Adjudication of Self-reported Symptomatic Stone Recurrence in the Prevention of Urinary Stones With Hydration Trial.

OBJECTIVE: To assess accuracy of self-reported stone events in a large clinical trial by adjudication against the weight of documentation for spontaneous stone passage or surgical intervention. METHODS: Participants in the Prevention of Urinary Stones with Hydration (PUSH) trial were randomized to a multi-component behavioral intervention or control arm to increase and maintain high fluid intake. The primary endpoint was urinary stone events including symptomatic stone passage or procedural intervention. An independent adjudication committee blinded to randomization assignments reviewed all events. Confirmed clinical stone events required typical stone symptoms and documentation of stone passage (eg, via photograph, clinical record) and/or surgical intervention. Events with typical symptoms and self-described stone passage but without objective documentation of passage were also considered as meeting the primary endpoint and classified separately as patient-reported passage. Non-events did not meet either criteria. RESULTS: At time of this blinded analysis, a total of 1658 participants were randomized and had a median follow-up of 19 months. Self-reported stone events (n = 217) were adjudicated by the committee as either confirmed clinical events (134; 61.8%), patient-reported passage (71; 32.7%), or non-events (12; 5.5%). Confirmed clinical events consisted of stone passage in 66/134 and procedural interventions in 68/134 (53 for symptoms and 15 without symptoms). CONCLUSION: Rigorous adjudication revealed that self-reported stone events in the PUSH trial overwhelmingly represented clinically documented passage, surgical intervention, and patient-reported passage outside healthcare settings, with only 5.5% failing to satisfy adjudication criteria. Similar adjudication and classification processes warrant consideration for implementation in future stone trials. CLINICAL TRIALS REGISTRATION: NCT03244189.

Changes in 24-hour Urine Chemistry in Patients with Nephrolithiasis during Weight Loss with Glucagon-Like Peptide-1 Based Therapies.

BACKGROUND: Obesity is an independent risk factor for incident and recurrent nephrolithiasis. The impact of weight loss through glucagon-like peptide 1 (GLP-1) receptor agonists and dual GLP-1/ gastric inhibitory polypeptide receptor agonists (GLP-based therapies) on nephrolithiasis is not well-understood. This study examined the changes in 24-hour urine chemistry assessing for stone risk during weight loss through GLP-based therapies. METHODS: This retrospective analysis identified adult stone formers followed at our academic institution's weight wellness clinic between September 2015 and August 2023 and included patients with at least two 24-hour urine collections for stone risk assessment. 24-hour urine parameters before and during weight loss in patients on GLP-based therapies were compared. RESULTS: Forty-four obese patients with nephrolithiasis experienced significant weight reduction (-6.6±7.3 kg, p<0.001) over a median 1.1 years of follow-up with GLP-based therapies. During this period, there was a significant decrease in 24-hour urine oxalate (40±16 to 32±11 mg/day, p=0.002), sulfate (21±10 to 17±9 mmol/day, p=0005), and ammonium (35±22 to 29±15 mEq/day, p=0.01). There were non-significant changes in urine calcium, citrate, uric acid, pH, phosphorus, sodium, potassium, magnesium, chloride, creatinine or total volume. Additionally, there was no statistical difference in urine supersaturation indices with respect to calcium oxalate, calcium phosphate and uric acid. CONCLUSION: Our results indicate that weight loss through GLP-based therapies is not associated with pro-lithogenic changes in 24-hour urine chemistry in patients with nephrolithiasis, unlike what happens with other weight loss modalities.

A larval zebrafish model of cardiac physiological recovery following cardiac arrest and myocardial hypoxic damage.

