DNA methylation signatures of early-life adversity are exposure-dependent in wild baboons.

The early-life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early-life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early-life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early-life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early-life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early-life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early-life effects on fitness-related traits.

Long COVID Definitions and Models of Care : A Scoping Review.

BACKGROUND: Definitions of long COVID are evolving, and optimal models of care are uncertain. PURPOSE: To perform a scoping review on definitions of long COVID and provide an overview of care models, including a proposed framework to describe and distinguish models. DATA SOURCES: English-language articles from Ovid MEDLINE, PsycINFO, the Cochrane Library, SocINDEX, Scopus, Embase, and CINAHL published between January 2021 and November 2023; gray literature; and discussions with 18 key informants. STUDY SELECTION: Publications describing long COVID definitions or models of care, supplemented by models described by key informants. DATA EXTRACTION: Data were extracted by one reviewer and verified for accuracy by another reviewer. DATA SYNTHESIS: Of 1960 screened citations, 38 were included. Five clinical definitions of long COVID varied with regard to timing since symptom onset and the minimum duration required for diagnosis; 1 additional definition was symptom score-based. Forty-nine long COVID care models were informed by 5 key principles: a core "lead" team, multidisciplinary expertise, comprehensive access to diagnostic and therapeutic services, a patient-centered approach, and providing capacity to meet demand. Seven characteristics provided a framework for distinguishing models: home department or clinical setting, clinical lead, collocation of other specialties, primary care role, population managed, use of teleservices, and whether the model was practice- or systems-based. Using this framework, 10 representative practice-based and 3 systems-based models of care were identified. LIMITATIONS: Published literature often lacked key model details, data were insufficient to assess model outcomes, and there was overlap between and variability within models. CONCLUSION: Definitions of long COVID and care models are evolving. Research is needed to optimize models and evaluate outcomes of different models. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (Protocol posted at https://effectivehealthcare.ahrq.gov/products/long-covid-models-care/protocol.).

Mechanisms, predictors, and evolution of severe peri-device leaks with two different left atrial appendage occluders.

AIMS: Incomplete left atrial appendage occlusion (LAAO) due to peri-device leak (PDL) is a limitation of the therapy. The Amulet IDE trial is the largest randomized head-to-head trial comparing the Amulet and Watchman 2.5 LAAO devices with fundamentally different designs. The predictors and mechanistic factors impacting differences in PDLs within the Amulet IDE trial are assessed in the current analysis. METHODS AND RESULTS: An independent core lab analysed all images for the presence or absence of severe PDL (>5 mm). The incidence, mechanistic factors, predictors using propensity score-matched controls, and evolution of severe PDLs through 18 months were assessed. Of the 1878 patients randomized in the trial, the Amulet occluder had significantly fewer severe PDLs than the Watchman device at 45 days (1.1 vs. 3.2%, P < 0.001) and 12 months (0.1 vs. 1.1%, P < 0.001). Off-axis deployment or missed lobes were leading mechanistic PDL factors in each device group. Larger left atrial appendage (LAA) dimensions including orifice diameter, landing zone diameter, and depth predicted severe PDL with the Watchman device, with no significant anatomical limitations noted with the Amulet occluder. Procedural and device implant predictors were found with the Amulet occluder attributed to the learning curve with the device. A majority of Watchman device severe PDLs did not resolve over time through 18 months. CONCLUSION: The dual-occlusive Amplatzer Amulet LAA occluder provided improved LAA closure compared with the Watchman 2.5 device. Predictors and temporal observations of severe PDLs were identified in the Amulet IDE trial. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov Unique identifier NCT02879448.

Medication Management of Neuropsychiatric Symptoms in Neurological Conditions: A Dimensional Transdiagnostic Approach.

