Persisting Symptomatic Severe Secondary Mitral Regurgitation in Heart Failure Patients.

Aims We aimed to assess the rate of persisting severe symptomatic secondary mitral regurgitation (MR) in a newly diagnosed heart failure (HF) population following optimisation of guideline directed medical therapy (GDMT), cardiac resynchronisation therapy (CRT) and revascularisation. Methods We assessed all new patients referred to our hospital group's HF clinics. We retrospectively reviewed these patients at HF clinic enrolment, HF programme completion, as well as most recent follow up. Results Of the 242 new patients referred to our HF clinics, there were 10 patients (4.1%) who had either persisting symptomatic severe secondary MR at HF programme completion, or had undergone mitral valve surgery. There were no percutaneous mitral valve repairs at the time of these patients' referrals. The rates of ACE/ARB/ARNI, BB and MRA use were 87.8%, 94.1%, and 49.8% in those with mid ranged, or reduced ejection fraction. The rates of ICD and CRT therapy were 15.1% and 4.4% at follow up. Patients with severe MR had higher time adjusted rates of death or hospitalization for heart failure. Conclusion In a well-treated newly diagnosed HF population, repeat assessment at HF programme completion suggests 4.1% of patients have a persisting indication for percutaneous mitral valve repair based on persisting severe symptomatic secondary MR.

Patient outcomes following transfer between intensive care units during the COVID-19 pandemic.

Transferring critically ill patients between intensive care units (ICU) is often required in the UK, particularly during the COVID-19 pandemic. However, there is a paucity of data examining clinical outcomes following transfer of patients with COVID-19 and whether this strategy affects their acute physiology or outcome. We investigated all transfers of critically ill patients with COVID-19 between three different hospital ICUs, between March 2020 and March 2021. We focused on inter-hospital ICU transfers (those patients transferred between ICUs from different hospitals) and compared this cohort with intra-hospital ICU transfers (patients moved between different ICUs within the same hospital). A total of 507 transfers were assessed, of which 137 met the inclusion criteria. Forty-five patients underwent inter-hospital transfers compared with 92 intra-hospital transfers. There was no significant change in median compliance 6 h pre-transfer, immediately post-transfer and 24 h post-transfer in patients who underwent either intra-hospital or inter-hospital transfers. For inter-hospital transfers, there was an initial drop in median PaO2 /FI O2 ratio: from median (IQR [range]) 25.1 (17.8-33.7 [12.1-78.0]) kPa 6 h pre-transfer to 19.5 (14.6-28.9 [9.8-52.0]) kPa immediately post-transfer (p < 0.05). However, this had resolved at 24 h post-transfer: 25.4 (16.2-32.9 [9.4-51.9]) kPa. For intra-hospital transfers, there was no significant change in PaO2 /FI O2 ratio. We also found no meaningful difference in pH; PaCO2 ;, base excess; bicarbonate; or norepinephrine requirements. Our data demonstrate that patients with COVID-19 undergoing mechanical ventilation of the lungs may have short-term physiological deterioration when transferred between nearby hospitals but this resolves within 24 h. This finding is relevant to the UK critical care strategy in the face of unprecedented demand during the COVID-19 pandemic.

Coral composition and bottom-wave metrics improve understanding of the patchiness of cyclone damage on reefs.

Coral reefs are likely to be exposed to more intense cyclones under climate change. Cyclone impacts are spatially highly variable given complex hydrodynamics, and coral-specific sensitivity to wave impacts. Predicting reef vulnerability to cyclones is critical to management but requires high resolution environmental data that are difficult to obtain over broad spatial scales. Using 30m-resolution wave modelling, we tested cyclonic and non-cyclonic wave metrics as predictors of coral damage on 22 reefs after severe cyclone Ita impacted the northern Great Barrier Reef, Australia in 2014. Analyses of coral cover change accounting for the type of coral along a gradient of vulnerability to wave damage (e.g., massive, branching, Acroporids) excluded cyclone-generated surface wave metrics (derived from wave height) as important predictors. Increased bottom stress wave environment (near-bed wave orbital velocity) due to Ita (Ita-Ub) explained spatial patterns of 17% to 46% total coral cover loss only when the initial abundance of Acroporids was accounted for, and only when exceeding 35% cover. Greater coral losses occurred closer to the cyclone path irrespective of coral type. Massive and encrusting corals, however, had losses exacerbated in higher non-cyclonic bottom-wave energy environments (nc-Ub). The effect of community composition on structural vulnerability to wave damage was more important predicting damage that the magnitude of the cyclone-generated waves, especially when reefs are surveyed well beyond where damaging waves are expected to occur. Exposure to Ita-Ub was greater in typically high nc-Ub environments with relatively low cover of the most fragile morphologies explaining why these were the least affected overall. We reveal that the common surface-wave metrics of cyclone intensity may not always be able to predict spatial impacts and conclude that reef vulnerability assessments need to account for chronic wave patterns and differences in community composition in order to provide predictive tools for future conservation and restoration.