Contemporary cardiac injury models in zebrafish larvae include cryoinjury, laser ablation, pharmacological treatment and cardiac dysfunction mutations. Although effective in damaging cardiomyocytes, these models lack the important element of myocardial hypoxia, which induces critical molecular cascades within cardiac muscle. We have developed a novel, tractable, high throughput in vivo model of hypoxia-induced cardiac damage that can subsequently be used in screening cardioactive drugs and testing recovery therapies. Our potentially more realistic model for studying cardiac arrest and recovery involves larval zebrafish (Danio rerio) acutely exposed to severe hypoxia (PO2=5-7 mmHg). Such exposure induces loss of mobility quickly followed by cardiac arrest occurring within 120 min in 5 days post fertilization (dpf) and within 40 min at 10 dpf. Approximately 90% of 5 dpf larvae survive acute hypoxic exposure, but survival fell to 30% by 10 dpf. Upon return to air-saturated water, only a subset of larvae resumed heartbeat, occurring within 4 min (5 dpf) and 6-8 min (8-10 dpf). Heart rate, stroke volume and cardiac output in control larvae before hypoxic exposure were 188±5 bpm, 0.20±0.001 nL and 35.5±2.2 nL/min (n=35), respectively. After briefly falling to zero upon severe hypoxic exposure, heart rate returned to control values by 24 h of recovery. However, reflecting the severe cardiac damage induced by the hypoxic episode, stroke volume and cardiac output remained depressed by ∼50% from control values at 24 h of recovery, and full restoration of cardiac function ultimately required 72 h post-cardiac arrest. Immunohistological staining showed co-localization of Troponin C (identifying cardiomyocytes) and Capase-3 (identifying cellular apoptosis). As an alternative to models employing mechanical or pharmacological damage to the developing myocardium, the highly reproducible cardiac effects of acute hypoxia-induced cardiac arrest in the larval zebrafish represent an alternative, potentially more realistic model that mimics the cellular and molecular consequences of an infarction for studying cardiac tissue hypoxia injury and recovery of function.

Species limits and hybridization in Andean leaf-eared mice (Phyllotis).

Leaf-eared mice (genus Phyllotis) are among the most widespread and abundant small mammals in the Andean Altiplano, but species boundaries and distributional limits are often poorly delineated due to sparse survey data from remote mountains and high-elevation deserts. Here we report a combined analysis of mitochondrial DNA variation and whole-genome sequence (WGS) variation in Phyllotis mice to delimit species boundaries, to assess the timescale of diversification of the group, and to examine evidence for interspecific hybridization. Estimates of divergence dates suggest that most diversification of Phyllotis occurred during the past 3 million years. Consistent with the Pleistocene Aridification hypothesis, our results suggest that diversification of Phyllotis largely coincided with climatically induced environmental changes in the mid- to late Pleistocene. Contrary to the Montane Uplift hypothesis, most diversification in the group occurred well after the major phase of uplift of the Central Andean Plateau. Species delimitation analyses revealed surprising patterns of cryptic diversity within several nominal forms, suggesting the presence of much undescribed alpha diversity in the genus. Results of genomic analyses revealed evidence of ongoing hybridization between the sister species Phyllotis limatus and P. vaccarum and suggest that the contemporary zone of range overlap between the two species represents an active hybrid zone.

The unique allosteric property of crocodilian haemoglobin elucidated by cryo-EM.

The principal effect controlling the oxygen affinity of vertebrate haemoglobins (Hbs) is the allosteric switch between R and T forms with relatively high and low oxygen affinity respectively. Uniquely among jawed vertebrates, crocodilians possess Hb that shows a profound drop in oxygen affinity in the presence of bicarbonate ions. This allows them to stay underwater for extended periods by consuming almost all the oxygen present in the blood-stream, as metabolism releases carbon dioxide, whose conversion to bicarbonate and hydrogen ions is catalysed by carbonic anhydrase. Despite the apparent universal utility of bicarbonate as an allosteric regulator of Hb, this property evolved only in crocodilians. We report here the molecular structures of both human and a crocodilian Hb in the deoxy and liganded states, solved by cryo-electron microscopy. We reveal the precise interactions between two bicarbonate ions and the crocodilian protein at symmetry-related sites found only in the T state. No other known effector of vertebrate Hbs binds anywhere near these sites.