Neuropsychiatric symptoms are prevalent in neurologic practice, but their complexity makes them challenging to manage. Many cognitive, affective, behavioral, and perceptual symptoms span multiple neurologic diagnoses-and there is prominent variability in neuropsychiatric symptom burden for a given condition. There is also a relative lack of robust controlled clinical trial evidence and expert consensus recommendations for a range of neuropsychiatric symptom presentations. Thus, the categorical approach (e.g., a discrete diagnosis equals a specific set of medication interventions) used in many other medical conditions can sometimes have limited utility in commonly encountered neuropsychiatric clinical scenarios. In this review, we explore medication management for a range of neuropsychiatric symptoms using a dimensional transdiagnostic approach applied to the neurological patient. This approach allows the clinician to think beyond the boundaries of a discrete diagnosis and treat specific symptom domains (e.g., apathy, impulsivity). Pharmacologic considerations, including mechanisms of action and their application to various neurotransmitter systems and brain networks, are discussed, as well as general recommendations to optimize medication adherence and rapport with the patient. The dimensional, transdiagnostic approach to pharmacological management of patients with neurological conditions will help the clinician treat neuropsychiatric symptoms safely, effectively, and confidently.

Pre-hospital tracheal intubation in severe traumatic brain injury: a systematic review and meta-analysis.

BACKGROUND: Severe traumatic brain injury (TBI) continues to be a leading cause of death, particularly in young adults. Severe TBI contributes to significant socioeconomic burden secondary to the long-term disability, impacting the individual and their family, and wider society. The aim of this study was to determine whether establishing a pre-hospital definitive airway was beneficial to mortality and morbidity when compared with no pre-hospital airway. METHODS: A literature search for all relevant studies was performed in Medline, Embase, Cochrane, EBSCO, and Emcare databases, with studies comparing effects of pre-hospital tracheal intubation vs noninvasive airway management on mortality in non-paediatric patients with severe TBI. There were 1025 studies that had abstracts screened from this search. This study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: We identified 19 studies that met inclusion criteria. The included studies identified no significant difference in mortality between pre-hospital and no pre-hospital tracheal intubation, with an odds ratio of 1.07 (95% CI, 0.72-1.57; P<0.001). The meta-analysis identified a trend favouring pre-hospital tracheal intubation with respect to long-term morbidity, with an odds ratio of 0.92 (95% CI, 0.51-1.67; P<0.001). CONCLUSIONS: Management of traumatic brain injuries is a constantly evolving field, with ever-changing target parameters regarding management. There is growing evidence, based on the RCTs and recent studies, that pre-hospital tracheal intubation in patients with severe TBI is beneficial if performed by well-trained, experienced practitioners in accordance with current TBI guidelines. PROSPERO REGISTRATION: CRD42021234439.

Sparrows and supergenes: Ecological epigenetics in action.

Despite the promise of ecological epigenetics, there remain few cases that clearly link epigenetic variation in wild animal populations to evolutionary change. In this issue of Molecular Ecology, Sun et al. provide such an example in white-throated sparrows-a fascinating system in which a large chromosomal rearrangement generates a "supergene" polymorphism linked to plumage colour, aggression and parenting behaviour. By combining whole genome bisulphite sequencing with RNA-sequencing and chromatin accessibility data, they show that the two alleles of this chromosomal polymorphism also exhibit substantial differences in DNA methylation levels, with implications for gene expression and transposable element activity. Their results provide a compelling case study for how genetic and epigenetic evolution proceed in concert. They also demonstrate the importance of integrating multiple types of genomic information to understand how gene regulation evolves, providing a model for future work in nonmodel species.

A Review and Expert Opinion on the Neuropsychiatric Assessment of Motor Functional Neurological Disorders.

Functional neurological (conversion) disorder (FND) is a prevalent and disabling condition at the intersection of neurology and psychiatry. Advances have been made in elucidating an emerging pathophysiology for motor FND, as well as in identifying evidenced-based physiotherapy and psychotherapy treatments. Despite these gains, important elements of the initial neuropsychiatric assessment of functional movement disorders (FND-movt) and functional limb weakness/paresis (FND-par) have yet to be established. This is an important gap from both diagnostic and treatment planning perspectives. In this article, the authors performed a narrative review to characterize clinically relevant variables across FND-movt and FND-par cohorts, including time course and symptom evolution, precipitating factors, medical and family histories, psychiatric comorbidities, psychosocial factors, physical examination signs, and adjunctive diagnostic tests. Thereafter, the authors propose a preliminary set of clinical content that should be assessed during early-phase patient encounters, in addition to identifying physical signs informing diagnosis and potential use of adjunctive tests for challenging cases. Although clinical history should not be used to make a FND diagnosis, characteristics such as acute onset, precipitating events (e.g., injury and surgery), and a waxing and waning course (including spontaneous remissions) are commonly reported. Active psychiatric symptoms (e.g., depression and anxiety) and ongoing psychosocial stressors also warrant evaluation. Positive physical examination signs (e.g., Hoover's sign and tremor entrainment) are key findings, as one of the DSM-5 diagnostic criteria. The neuropsychiatric assessment proposed emphasizes diagnosing FND by using "rule-in" physical signs while also considering psychiatric and psychosocial factors to aid in the development of a patient-centered treatment plan.

