) of patients were willing to try a WFPB diet, expressing a desire for additional information and help with its practical application. Over half (53%) of trainees were willing to recommend a WFPB diet to patients but expressed concern about its acceptability and feasibility. Patients perceived significantly more barriers related to personal enjoyment of animal products while trainees perceived more socioeconomic barriers. Conclusion: Poor diet has been identified as the United States' leading risk factor for mortality from chronic diseases. Plant-predominant diets, such as a WFPB diet, are associated with improved health outcomes and may be an acceptable solution for many patients. WFPB dietary modification could be pursued with a motivational interviewing approach that targets patients' individual goals. Medical providers should address their own assumptions regarding the dietary changes their patients are willing to make.

A Place for Plant-Based Nutrition in US Medical School Curriculum: A Survey-Based Study.

Purpose. To evaluate medical students' and family medicine residents' perceptions of their current degree of nutrition training in general and regarding a whole-foods, plant-based (WFPB) diet. Methods. An original survey instrument was administered to medical students and family medicine residents. Quantitative and qualitative data were collected to evaluate perceptions of nutrition education in medical training, a WFPB diet, and ideas for nutrition-focused curricular reform. Results. Of the 668 trainees surveyed, 200 responded (response rate = 30%). Of these, 22% agreed that they received sufficient nutrition education in medical school and 41% agreed that a WFPB diet should be a focus. Respondents with personal experiences with a plant-based diet were more willing to recommend it to future patients. Common ideas for curricular reform were instruction on a WFPB diet along with other healthy dietary patterns, patient counseling, a dedicated nutrition course, and electives. Conclusions. Nutrition education in US medical training needs improvement to address the growing burden of obesity-related chronic disease. Proper nutrition and lifestyle modification should therefore play a larger role in the education of future physicians. A focus on plant-predominant diets, such as the WFPB diet, may be an acceptable and effective addition to current medical school curriculum, and deserves further study.

Treatment of COVID-19 in a Patient With Maple Syrup Urine Disease.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a defect in the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC). This leads to the accumulation of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, which can cause neurotoxicity. Patients with MSUD are carefully managed from birth with dietary restrictions and can acutely decompensate in the setting of infections or injury. We present the case of a 29-year-old female with a history of MSUD and rheumatoid arthritis on methotrexate and adalimumab who presented to our emergency department with symptoms suggestive of a metabolic crisis including nausea, vomiting, and presyncope. She was diagnosed with coronavirus disease 2019 (COVID-19) and admitted. An initial leucine level was mildly elevated at 253 µmol/L, consistent with her underlying metabolic condition. She was placed on an infusion of normal saline and 10% Dextrose (D10) in addition to a protein-restricted sick-day diet. Remdesivir therapy was initiated due to her immunocompromised status and high risk for decompensation but had to be discontinued due to nausea and vomiting that negatively impacted the patient's oral intake. Her leucine level peaked at 647 µmol/L; however, her neurologic examination remained benign without signs of cerebral edema. With prompt involvement of our metabolic genetics team and initiation of intravenous fluids and the sick-day diet protocol, we avoided a metabolic crisis. The patient was discharged on day 5 of hospitalization with no complications from COVID-19 infection. This case highlights the individualized approach to the treatment of COVID-19 infection in a patient with a metabolic disorder. COVID-19 infection in the setting of MSUD has only been reported in two prior publications, one being a severe metabolic crisis with neurologic involvement. Fortunately, our patient experienced a mild case of COVID-19 without significant respiratory symptoms, and we were able to prevent a metabolic crisis during admission.

The Role of Experiential Avoidance in Terms of Fatigue and Pain During COVID-19 Among Latinx Adults.

