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Purpose To evaluate longer outcomes of primary nitinol stenting for the treatment of femoropopliteal lesions up to 15 cm long after these stents were found to have superior short-term patency vs. balloon angioplasty. Methods Two hundred and six patients (143 men; mean age 67 years) with intermittent claudication due to superficial femoral and proximal popliteal artery lesions were randomized (2:1) to treatment with nitinol stents or balloon angioplasty at 24 US and European centers and followed for 3 years. In that time, 15 patients died, 20 withdrew consent, and 10 were lost to follow-up, leaving 161 (78.2%) patients for 36-month assessment. Results The 12-month freedom from target lesion revascularization (TLR) was 87.3% for the stent group vs. 45.2% for the angioplasty group (p<0.0001). At 3 years, there was no difference in survival (90.0% vs. 91.7%, p=0.71) or major adverse events (75.2% vs. 75.2%, p=0.98) between the stent and angioplasty groups. Duplex ultrasound was not mandated after the first year, so stent patency could not be ascertained beyond 1 year, but freedom from TLR at 3 years was significantly better in the stent group (75.5% vs. 41.8%, p<0.0001), as was clinical success (63.2% vs. 17.9%, p<0.0001). At 18 months, a 4.1% (12/291) stent fracture rate was documented. Conclusion In this multicenter trial, primary implantation of a nitinol stent for moderate-length lesions in the femoropopliteal segment of patients with claudication was associated with better long-term results vs. balloon angioplasty alone.

Each of the eight enzymes involved in porphyrin synthesis can be defective and can produce a distinctive form of porphyria. The diagnosis of porphyria can be obscure and the symptoms severe. New treatments are emerging to manage the wide constellation of symptoms.

Lower extremity peripheral artery disease (PAD) affects 12% to 20% of Americans 60 years and older. The most significant risk factors for PAD are hyperlipidemia, hypertension, diabetes mellitus, chronic kidney disease, and smoking; the presence of three or more factors confers a 10-fold increase in PAD risk. Intermittent claudication is the hallmark of atherosclerotic lower extremity PAD, but only about 10% of patients with PAD experience intermittent claudication. A variety of leg symptoms that differ from classic claudication affects 50% of patients, and 40% have no leg symptoms at all. Current guidelines recommend resting ankle-brachial index (ABI) testing for patients with history or examination findings suggesting PAD. Patients with symptoms of PAD but a normal resting ABI can be further evaluated with exercise ABI testing. Routine ABI screening for those not at increased risk of PAD is not recommended. Treatment of PAD includes lifestyle modifications-including smoking cessation and supervised exercise therapy-plus secondary prevention medications, including antiplatelet therapy, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins. Surgical revascularization should be considered for patients with lifestyle-limiting claudication who have an inadequate response to the aforementioned therapies. Patients with acute or limb-threatening limb ischemia should be referred immediately to a vascular surgeon.

BackgroundIntermittent claudication (IC) is a classic symptom of peripheral artery disease, with first line treatment being supervised exercise therapy (SET). Despite this, SET is frequently underutilised, and adherence is often poor. An alternative option are home-based exercise programmes (HBEP). Although HBEPs are well tolerated, to the authors’ knowledge, no research has assessed their safety.AimThe aim of this review was to assess the safety of HBEPs in people living with IC.MethodsWe performed an electronic search of the MEDLINE, CINAHL, and Cochrane Library databases. The main parameter of interest was complication rate, calculated as the number of related adverse events per patient-hours. Sub-analysis was undertaken to determine differences in safety for studies that did and did not include pre-exercise cardiac screening, and for studies with exercise at low, moderate, and high levels of claudication pain.ResultsOur search strategy identified 8693 results, of which 27 studies were included for full review. Studies included 1642 participants completing 147,810 patient-hours of home-based exercise. Four related adverse events were reported, three of which were cardiac in origin, giving an all-cause complication rate of one event per 36,953 patient-hours. Three of these events occurred following exercise to high levels of claudication pain, and one occurred with pain-free exercise. One event occurred in a study without cardiac screening.ConclusionBased on the low number of related adverse events, HBEPs appear to be a safe method of exercise prescription for people with IC. Our results strengthen the rationale for providing alternative exercise options for this population.