LightBox: A multiwell plate illumination system for photoactive molecule characterization.

Multiwell plates (MWPs) are the workhorses of the life sciences. However, biophotonics research with MWPs is limited, in part due to the lack of equipment suitable for photo-irradiation of photoactive molecules in a MWP-suitable, high-throughput manner, either commercially or through open-source MWP systems. Here we present "LightBox", a calibrated controllable MWP illumination system with broad applications including screening of photoactive molecules and characterization of photocatalytic chemicals. LightBox is a high intensity, accurately controllable, uniform illumination system designed for MWPs with electronics and a control unit that provides a simple and intuitive interface. LightBox can reach intensities of 0.23 mW/mm2 at wavelengths of 405 nm with variance between well sites of <5%. The usefulness of LightBox is demonstrated by assessing the IC50 of a photosensitizing compound using a live/dead assay following simultaneous irradiation of the sample at a range of concentrations, eliminating uncontrolled variables between concentrations and drastically increasing assessment speed.

Brucella suis biovar 2 infection in humans in France: emerging infection or better recognition?

Brucellosis is usually acquired by humans through contact with infected animals or the consumption of raw milk from infected ruminants. Brucella suis biovar 2 (BSB2) is mainly encountered in hares and wild boars (Sus scrofa), and is known to have very low pathogenicity to humans with only two case reports published in the literature. Human cases of brucellosis caused by BSB2 were identified through the national mandatory notification of brucellosis. The identification of the bacterium species and biovar were confirmed by the national reference laboratory. Epidemiological data were obtained during medical follow-up visits. Seven human cases were identified between 2004 and 2016, all confirmed by the isolation of BSB2 in clinical specimens. All patients had direct contact with wild boars while hunting or preparing wild boar meat for consumption. Five patients had chronic medical conditions possibly responsible for an increased risk of infection. Our findings suggest that BSB2 might be an emerging pathogen in hunters with massive exposure through the dressing of wild boar carcasses. Hunters, especially those with chronic medical conditions, should be informed about the risk of BSB2 infection and should receive information on protective measures.

Human brucellosis in France in the 21st century: Results from national surveillance 2004-2013.

Brucellosis is a bacterial zoonotic disease mainly transmitted to humans by ruminants. In France, brucellosis has disappeared from ruminants herds. Human brucellosis surveillance is performed through mandatory notification and the national reference center. METHODS: We report the results of human brucellosis surveillance from 2004 to 2013 with regards to epidemiological, clinical and microbiological data. RESULTS: A total of 250 cases were notified, making an annual incidence of 0.3 cases per million inhabitants. Brucella melitensis biovar 3 was the most frequently identified bacterium (79% of isolated strains). In total, 213 (85%) cases had been contaminated abroad in endemic countries. In 2012, an episode of re-emergence of brucellosis in cattle occurred in Haute-Savoie, in the French Alps, and was responsible for 2 human cases. CONCLUSION: Brucellosis has become a disease of travelers in France. However, maintaining a stringent epidemiological surveillance is necessary to be able to early detect any local re-emergence in humans or animals. The multidisciplinary surveillance was implemented in France years ago and is a successful example of the One Health Concept.

Differentiating sepsis from non-infectious systemic inflammation based on microvesicle-bacteria aggregation.