Development of drug-coated balloon for the treatment of multiple peripheral artery segments.

OBJECTIVE: Peripheral artery disease is the second most common cardiovascular disease. It can often occur in complex form when there is a presence of long, diffuse, and multiple lesions. Current treatments use either single long drug-coated balloons (DCBs) or multiple DCBs; however, treatment success is limited. The purpose of this study was to investigate the preclinical feasibility of our multiple-release Tailored Medical Devices DCB (MR-TMD-DCB) to treat multiple arterial segments using a single DCB. METHODS: The MR-TMD-DCBs were developed using a two-layer coating approach. The DCBs were developed in a certified Current Good Manufacturing Practices facility using presterilized materials and reagent and then characterized for coating morphology, thermal and chemical changes, and in vitro particulate shedding. The drug loss, tissue uptake, and undelivered drug amounts were analyzed using an in vitro peripheral artery flow model and explanted pig arteries. Then, an in vivo survival study was performed using a healthy porcine model to measure the short-term drug uptake (seven swine; 14 treatments at day 1) and retention (seven swine; 14 treatments at day 7) in two different arterial segments after treatment with a single MR-TMD-DCB. RESULTS: The coating on the MR-TMD-DCB was smooth and homogeneous with paclitaxel molecularly dispersed in its amorphous state. A negligible number of particulates were shed from the MR-TMD-DCB coating. A similar amount of drug was accurately delivered into two separate explanted arteries using a single MR-TMD-DCB during the in vitro flow model testing (707 ± 109 ng/mg in the first explanted artery and 783 ± 306 ng/mg in the second explanted artery). The MR-TMD-DCB treatment resulted in equivalent drug amounts in the two arterial segments at day 1 (63 ± 19 ng/mg in the first treatment site and 59 ±19 ng/mg in the second treatment site) and at day 7 (9 ± 6 ng/mg in the first treatment site and 10 ± 6 ng/mg in the second treatment site). In addition, the drug levels at each time point were in the clinically relevant range to prevent neointimal hyperplasia. CONCLUSIONS: The MR-TMD-DCBs provided equivalent and clinically relevant drug retention levels into two different arterial segments. Thus, MR-TMD-DCBs can be used to accurately deliver drug into multiple arterial segments with the use of a single DCB. The clinical outcomes of these findings need further investigation. Future long-term pharmacokinetics and safety studies will be performed to evaluate the safety and efficacy of the MR-TMD-DCB.

Feasibility, Effectiveness and Safety of Prehospital Intravenous Bolus Dose Nitroglycerin in Patients with Acute Pulmonary Edema.