Thiazide Dose, Urine Calcium, and Symptomatic Kidney Stone Events.

This cohort study examines the association between thiazide dose and urine calcium reduction and correlates urine calcium changes with the occurrence of symptomatic kidney stone events.

Long-term Evolution of Hypophosphatemia and Osteomalacia in a Patient With Multiple Myeloma.

Multiple myeloma commonly manifests with symptoms arising from the involvement of various organs, particularly the bone and kidneys. In this report, we detail the case of a 44-year-old man who was diagnosed with multiple myeloma associated with reduced bone density. He exhibited clinical findings of osteomalacia due to Fanconi syndrome (characterized clinically by bone pain and proximal weakness and biochemically by elevated serum alkaline phosphatase, hypophosphatemia, hypouricemia, and glucosuria). With phosphate replacement, there was a notable improvement in bone pain, osteomalacia, and bone mineral density. Nevertheless, the patient continued to experience renal wasting of phosphate, uric acid, and glucose despite achieving remission from multiple myeloma for nearly 2 years. Our case highlights several important clinical features of myeloma-associated Fanconi syndrome, including the need to recognize this complication to appropriately treat the underlying bone disease while avoiding osteoclast inhibitors and the long-term persistence of the proximal renal tubulopathy despite achieving remission from myeloma and correction of osteomalacia.

Patient Characteristics, Management, and Outcomes in a Novel Cohort of Primary Hyperparathyroidism.

Context: Primary hyperparathyroidism (PHPT) increases the risk of bone loss, debilitating fractures, kidney stones, impaired renal function, and neurocognitive symptoms. Studies describing the natural history of PHPT have been limited to small samples, single institutions, or specific populations. Objective: We assessed the natural history of PHPT through a large, diverse national cohort from an electronic health record dataset representing more than 100 million patients. Methods: The TriNetX database was queried for adult patients with PHPT. We extracted demographics, comorbidities, and longitudinal biochemistries. Primary outcomes included major osteoporotic fracture (MOF) and chronic kidney disease (CKD). Outcomes were stratified by treatment strategy (surgical parathyroidectomy [PTX] vs nonsurgical) and age. Results: Among 50 958 patients with PHPT, 26.5% were treated surgically at a median of 0.3 years postdiagnosis. At diagnosis, median age was 65 years, 74.0% were female, and median calcium level was 10.9 mg/dL. Black and older patients underwent PTX less frequently than White and younger patients. MOF 10-year incidence was 5.20% (PTX) and 7.91% (nonsurgical), with median 1.7-year delay with PTX compared to nonsurgical. PTX-associated MOF absolute risk reduction was 0.83% (age < 65 years) and 3.33% (age ≥ 65 years). CKD 10-year incidence was 21.2% (PTX) and 33.6% (nonsurgical), with median 1.9-year delay with PTX. PTX-associated CKD absolute risk reduction was 12.2% (age < 65 years) and 9.5% (age ≥ 65 years). Conclusion: We report 1 of the largest, representative, population-based natural histories of PHPT with different management strategies. A minority of patients underwent PTX, especially in older age. Patients managed surgically had lower incidence of fracture and CKD, and older patients experienced differential benefit.

Use of Cinacalcet for the Management of Primary Hyperparathyroidism in Pregnancy.

Primary hyperparathyroidism in pregnancy is uncommon. Consequently, there are no randomized controlled studies that address treatment of primary hyperparathyroidism in pregnancy, and the efficacy and safety of medical management with cinacalcet in this setting is unknown. We report a case of a 28-year-old woman with primary hyperparathyroidism and hypercalcemia that worsened during her third trimester of pregnancy. Cinacalcet led to achievement of normocalcemia, allowing the delay of parathyroidectomy until after delivery of the baby. We also review the published literature on cinacalcet use in the management of primary hyperparathyroidism during pregnancy. Cinacalcet is typically reserved for pregnant patients with severe and symptomatic hypercalcemia, primarily serving as a last resort to delay parathyroidectomy until either the second trimester or the postpartum period.