Background: Latinx persons are overrepresented in terms of 2019 Coronavirus (COVID-19) infection rates and constitute a subpopulation at increased risk for COVID-19 related physical ailments. Fatigue and pain are among the most prevalent somatic symptoms among the Latinx population; however, there is little understanding of individual difference factors that are related to fatigue and pain during COVID-19 among this health disparities population. Experiential avoidance (EA) reflects the persistent tendency to avoid aversive internal sensations. Methods: The current study sought to extend past work by exploring EA in relation to fatigue severity, pain intensity, and pain disability among 182 Latinx adult persons during the COVID-19 pandemic. Results: Results indicated that EA accounted for a statistically significant amount of variance across the criterion variables. Conclusions: Overall, the current work provides initial empirical evidence that EA is related to greater fatigue severity and pain severity/disability among Latinx persons during COVID-19.

Evaluating Experiential Avoidance in terms of COVID-19 Fear and Pandemic Emotional Distress Symptoms Among Latinx Adults.

BACKGROUND: The outbreak of the novel 2019 SARS2-Coronavirus disease (COVID-19) has led to substantial psychological distress across the United States and the world. However, emerging work suggests that prominent COVID-19 consequences such as fear of COVID-19 infection and emotional distress resulting from economic adversity and social distancing may afflict the Latinx population disproportionately. The current study sought to investigate the influence of experiential avoidance (EA), or an individual's tendency to rigidly avoid negative internal experiences (i.e. feelings, thoughts, etc.), on the severity of COVID-19 fear and emotional distress symptoms due to economic adversity and social distancing. METHOD: Participants included 188 Latinx persons recruited via an online survey panel program. RESULTS: Results indicated that EA was a statistically significant contributing factor to fear of COVID-19 and emotional distress associated with economic adversity and social distancing. These effects were evident over and above the variance accounted for by gender, years living in the United States, education, and COVID-19 related work and home life stress. CONCLUSIONS: Overall, the present work is the first to document empirically EA as it relates to fear of COVID-19 infection and related emotional distress resulting from economic adversity and social distancing among Latinx persons.

Short-term continuous intraparenchymal intracranial pressure monitoring in presumed idiopathic intracranial hypertension.

BACKGROUND: The management of idiopathic intracranial hypertension (IIH) depends on a reliable assessment of intracranial pressure (ICP), particularly when visual function measures or ophthalmoscopic indicators are confusing and when invasive surgical procedures are being considered. Although ICP monitoring has been widely applied in many neurologic conditions as a more reliable measure of ongoing ICP than lumbar puncture (LP), it has not often been widely used in the management of IIH. METHODS: We searched the records of the University of Michigan between 2001 and 2008 for patients with IIH who had undergone LP and continuous ICP monitoring with an intraparenchymal Codman ICP Monitoring System and in whom at least 1 year of follow-up information was available. Ten patients met entry criteria. RESULTS: There were no complications from the ICP monitoring. ICP monitoring influenced management in all 10 patients. In 8 patients, LP had shown elevated opening pressures; in 7 of them, ICP monitoring failed to confirm a consistently high ICP. In these patients, the decision to withdraw ICP-lowering agents or shunts, or not to revise indwelling shunts, produced no change in visual function or optic disc appearance over a follow-up period of at least 1 year. In 1 patient, ICP monitoring confirmed the high ICP suggested by LP, justifying placement of a ventriculoperitoneal shunt. In 1 patient, ICP monitoring was performed instead of LP because a petroclival mass posed a danger to the performance of LP; a shunt was subsequently placed due to elevated ICP. CONCLUSION: In providing more accurate information about ICP than about LP, short-term continuous ICP intraparenchymal monitoring may be a useful adjunct in the management of IIH when clinical data are confusing and invasive interventions are under consideration.

A macrocycle directed total synthesis of di-O-methylendiandrin A.

The total synthesis of the lignan-based cyclobutane di-O-methylendiandrin A has been achieved using diastereoselective, vicinal alkylation and transannular McMurry reactions of a macrocyclic 1,4-diketone as key transformations for establishing relative stereochemistry and furnishing the strained 4-membered ring of the natural product.