Introduction: The necessity of rapid preload and afterload reduction in patients with decompensated congestive heart failure (CHF) and acute pulmonary edema (APE) is well established. In the hospital setting, intravenous (IV) nitroglycerin demonstrates improved patient morbidity and mortality. However, prehospital treatment is typically limited to sublingual nitroglycerin at doses that often do not affect afterload. In this study, we assessed feasibility, safety and effectiveness of prehospital IV bolus nitroglycerin in decompensated CHF patients with APE. Methods: This was a retrospective chart review of all emergency medical services (EMS) and ED patient care records of subjects treated for presumed decompensated CHF with APE with bolus-dose IV nitroglycerin between March 15, 2018 and March 15, 2019 by a large, suburban, county-based EMS service in Texas. Inclusion criteria for treatment included both hypertension (systolic blood pressure [SBP] > 160 mmHg) and acute respiratory distress with a paramedic clinical impression of decompensated CHF with APE. Treatment consisted of a 1 mg nitroglycerin bolus, repeated in 5 minutes if SBP > 160 mmHg. Results: During the study period, 48 patients were treated with IV bolus nitroglycerin. Initially, the median (IQR) SBP was 211.0 mmHg (190.0-229.5), 5-minutes post IV NTG was 177.0 mmHg (155.0-199.0), and upon ED arrival was 181.5 mmHg (157.0-207.0). 5 minutes after IV nitroglycerin, the median pulse decreased from 113 (96-124) to 103 (85-117) beats per minute and the median oxygen saturation increased from 86% (74-89) to 98% (96-99). Based on hospital records review, 45/48 (94%) of patients treated with IV nitroglycerin were found to have CHF with APE. A single episode of transient hypotension, which resolved without treatment, did occur during EMS transport. Conclusion: This case series found that patients who were treated by paramedics with IV NTG had improved systolic blood pressure and oxygen saturation upon ED arrival as compared to their initial presentation. Over 90% of these patients were correctly identified by paramedics as having CHF with APE based on ED evaluation. Only one patient had an adverse event, which was transient hypotension that did not require intervention.

Functional (Psychogenic) Neurological Disorders: Assessment and Acute Management in the Emergency Department.

Functional neurological disorders (FND) are complex and prevalent neuropsychiatric conditions. Importantly, some patients with FND develop acute onset symptoms requiring emergency department (ED) evaluations. Historically, FND was a "rule-out" diagnosis, making assessment and management in the ED difficult. While the rapid triage of potential neurological emergencies remains the initial task, advancements have altered the approach to FND. FND is now a "rule-in" diagnosis based on validated neurological examination signs and semiological features. In this perspective article, we review signs and semiological features that can help guide the initial assessment of FND in the acute setting. Thereafter, we outline potential approaches to introduce a suspected diagnosis of FND to patients in the ED, while emphasizing the need for a comprehensive neurological evaluation. Physical and occupational therapy may be useful adjunct assessments in some individuals. Notably, clinicians in the ED setting are important members of the interdisciplinary approach to FND.

In vitro particulate and in vivo drug retention study of a novel polyethylene oxide formulation for drug-coated balloons.

OBJECTIVE: The purpose of this study was to investigate the newly developed drug-coated balloon (DCB) using polyethylene oxide (PEO) as a platform and to compare it directly with a commercially available DCB in a preclinical experimental setting. METHODS: The PEO balloon was characterized for coating morphology and degree of paclitaxel (PAT) crystallinity. PAT tissue levels were then measured up to 30 days in a healthy porcine model (10 swine, 20 vessels) after treatment with either a PEO balloon or a commercially available DCB. An in vitro bench-top model was used to compare the particulates released from the PEO balloon and commercially available DCB. RESULTS: The coating on the PEO balloon was smooth and homogeneous with PAT in its amorphous state. From the porcine survival study, the PAT tissue levels were comparable between PEO balloon and commercially available DCB after 7 days of treatment. Both the PEO balloon and the commercially available DCB retained therapeutic drug up to 30 days. During the simulated in vitro model, the PEO balloon shed significantly fewer particulates that were smaller than those of the commercially available DCB. Most important, the PEO balloon shed 25 times fewer large particulates than the commercially available DCB. CONCLUSIONS: The amorphous PAT in the PEO balloon provided comparable drug tissue retention levels to those of the commercially available DCB and fewer particulates. Thus prepared PEO balloon proved to be safe and effective in the preclinical experimental setting. The clinical outcomes of these findings need further investigation.

Point-of-Care Ultrasound in Undergraduate Urology Education: A Prospective Control-Intervention Study.