Local adaptation, plasticity, and evolved resistance to hypoxic cold stress in high-altitude deer mice.

A fundamental question in evolutionary biology concerns the relative contributions of phenotypic plasticity vs. local adaptation (genotypic specialization) in enabling wide-ranging species to inhabit diverse environmental conditions. Here we conduct a long-term hypoxia acclimation experiment to assess the relative roles of local adaptation and plasticity in enabling highland and lowland deer mice (Peromyscus maniculatus) to sustain aerobic thermogenesis at progressively increasing elevations. We assessed the relative physiological performance capacities of highland and lowland natives as they were exposed to progressive, stepwise increases in hypoxia, simulating the gradual ascent from sea level to an elevation of 6000 m. The final elevation of 6000 m far exceeds the highest attainable elevations within the species' range, and therefore tests the animals' ability to tolerate levels of hypoxia that surpass the prevailing conditions within their current distributional limits. Our results demonstrate that highland natives exhibit superior thermogenic capacities at the most severe levels of hypoxia, suggesting that the species' broad fundamental niche and its ability to inhabit such a broad range of elevational zones is attributable to a combination of genetically based local adaptation and plasticity. Transcriptomic and physiological measurements identify evolved changes in the acclimation response to hypoxia that contribute to the enhanced thermogenic capacity of highland natives.

Using structured problem solving to promote fluid consumption in the prevention of urinary stones with hydration (PUSH) trial.

BACKGROUND: Structured Problem Solving (SPS) is a patient-centered approach to promoting behavior change that relies on productive collaboration between coaches and participants and reinforces participant autonomy. We aimed to describe the design, implementation, and assessment of SPS in the multicenter Prevention of Urinary Stones with Hydration (PUSH) randomized trial. METHODS: In the PUSH trial, individuals with a history of urinary stone disease and low urine output were randomized to control versus a multicomponent intervention including SPS that was designed to promote fluid consumption and thereby prevent recurrent stones. We provide details specifically about training and fidelity assessment of the SPS coaches. We report on implementation experiences related to SPS during the initial conduct of the trial. RESULTS: With training and fidelity assessment, coaches in the PUSH trial applied SPS to help participants overcome barriers to fluid consumption. In some cases, coaches faced implementation barriers such as variable participant engagement that required tailoring their work with specific participants. The coaches also faced challenges including balancing rapport with problem solving, and role clarity for the coaches. CONCLUSIONS: We adapted SPS to the setting of kidney stone prevention and overcame challenges in implementation, such as variable patient engagement. Tools from the PUSH trial may be useful to apply to other health behavior change settings in nephrology and other areas of clinical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03244189.

Extreme High-Elevation Mammal Surveys Reveal Unexpectedly High Upper Range Limits of Andean Mice.

AbstractIn the world's highest mountain ranges, uncertainty about the upper elevational range limits of alpine animals represents a critical knowledge gap regarding the environmental limits of life and presents a problem for detecting range shifts in response to climate change. Here we report results of mountaineering mammal surveys in the Central Andes, which led to the discovery of multiple species of mice living at extreme elevations that far surpass previously assumed range limits for mammals. We livetrapped small mammals from ecologically diverse sites spanning >6,700 m of vertical relief, from the desert coast of northern Chile to the summits of the highest volcanoes in the Andes. We used molecular sequence data and whole-genome sequence data to confirm the identities of species that represent new elevational records and to test hypotheses regarding species limits. These discoveries contribute to a new appreciation of the environmental limits of vertebrate life.

Genomic insights into the mystery of mouse mummies on the summits of Atacama volcanoes.