Cilostazol is indicated for alleviating intermittent claudication (IC) in stable-phase peripheral arterial disease (PAD) patients. Conducting data mining on adverse events (AEs) of cilostazol in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to explore its potential medication risks and advance more rational and secure clinical medication practices. This study utilized the Open Vigil 2.1-MedDRA tool to retrieve and extract AE reporting data related to cilostazol from the FAERS database spanning the first quarter of 2004 to the first quarter of 2024. The primary methodology employed was the application of the reporting odds ratio (ROR) method to detect risk signals associated with AEs of cilostazol. A total of 2,130 AE reports involving cilostazol were identified as the primary suspect drug, with a total of 7,134 AEs reported. These reports were predominantly concentrated among patients aged 60 and above, with a higher occurrence in males compared to females. Japan ranked first among the reporting countries, and the majority of reports were submitted by healthcare professionals. Through the screening of cilostazol, a total of 323 positive risk signals for AEs were identified, encompassing 23 system organ classes (SOCs). A comparison with the existing cilostazol product label revealed 8 AEs that were not included based on the number of AE reports, and 19 AEs that were not included based on the strength of the risk signals. Cilostazol exhibited positive risk signals for AEs primarily affecting 8 organ systems based on the SOC classification. Among these, cardiac disorders ranked highest, with a total of 53 positive risk signals for cardiovascular-related AEs identified. In terms of the number of reports, cardiac failure ranked first, aligning with the black box warning issued by the FDA regarding cilostazol. The occurrence of adverse reactions related to cilostazol is primarily concentrated within the first month of treatment. However, a certain proportion of adverse reactions have been reported to occur after long-term use (exceeding 360 days) of cilostazol therapy. Our results have further enriched the observations from existing clinical and real-world studies, uncovering new AE signals for cilostazol, including fall, cerebral infarction, pneumonia, loss of consciousness, acute kidney injury, renal impairment, renal failure, cardiac vein perforation, basal ganglia haematoma, cerebral hyperperfusion syndrome, et al. This study also highlights the significant impact of cilostazol on the cardiovascular system, necessitating close attention to potential cardiovascular toxicities. In addition to focusing on the short-term adverse reactions following cilostazol administration, thorough research into its long-term safety profile is also imperative. This study provides recommendations and guidance for the rational and safe clinical use of cilostazol. In the future, prospective studies are needed to explore the occurrence of related AEs further.

Cilostazol is indicated for alleviating intermittent claudication (IC) in stable-phase peripheral arterial disease (PAD) patients. Conducting data mining on adverse events (AEs) of cilostazol in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to explore its potential medication risks and advance more rational and secure clinical medication practices. This study utilized the Open Vigil 2.1-MedDRA tool to retrieve and extract AE reporting data related to cilostazol from the FAERS database spanning the first quarter of 2004 to the first quarter of 2024. The primary methodology employed was the application of the reporting odds ratio (ROR) method to detect risk signals associated with AEs of cilostazol. A total of 2,130 AE reports involving cilostazol were identified as the primary suspect drug, with a total of 7,134 AEs reported. These reports were predominantly concentrated among patients aged 60 and above, with a higher occurrence in males compared to females. Japan ranked first among the reporting countries, and the majority of reports were submitted by healthcare professionals. Through the screening of cilostazol, a total of 323 positive risk signals for AEs were identified, encompassing 23 system organ classes (SOCs). A comparison with the existing cilostazol product label revealed 8 AEs that were not included based on the number of AE reports, and 19 AEs that were not included based on the strength of the risk signals. Cilostazol exhibited positive risk signals for AEs primarily affecting 8 organ systems based on the SOC classification. Among these, cardiac disorders ranked highest, with a total of 53 positive risk signals for cardiovascular-related AEs identified. In terms of the number of reports, cardiac failure ranked first, aligning with the black box warning issued by the FDA regarding cilostazol. The occurrence of adverse reactions related to cilostazol is primarily concentrated within the first month of treatment. However, a certain proportion of adverse reactions have been reported to occur after long-term use (exceeding 360 days) of cilostazol therapy. Our results have further enriched the observations from existing clinical and real-world studies, uncovering new AE signals for cilostazol, including fall, cerebral infarction, pneumonia, loss of consciousness, acute kidney injury, renal impairment, renal failure, cardiac vein perforation, basal ganglia haematoma, cerebral hyperperfusion syndrome, et al. This study also highlights the significant impact of cilostazol on the cardiovascular system, necessitating close attention to potential cardiovascular toxicities. In addition to focusing on the short-term adverse reactions following cilostazol administration, thorough research into its long-term safety profile is also imperative. This study provides recommendations and guidance for the rational and safe clinical use of cilostazol. In the future, prospective studies are needed to explore the occurrence of related AEs further.

Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS ) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP. Systemic administration of human PBGD mRNA encapsulated in lipid nanoparticles ameliorates disease phenotypes in mouse and rabbit models of acute hepatic porphyria and is safe in nonhuman primates.

Introduction A retrospective case series of acute intermittent porphyria (AIP) presenting with acute quadriparesis is described with a focus on patterns of neuropathy and nerve conduction study findings. Methods Six patients with acute polyneuropathy were diagnosed with AIP on the basis of characteristic clinical findings, urine porphobilinogen levels, and pathogenic variants in the hydroxymethylbilane synthase gene. Vital function impairment, neuropathic patterns, serial changes in nerve conduction studies (NCS), and laboratory findings are reviewed. Results A total of six patients with acute porphyric neuropathy were included. Patterns of weakness varied between upper and lower extremities. Three patients exhibited allodynia with preservation of large fiber sensory modalities in the acute polyneuropathy phase. Initial NCS revealed motor axonal polyneuropathy in four patients with sparing of motor conduction velocities and latencies. Relative sparing of tibial compound muscle action potential amplitudes is seen in two patients. Serial NCS revealed interval reduction of compound muscle action potential amplitudes in the upper extremity only in one patient and selective reduction of sensory nerve action potential amplitudes of the lower extremity in another patient. There were substantial delays in diagnoses, with all but one patient misdiagnosed as GBS. All but two patients required ambulation aids at last follow‐up assessment. Conclusion The findings in this series show variability in neuropathic patterns and NCS changes over time in AIP presenting with acute polyneuropathy. Small fiber neuropathy and allodynia with sparing of large fiber sensory modalities may serve as a diagnostic clue guiding early recognition of AIP in patients presenting with acute polyneuropathy.

To examine the effects of different protocols of high-intensity interval training (HIIT) on VO2max improvements in healthy, overweight/obese and athletic adults, based on the classifications of work intervals, session volumes and training periods. Systematic review and meta-analysis. PubMed, Scopus, Medline, and Web of Science databases were searched up to April 2018. Inclusion criteria were randomised controlled trials; healthy, overweight/obese or athletic adults; examined pre- and post-training VO2max/peak; HIIT in comparison to control or moderate intensity continuous training (MICT) groups. Fifty-three studies met the eligibility criteria. Overall, the degree of change in VO2max induced by HIIT varied by populations (SMD=0.41–1.81, p<0.05). When compared to control groups, even short-intervals (≤30s), low-volume (≤5min) and short-term HIIT (≤4weeks) elicited clear beneficial effects (SMD=0.79–1.65, p<0.05) on VO2max/peak. However, long-interval (≥2min), high-volume (≥15min) and moderate to long-term (≥4–12weeks) HIIT displayed significantly larger effects on VO2max (SMD=0.50–2.48, p<0.05). When compared to MICT, only long-interval (≥2min), high-volume (≥15min) and moderate to long-term (≥4–12weeks) HIIT showed beneficial effects (SMD=0.65–1.07, p<0.05). Short-intervals (≤30s), low-volume (≤5min) and short-term (≤4weeks) HIIT represent effective and time-efficient strategies for developing VO2max, especially for the general population. To maximize the training effects on VO2max, long-interval (≥2min), high-volume (≥15min) and moderate to long-term (≥4–12weeks) HIIT are recommended.