OBJECTIVES: The effect of point-of-care ultrasound (US) training on clinical reasoning in undergraduate medical education remains largely unknown, with concerns arising about possible confusion among learners when such clinical tools are introduced too early. We studied the effect of a urology point-of-care US module on the performance of questions designed to assess clinical reasoning in urinary tract obstruction and voiding dysfunction. METHODS: All second-year medical students at the University of Saskatchewan (Regina [n = 36] and Saskatoon [n = 61]) were enrolled in the study. Each cohort participated in the urology point-of-care US module concurrently with its Foundations in the Kidney and Urinary Tract course. The Regina cohort completed the point-of-care US module 1 week before the Saskatoon cohort, thus allowing for a control-intervention comparison of script concordance question scores to evaluate the effect that the urology point-of-care US module had on clinical reasoning skills. Secondary outcomes included program evaluation metrics, such as overall course performance, urology point-of-care US objective structured clinical examination performance, and student course evaluation data. RESULTS: The introduction of the urology point-of-care US module was not associated with a deterioration in scores on script concordance questions. There were no statistically significant differences between the Regina and Saskatoon students in their responses to the script concordance questions. There were statistically significant increases in student self-reported achievement of learning objectives, with the effect size being medium to large (Cohen d, 0.5-0.8). CONCLUSIONS: Point-of-care US training complements standard undergraduate classroom teaching of urology. Students effectively learned the skills to apply point-of-care US in their assessment of patients, and this process did not interfere with achieving the course objectives.

You've made the diagnosis of functional neurological disorder: now what?

Patients with functional neurological disorders (FND)/conversion disorder commonly present to outpatient clinics. FND is now a 'rule in' diagnosis based on neurological examination findings and semiological features. While neurologists may be more comfortable diagnosing patients with FND, there is only limited guidance as to how to conduct follow-up outpatient visits. Using clinical vignettes, we provide practical suggestions that may help guide clinical encounters including how to: (1) explore illness beliefs openly; (2) enquire longitudinally about predisposing vulnerabilities, acute precipitants and perpetuating factors that may be further elucidated over time; (3) facilitate psychotherapy engagement by actively listening for potentially unhelpful or maladaptive patterns of thoughts, behaviours, fears or psychosocial stressors that can be reflected back to the patient and (4) enquire about the fidelity of individual treatments and educate other providers who may be less familiar with FND. These suggestions, while important to individualise, provide a blueprint for follow-up FND clinical care.

Optimization of a ß-sheet-cap for long loop closure.

Protein loops make up a large portion of the secondary structure in nature. But very little is known concerning loop closure dynamics and the effects of loop composition on fold stability. We have designed a small system with stable ß-sheet structures, including features that allow us to probe these questions. Using paired Trp residues that form aromatic clusters on folding, we are able to stabilize two ß-strands connected by varying loop lengths and composition (an example sequence: RWITVTI - loop - KKIRVWE). Using NMR and CD, both fold stability and folding dynamics can be investigated for these systems. With the 16 residue loop peptide (sequence: RWITVTI-(GGGGKK)2 GGGG-KKIRVWE) remaining folded (ΔGU = 1.6 kJ/mol at 295K). To increase stability and extend the series to longer loops, we added an additional Trp/Trp pair in the loop flanking position. With this addition to the strands, the 16 residue loop (sequence: RWITVRIW-(GGGGKK)2 GGGG-WKTIRVWE) supports a remarkably stable ß-sheet (ΔGU = 6.3 kJ/mol at 295 K, Tm = ∼55°C). Given the abundance of loops in binding motifs and between secondary structures, these constructs can be powerful tools for peptide chemists to study loop effects; with the Trp/Trp pair providing spectroscopic probes for assessing both stability and dynamics by NMR.

Three Sets of Case Studies Suggest Logic and Consistency Challenges with Value Frameworks.

OBJECTIVE: To assess the logic and consistency of three prominent value frameworks. METHODS: We reviewed the value frameworks from three organizations: the Memorial Sloan Kettering Cancer Center (DrugAbacus), the American Society of Clinical Oncologists, and the Institute for Clinical and Economic Review. For each framework, we developed case studies to explore the degree to which the frameworks have face validity in the sense that they are consistent with four important principles: value should be proportional to a therapy's benefit; components of value should matter to framework users (patients and payers); attribute weights should reflect user preferences; and value estimates used to inform therapy prices should reflect per-person benefit. RESULTS: All three frameworks can aid decision making by elucidating factors not explicitly addressed by conventional evaluation techniques (in particular, cost-effectiveness analyses). Our case studies identified four challenges: 1) value is not always proportional to benefit; 2) value reflects factors that may not be relevant to framework users (patients or payers); 3) attribute weights do not necessarily reflect user preferences or relate to value in ways that are transparent; and 4) value does not reflect per-person benefit. CONCLUSIONS: Although the value frameworks we reviewed capture value in a way that is important to various audiences, they are not always logical or consistent. Because these frameworks may have a growing influence on therapy access, it is imperative that analytic challenges be further explored.