Our understanding of the limits of animal life is continually revised by scientific exploration of extreme environments. Here we report the discovery of mummified cadavers of leaf-eared mice, Phyllotis vaccarum, from the summits of three different Andean volcanoes at elevations 6,029-6,233 m above sea level in the Puna de Atacama in Chile and Argentina. Such extreme elevations were previously assumed to be completely uninhabitable by mammals. In combination with a live-captured specimen of the same species from the nearby summit of Volcán Llullaillaco (6,739 m)1, the summit mummies represent the highest altitude physical records of mammals in the world. We also report a chromosome-level genome assembly for P. vaccarum that, in combination with a whole-genome re-sequencing analysis and radiocarbon dating analysis, provides insights into the provenance and antiquity of the summit mice. Radiocarbon data indicate that the most ancient of the mummies are, at most, a few centuries old. Genomic polymorphism data revealed a high degree of continuity between the summit mice and conspecifics from lower elevations in the surrounding Altiplano. Genomic data also revealed equal numbers of males and females among the summit mice and evidence of close kinship between some individuals from the same summits. These findings bolster evidence for resident populations of Phyllotis at elevations >6,000 m and challenge assumptions about the environmental limits of vertebrate life and the physiological tolerances of small mammals.

Extreme high-elevation mammal surveys reveal unexpectedly high upper range limits of Andean mice.

In the world's highest mountain ranges, uncertainty about the upper elevational range limits of alpine animals represents a critical knowledge gap regarding the environmental limits of life and presents a problem for detecting range shifts in response to climate change. Here we report results of mountaineering mammal surveys in the Central Andes, which led to the discovery of multiple species of mice living at extreme elevations that far surpass previously assumed range limits for mammals. We live-trapped small mammals from ecologically diverse sites spanning >6700 m of vertical relief, from the desert coast of northern Chile to the summits of the highest volcanoes in the Andes. We used molecular sequence data and whole-genome sequence data to confirm the identities of species that represent new elevational records and to test hypotheses regarding species limits. These discoveries contribute to a new appreciation of the environmental limits of vertebrate life.

Patients' Experiences With the Removal of a Ureteral Stent: Insights From In-depth Interviews With Participants in the USDRN STENTS Qualitative Cohort Study.

OBJECTIVE: To describe the experiences of patients undergoing stent removal in the USDRN Study to Enhance Understanding of Stent-Associated Symptoms (STENTS), a prospective, observational cohort study of patients with short-term ureteral stent placement post-ureteroscopy. METHODS: We conducted a qualitative descriptive study using in-depth interviews. Participants reflected on (1) painful or bothersome aspects of stent removal, (2) symptoms immediately after removal, and (3) symptoms in the days following removal. Interviews were audio-recorded, transcribed, and analyzed using applied thematic analysis. RESULTS: The 38 participants interviewed were aged 13-77 years, 55% female, and 95% White. Interviews were conducted 7-30 days after stent removal. Almost all participants (n = 31) described that they experienced either pain or discomfort during stent removal, but for most (n = 25) pain was of short duration. Many participants (n = 21) described anticipatory anxiety related to the procedure, and several (n = 11) discussed discomfort arising from lack of privacy or feeling exposed. Interactions with medical providers often helped put participants at ease, but also increased discomfort for some. Following stent removal, several participants described lingering pain and/or urinary symptoms, but these largely resolved within 24 hours. A few participants described symptoms persisting for more than a day post stent removal. CONCLUSION: These findings on patients' experiences during and shortly after ureteral stent removal, particularly the psychological distress they experienced, identify opportunities for improvement in patient care. Clear communication from providers about what to expect with the removal procedure, and the possibility of delayed pain, may help patients adapt to discomfort.

Dietary crude oil exposure during sex differentiation skewed adult sex ratio towards males in the zebrafish.