Sepsis is a severe medical condition and a leading cause of hospital mortality. Prompt diagnosis and early treatment has a significant, positive impact on patient outcome. However, sepsis is not always easy to diagnose, especially in critically ill patients. Here, we present a conceptionally new approach for the rapid diagnostic differentiation of sepsis from non-septic intensive care unit patients. Using advanced microscopy and spectroscopy techniques, we measure infection-specific changes in the activity of nano-sized cell-derived microvesicles to bind bacteria. We report on the use of a point-of-care-compatible microfluidic chip to measure microvesicle-bacteria aggregation and demonstrate rapid (≤1.5 hour) and reliable diagnostic differentiation of bacterial infection from non-infectious inflammation in a double-blind pilot study. Our study demonstrates the potential of microvesicle activities for sepsis diagnosis and introduces microvesicle-bacteria aggregation as a potentially useful parameter for making early clinical management decisions.

Mercury concentrations in feathers of marine birds in Arctic Canada.

Mercury (Hg) concentrations are a concern in the Canadian Arctic, because they are relatively high compared to background levels and to similar species farther south, and are increasing in many wildlife species. Among marine birds breeding in the Canadian Arctic, Hg concentrations have been monitored regularly in eggs and intermittently in livers, but feathers have generally not been used as an indicator of Hg exposure or burden. We examined Hg concentrations in six marine bird species in the Canadian Arctic. Ivory gull Pagophila eburnea, feather Hg was exceptionally high, while glaucous gull Larus hyperboreus feather Hg was unexpectedly low, and ratios of feather THg to egg THg varied across species. The proportion of total Hg that was comprised of methyl Hg in ivory gull feathers was lower than in other species, and may be related to photo-demethylation or keratin breakdown in semi-opaque feather tissue.

Impact of sea-level rise on cross-shore sediment transport on fetch-limited barrier reef island beaches under modal and cyclonic conditions.

A one-dimensional wave model is combined with an analytical sediment transport model to investigate the likely influence of sea-level rise on net cross-shore sediment transport on fetch-limited barrier reef and lagoon island beaches. The modelling considers if changes in the nearshore wave height and wave period in the lagoon induced by different water levels over the reef flat are likely to lead to net offshore or onshore movement of sediment. The results indicate that the effects of SLR on net sediment movement are highly variable and controlled by the bathymetry of the reef and lagoon. A significant range of reef-lagoon bathymetry, and notably shallow and narrow reefs, appears to lead hydrodynamic conditions and beaches that are likely to be stable or even accrete under SLR. Loss of reef structural complexity, particularly on the reef flat, increases the chance of sediment transport away from beaches and offshore.

Impact of sea-level rise and coral mortality on the wave dynamics and wave forces on barrier reefs.

A one-dimensional wave model was used to investigate the reef top wave dynamics across a large suite of idealized reef-lagoon profiles, representing barrier coral reef systems under different sea-level rise (SLR) scenarios. The modeling shows that the impacts of SLR vary spatially and are strongly influenced by the bathymetry of the reef and coral type. A complex response occurs for the wave orbital velocity and forces on corals, such that the changes in the wave dynamics vary reef by reef. Different wave loading regimes on massive and branching corals also leads to contrasting impacts from SLR. For many reef bathymetries, wave orbital velocities increase with SLR and cyclonic wave forces are reduced for certain coral species. These changes may be beneficial to coral health and colony resilience and imply that predicting SLR impacts on coral reefs requires careful consideration of the reef bathymetry and the mix of coral species.

Salvelinus namaycush spawning substratum attracts egg predators and opportunists through chemosensory cues.

Two separate field experiments were conducted in a series of small boreal lakes to test for the attraction of egg predators to lake trout Salvelinus namaycush spawning shoals and subsequently to determine whether chemosensory cues attract egg predators to these sites. In the first experiment, minnow traps set on spawning sites captured significantly more egg predators than those set on structurally similar non-spawning sites. Captures of slimy sculpin Cottus cognatus, common shiner Luxilus cornutus, blacknose shiner Notropis heterolepis and virile crayfish Orconectes virilis were more than double on spawning sites relative to non-spawning sites for the two study lakes. To test whether chemosensory cues could attract egg predators to S. namaycush spawning sites, paired minnow traps were placed on eight to 10 sites in each of the three study lakes; one trap contained visually concealed S. namaycush spawning substratum and the other with visually concealed non-spawning substratum. Traps containing spawning substratum consistently captured more fish and had higher mean daily catches than those that contained non-spawning substratum. The combined results demonstrate a greater prevalence of egg predators on S. namaycush spawning shoals that appears to be the result of chemosensory attraction to spawning substratum.