EXAMINING EVIDENCE IN U.S. PAYER COVERAGE POLICIES FOR MULTI-GENE PANELS AND SEQUENCING TESTS.

OBJECTIVES: The aim of this study was to examine the evidence payers cited in their coverage policies for multi-gene panels and sequencing tests (panels), and to compare these findings with the evidence payers cited in their coverage policies for other types of medical interventions. METHODS: We used the University of California at San Francisco TRANSPERS Payer Coverage Registry to identify coverage policies for panels issued by five of the largest US private payers. We reviewed each policy and categorized the evidence cited within as: clinical studies, systematic reviews, technology assessments, cost-effectiveness analyses (CEAs), budget impact studies, and clinical guidelines. We compared the evidence cited in these coverage policies for panels with the evidence cited in policies for other intervention types (pharmaceuticals, medical devices, diagnostic tests and imaging, and surgical interventions) as reported in a previous study. RESULTS: Fifty-five coverage policies for panels were included. On average, payers cited clinical guidelines in 84 percent of their coverage policies (range, 73-100 percent), clinical studies in 69 percent (50-87 percent), technology assessments 47 percent (33-86 percent), systematic reviews or meta-analyses 31 percent (7-71 percent), and CEAs 5 percent (0-7 percent). No payers cited budget impact studies in their policies. Payers less often cited clinical studies, systematic reviews, technology assessments, and CEAs in their coverage policies for panels than in their policies for other intervention types. Payers cited clinical guidelines in a comparable proportion of policies for panels and other technology types. CONCLUSIONS: Payers in our sample less often cited clinical studies and other evidence types in their coverage policies for panels than they did in their coverage policies for other types of medical interventions.

High-Risk Percutaneous Coronary Intervention in Public Reporting States: the Evidence, Exclusion of Critically Ill Patients, and Implications.

PURPOSE OF REVIEW: Public reporting of outcomes for percutaneous coronary intervention (PCI) is used in some states to drive improvements in care delivery and performance. However, a growing body of evidence suggests unintended consequences, particularly provider aversion to performing PCI in high-risk patients. RECENT FINDINGS: There is mixed evidence regarding the impact of PCI public reporting on patient outcomes. In addition, providers in public reporting states likely have a higher threshold or potentially avoid performing PCI on high-risk patients, such as those with cardiogenic shock. The exclusion of patients with refractory cardiogenic shock from public reports in New York state has reduced provider risk aversion. Though this represents a step in the right direction, other strategies are needed to diminish continued provider risk aversion and strengthen PCI care quality. Public reporting initiatives for PCI are beginning to proliferate nationally. However, the challenge of fostering the positive of aspects of reporting, which incentivize improved care quality and procedural performance, while ensuring that high-risk patients continue to receive appropriate care remains. It is imperative that policymakers and cardiologists continue to develop innovative solutions that address risk aversive provider behaviors towards high-risk patients.

A pH Switch for ß-Sheet Protein Folding.

Protein design advancements have led to biotechnological strategies based on more stable and more specific structures. Herein we present a 6-residue sequence (HPATGK) that acts as a stable structure-nucleating turn at physiological and higher pH but is notably unfavorable for chain direction reversal at low pH. When placed into the turn of a ß-sheet, this leads to a pH switch of folding. Using a standard 3-stranded ß-sheet model, the WW domain, it was found that the pH switch sequence insertion caused minimal change at pH 8 but a ca. 50 °C drop in the melting temperature (Tm ) was observed at pH 2.5: ΔΔGF ≥11.3 kJ mol-1 . Using the strategies demonstrated in this article, the redesign of ß-sheets to contain a global, or local, pH-dependent conformational switch should be possible.