Dietary crude oil exposure has detrimental morpho-physiological effects in fishes, including endocrine disruption. However, little is known about how it influences sex differentiation and its potential for skewing sex ratios of populations. Appropriate sex ratio is important for maintaining effective population size and structure. Deviations of these ratios can compromise population growth and maintenance and may induce changes in a species' evolutionary trajectory. We assessed the potential of dietary exposure to crude oil (6.5, 11.4, and 17.5 mg/kg food) to alter sex differentiation in the zebrafish (Danio rerio) (20-35 days post fertilization (dpf)) and subsequently skew the adult (90 dpf) sex ratio. Multiple health- and fitness-related phenotypic traits (i.e., body mass and length, condition factor, heart rate, oxygen consumption, and their capacity to cope with hypoxia) were also assessed to better understand the effects of dietary crude oil exposure. We showed that dietary exposure to crude oil during the process of sex differentiation skewed sex ratio towards males (up to 0.34:1 female to male ratio in the highest oil concentration). Remarkably, this effect occurred independently of affecting physiological variables and female gonad characteristics, thus highlighting just how subtle the effects of dietary crude oil exposure can be. Our results suggest that, although fish were in an apparently healthy state during experimentation, sex ratio was still impacted, potentially compromising the resilience of the population. Therefore, considering how complex chemical mixtures affect organisms at several levels (molecular-individual) in experimental designs is warranted to better understand the implications of the exposures and the hazards that populations face in the wild.

The Patient Voice: Stent Experiences After Ureteroscopy-Insights from In-Depth Interviews with Participants in the USDRN STENTS Nested Qualitative Cohort Study.

Purpose: Ureteral stents are commonly used after ureteroscopy and cause significant discomfort, yet qualitative perspectives on patients' stent experiences remain unknown. We describe psychological, functional, and interpersonal effects of post-ureteroscopy stents and whether additional patient-reported assessments may be needed. Materials and Methods: Using a qualitative descriptive study design, we conducted in-depth interviews with a nested cohort of participants in the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS). Participants shared their symptoms with a post-ureteroscopy stent and described symptom bother and impact on daily activities. All interviews were audio-recorded, transcribed, and analyzed using applied thematic analysis. During analysis, participants' experiences with interference in daily activities were categorized into three groups based on their impact: minimal, moderate, and substantial. Results: All 39 participants experienced pain, although descriptions varied and differentiated between feelings of pain vs discomfort. Almost all experienced urinary symptoms. Only a few reported other physical symptoms, although several psychological aspects were identified. In the areas of sleep, mood, life enjoyment, work, exercise, activities of daily living, driving, childcare, and leisure/social activities, the stent had little impact on daily living among participants placed in the minimal group (n = 12) and far greater impact for participants in the substantial group (n = 8). For patients in the moderate group (n = 19), some daily activities were moderately or substantially affected, whereas other activities were minimally affected. Conclusions: Counseling to better prepare patients for the impact of stent-associated symptoms may help mitigate symptom burden. While existing instruments adequately cover most symptoms, additional assessments for other domains, particularly psychological factors, may be needed.

Type 4 renal tubular acidosis and uric acid nephrolithiasis: two faces of the same coin?

PURPOSE OF REVIEW: The present review summarizes findings of recent studies examining the epidemiology, pathophysiology, and treatment of type 4 renal tubular acidosis (RTA) and uric acid nephrolithiasis, two conditions characterized by an abnormally acidic urine. RECENT FINDINGS: Both type 4 RTA and uric acid nephrolithiasis disproportionately occur in patients with type 2 diabetes and/or chronic kidney disease. Biochemically, both conditions are associated with reduced renal ammonium excretion resulting in impaired urinary buffering and low urine pH. Reduced ammoniagenesis is postulated to result from hyperkalemia in type 4 RTA and from insulin resistance and fat accumulation in the renal proximal tubule in uric acid nephrolithiasis. The typical biochemical findings of hyperkalemia and systemic acidosis of type 4 RTA are rarely reported in uric acid stone formers. Additional clinical differences between the two conditions include findings of higher urinary uric acid excretion and consequent urinary uric acid supersaturation in uric acid stone formers but not in type 4 RTA. SUMMARY: Type 4 RTA and uric acid nephrolithiasis share several epidemiological, clinical, and biochemical features. Although both conditions may be manifestations of diabetes mellitus and thus have a large at-risk population, the means to the shared biochemical finding of overly acidic urine are different. This difference in pathophysiology may explain the dissimilarity in the prevalence of kidney stone formation.