The Brucella suis IbpA heat-shock chaperone is not required for virulence or for expression of the VirB type IV secretion system VirB8 protein.

UNLABELLED: Brucella suis, facultative intracellular bacterial pathogen of mammals, and Agrobacterium tumefaciens, a plant pathogen, both use a VirB type IV secretion system (T4SS) to translocate effector molecules into host cells. HspL, an α-crystalline-type small heat-shock protein, acts as a chaperone for the Agrobacterium VirB8 protein, an essential component of the VirB system. An Agrobacterium mutant lacking hspL is attenuated due to a misfunctional T4SS. We have investigated whether IbpA (BRA0051), the Brucella HspL homologue, plays a similar role. Unlike HspL, IbpA does not interact with VirB8, and an IbpA mutant shows full virulence and no defect in VirB expression. These data show that the Brucella α-crystalline-type small heat-shock protein IbpA is not required for Brucella virulence. SIGNIFICANCE AND IMPACT OF STUDY: Many bacteria use type IV secretion systems (T4SS), multi-protein machines, to translocate DNA and protein substrates across their envelope. Understanding how T4SS function is important as they play major roles in the spread of plasmids carrying antibiotic resistance and in pathogenicity. In the plant pathogen Agrobacterium tumefaciens, HspL, an α-crystalline-type small heat-shock protein, acts as a chaperone for the essential type IV secretion system component VirB8. Here, we show that this is not the case for all T4SS; in the zoonotic pathogen Brucella suis, IbpA, the protein most related to HspL, does not play this role.

The quest for a true One Health perspective of brucellosis.

One Health is an interdisciplinary collaboration that aims at mitigating risks to human health arising from microorganisms present in non-human animal species, which have the potential to be transmitted and cause disease in humans. Different degrees of scientific collaboration and sectoral integration are needed for different types of zoonotic diseases, depending on the health and associated economic gains that can be expected from a One Health approach. Indeed, mitigating zoonotic risks related to emerging diseases with pandemic potential is different from mitigating risks related to endemic zoonotic diseases like brucellosis. Likewise, management of brucellosis at the wildlife-livestock interface in wildlife conservation areas is in essence different from mitigating transmission of a given Brucella species within its preferential host species, which in turn is different from mitigating the spillover of a given Brucella species to non-preferential host species, humans included. Brucellosis economic models often oversimplify and/or wrongly assess transmission between reservoir hosts and spillover hosts. Moreover,they may not properly value non-market outcomes, such as avoidance of human disease, consumer confidence and conservation biology issues. As a result, uncertainty is such that the economic predictions of these models can be questionable. Therefore, understanding the infection biology of Brucella species is a prerequisite. This paper reviews and highlights important features of the infection biology of Brucella species and the changing epidemiology of brucellosis that need to be integrated into a true One Health perspective of brucellosis.

Effect of increasing the protein-to-fat ratio and reducing fat content on the chemical and physical properties of processed cheese product.

Scientific studies indicate that the intake of dietary fat and saturated fats in the modern Western diet is excessive and contributes adversely to health, lifestyle, and longevity. In response, manufacturers of cheese and processed cheese products (PCP) are pursuing the development of products with reduced fat contents. The present study investigated the effect of altering the fat level (13.8, 18.2, 22.7, 27.9, and 32.5 g/100g) in PCP on their chemical and physical properties. The PCP were formulated in triplicate to different fat levels using Cheddar cheese, skim milk cheese, anhydrous milk fat, emulsifying salt (ES), NaCl, and water. The formulations were designed to give fixed moisture (~53 g/100g) and ES:protein ratio (0.105). The resultant PCP, and their water-soluble extracts (WSE), prepared from a macerated blend of PCP and water at a weight ratio of 1:2, were analyzed at 4d. Reducing the fat content significantly increased the firmness of the unheated PCP and reduced the flowability and maximum loss tangent (fluidity) of the melted PCP. These changes coincided with increases in the levels of total protein, water-soluble protein, water-insoluble protein, and water-soluble Ca, and a decrease in the molar ratio of water-soluble Ca to soluble P. However, both water-soluble Ca and water-soluble protein decreased when expressed as percentages of total protein and total Ca, respectively, in the PCP. The high level of protein was a major factor contributing to the deterioration in physical properties as the fat content of PCP was reduced. Diluting the protein content or reducing the potential of the protein to aggregate, and thereby form structures that contribute to rigidity, may provide a means for improving quality of reduced-fat PCP by using natural cheese with lower intact casein content and lower calcium:casein ratio, for example, or by decreasing the ratio of sodium phosphate to sodium citrate-based ES.

Surgical resection for non-small cell lung cancer: clinical features and outcomes for a consecutive series at an Irish tertiary referral centre.

BACKGROUND: Few patients diagnosed with lung cancer are still alive 5 years after diagnosis. The aim of the current study was to conduct a 10-year review of a consecutive series of patients undergoing curative-intent surgical resection at the largest tertiary referral centre to identify prognostic factors. METHODS: Case records of all patients operated on for lung cancer between 1998 and 2008 were reviewed. The clinical features and outcomes of all patients with non-small cell lung cancer (NSCLC) stage I-IV were recorded. RESULTS: A total of 654 patients underwent surgical resection with curative intent during the study period. Median overall survival for the entire cohort was 37 months. The median age at operation was 66 years, with males accounting for 62.7 %. Squamous cell type was the most common histological subtype, and lobectomies were performed in 76.5 % of surgical resections. Pneumonectomy rates decreased significantly in the latter half of the study (25 vs. 16.3 %), while sub-anatomical resection more than doubled (2 vs. 5 %) (p < 0.005). Clinico-pathological characteristics associated with improved survival by univariate analysis include younger age, female sex, smaller tumour size, smoking status, lobectomy, lower T and N status and less advanced pathological stage. Age, gender, smoking status and tumour size, as well as T and N descriptors have emerged as independent prognostic factors by multivariate analysis. CONCLUSION: We identified several factors that predicted outcome for NSCLC patients undergoing curative-intent surgical resection. Survival rates in our series are comparable to those reported from other thoracic surgery centres.

Effects of diet type on establishment of pregnancy and embryo development in beef heifers.

The objectives were to determine the effects of elevated blood urea concentrations on: (i) the response to superovulation, fertilisation rate, and early embryonic development in beef heifers, and (ii) embryo survival from days 7 to 35 of gestation. In Experiment 1, heifers (18-24 months) were allocated at random (n=20 per treatment) to one of the following diets: (i) ad libitum grass silage plus 5 kg commercial beef concentrates per day (controls); (ii) ad libitum grass silage plus 5 kg concentrates and 250 g feed grade urea per day (HE/HU); or (iii) ad libitum wheaten straw plus 250 g feed grade urea and 50 g vitamin/mineral mix per day (LE/HU). Serum urea concentrations were monitored throughout the experiment. Oestrus in heifers was synchronised using an intravaginal releasing device (CIDR(®), InterAg, New Zealand). Oestrus was detected and in vitro produced blastocysts (day 7, morphological grades 1 and 2) were transferred to the heifers 7 days later (19 days after start of treatment diets). The heifers were maintained on the dietary treatments for a further 28 days, when pregnancy status was determined by transrectal ultrasonography. Detected pregnancies were terminated using 15 mg luprostiol and recycled for Experiment 2. In Experiment 2, following a 14-day dietary rest period, the heifers were re-allocated at random to the three dietary treatments above. Heifers were treated with a CIDR for 8 days and 15 mg luprostiol was given 12h before pessary withdrawal. They received 144 mg pFSH (Folltropin(®)-V, Vetrepharm, Canada) given as 8 injections over 4 days commencing on day 6 of CIDR/dietary treatment. Heifers were artificially inseminated 48 h after progesterone pessary withdrawal using commercial semen of proven fertility by a competent inseminator. The heifers were maintained on their diets until slaughter, 3 days post insemination when corpora lutea numbers were determined and embryos were recovered and cell numbers determined visually. Serum urea concentrations were greater in heifers on LE/HU than in those on HE/HU diets, which in turn were greater than controls (7.1 ± 0.5, 4.9 ± 0.3 and 3.2 ± 0.1 mmol/L, respectively; P<0.05). There was no effect of diet type on pregnancy rate at day 35 (42%, 47% and 46%) and on the number of corpora lutea following superovulation (5.2 ± 0.8, 5.8 ± 1.5 and 6.8 ± 1.1) for heifers on control, HE/HU and LE/HU diets, respectively. The total number of embryos recovered per heifer was not different between the three groups (2.7 ± 0.6, 3.4 ± 1.1 and 4.8 ± 0.8 for heifers on control, HE/HU and LE/HU diets, respectively; P>0.05), but the number of embryos with 8 or more cells at recovery was greater in heifers on LE/HU than on control diets (3.4 ± 0.8 compared with 1.0 ± 0.3; P<0.05). However the percentage of embryos recovered with 8 or more cells was not different between groups (70.0 ± 13.3, 86.9 ± 7.2 and 76.5 ± 7.9%, for heifers on control, HE/HU and LE/HU diets respectively). Fertilisation rate, expressed as the proportion of embryos with more than one cell at recovery relative to the total number of embryos recovered, was less in the heifers on the control diet than in the other two dietary treatments (61.3 ± 11.8, 92.0 ± 3.5 and 86.8 ± 5.4% for heifers on control, HE/HU and LE/HU diets, respectively; P<0.05). Deleterious effects of urea on reproduction were not found, suggesting that adverse effects of urea are likely to take place at the early oocyte development stage prior to ovulation or fertilisation following an increase in protein intake.

Effects of hydrolysis on solid-state relaxation and stickiness behavior of sodium caseinate-lactose powders.

Hydrolyzed or nonhydrolyzed sodium caseinate-lactose dispersions were spray dried, at a protein: lactose ratio of 0.5, to examine the effects of protein hydrolysis on relaxation behavior and stickiness of model powders. Sodium caseinate (NC) used included a nonhydrolyzed control (DH 0) and 2 hydrolyzed variants (DH 8.3 and DH 15), where DH = degree of hydrolysis (%). Prior to spray drying, apparent viscosities of liquid feeds (at 70°C) at a shear rate of 20/s were 37.6, 3.14, and 3.19 mPa·s, respectively, for DH 0, DH 8, and DH 15 dispersions. Powders containing hydrolyzed casein were more susceptible to sticking than those containing intact NC. The former had also lower bulk densities and powder particle sizes. Scanning electron microscopy showed that hydrolyzed powders had thinner particle walls and were more friable than powders containing intact NC. Secondary structure of caseinates, determined by Fourier transform infrared spectroscopy, was affected by the relative humidity of storage and the presence of lactose as co-solvent rather than its physical state. Glass transition temperatures and lactose crystallization temperatures, determined by differential scanning calorimetry were not affected by caseinate hydrolysis, although the effects of protein hydrolysis on glass-rubber transitions (T(gr)) could be determined by thermo-mechanical analysis. Powders containing hydrolyzed NC had lower T(gr) values (~30°C) following storage at a higher subcrystallization relative humidity (33%) compared with powder with nonhydrolyzed NC (T(gr) value of ~40°C), an effect that reflects more extensive plasticization of powder matrices by moisture. Results support that sodium caseinate-lactose interactions were weak but that relaxation behavior, as determined by the susceptibility of powder to sticking, was affected by hydrolysis of sodium caseinate.

The association between resting and mild-to-moderate exercise pulmonary artery pressure.

The mean pulmonary artery pressure (P(pa)) achieved on mild-to-moderate exercise is age related and its haemodynamic correlates remain to be documented in patients free of pulmonary hypertension (PH). Our retrospective study involved patients free of PH investigated in our centre for possible pulmonary vascular disease between January 1, 2007 and October 31, 2009 who underwent right heart catheterisation at rest and during supine exercise up to 60 W. The 38 out of 99 patients aged <50 yrs were included and a P(pa) of 30 mmHg was considered the upper limit of normal on exercise. The 24 subjects who developed P(pa)>30 mmHg on exercise had higher resting P(pa) (19±3 versus 15±4 mmHg) and indexed pulmonary vascular resistance (PVRi; 3.4±1.5 versus 2.2±1.1 WU·m(2); p<0.05) than the remaining 14 subjects. Resting P(pa) >15 mmHg predicted exercise P(pa) >30 mmHg with 88% sensitivity and 57% specificity. The eight patients with resting P(pa) 22-24 mmHg all had exercise P(pa) >30 mmHg. In subjects aged <50 yrs investigated for possible pulmonary vascular disease and free of PH, patients with mild-to-moderate exercise P(pa) >30 mmHg had higher resting PVRi and higher resting P(pa), although there was no resting P(pa) threshold value that could predict normal response on mild-to-moderate exercise. The clinical relevance of such findings deserves further long-term follow-up studies.