Screening for - and prevalence of - anxiety and depression in cardiac rehabilitation in the post-COVID era. An observational study.

BACKGROUND: Approximately 20-30% of patients with a cardiac disease suffer from anxiety and/or depression, leading to poor health outcomes. To identify this subgroup, clinical guidelines recommend screening for anxiety and depression in cardiac rehabilitation (CR). It is unknown how screening practice is delivered post-COVID. METHODS: This observational study used data from the National Audit of Cardiac Rehabilitation from April 2018-March 2022. Descriptive statistics were used to assess screening rates and prevalence, while a multivariate logistic regression model was performed to analyse determinants for screening for anxiety and depression among patients participating in cardiac rehabilitation. RESULTS: The population consisted of 245,705 patients, where 128,643 (52.4%) were screened and 117,062 (47.6%) were not. Patients attending CR during first year of COVID-19 were less likely to be screened. Patients with female gender, living alone, non-white ethnicity, living in the most deprived areas, current smoking, and physical inactivity were less likely to be screened, while patients who were revascularized, having an objective physical fitness test, and attending a certified CR center were more likely to be screened. For patients attending CR during COVID-19, the prevalence of anxiety and depression decreased significantly. For anxiety the prevalence dropped from 34.4% to 15.8%, for depression the prevalence dropped from 33.5% to 16.5%. CONCLUSION: CR service provision was negatively impacted during COVID-19, leading to much lower screening for anxiety and depression in the CR setting. Prevalence of anxiety and depression decreased during COVID-19 for this population, possibly because psychologically affected patients refrained from attending CR.

A case report of granulomatous lymphomatoid papulosis.

Lymphomatoid papulosis is a chronic CD30-positive cutaneous lymphoproliferative disorder that is characterized by recurring red-brown necrotic papules. It exhibits a wide spectrum of histopathologic findings and is often associated with cutaneous T-cell lymphomas. Six different histological subtypes have been classified by the WHO, but there is limited understanding regarding rare histopathologic variants. We describe a 51-year-old man who presented with recurring, necrotic papules for 6 years that progressed to involve the face, scalp, trunk, axilla, and scrotum. Histopathology demonstrated sarcoidal granulomas, along with a CD30-positive T cell infiltrate which demonstrated clonality by T cell receptor gamma gene rearrangement. A diagnosis of lymphomatoid papulosis associated with granulomas was established based on the clinical and histopathologic presentation. The clinical understanding of granulomatous lymphomatoid papulosis is limited in the available literature and more awareness of this histopathologic variant is required for accurate classification of this disorder.

Systematic screening for anxiety and depression in cardiac rehabilitation - are we there yet?

BACKGROUND: Anxiety and depression are prevalent in 20% of patients with acute coronary syndrome (ACS) and associated with poor outcomes. Guidelines recommend screening for these conditions in cardiac rehabilitation (CR) however, clinical practice is inconsistent. Sparse knowledge exists on determinants for screening. METHODS: This observational study used data from the National Audit of Cardiac Rehabilitation from January 2016-December 2019. A multivariate logistic regression model was performed to analyze patient- and provider level determinants for screening for anxiety and depression among patients with ACS. RESULTS: The population consisted of 138,018 patients, where 82,507 (59.8%) were screened and 55,511 (40.2%) were not. Younger age, non-white ethnicity, living in areas of social deprivation, current smoking, body mass index>30, and physical activity<150 min per week were negatively correlated with patients being screened. Compared to patients having a percutaneous coronary intervention, patients undergoing coronary artery bypass grafting or medical treatment were less likely to be screened. History of anxiety, depression, osteoporosis, chronic back problems, and asthma were positively correlated with screening, while chronic obstructive pulmonary disease, diabetes, hypertension, and stroke were negatively correlated with screening. Regarding provider level, certification of CR centers was positively associated with screening, while looking over time data showed an incremental negative trend in screening from 2016 to 2019. CONCLUSION: We found both patient and provider level determinants of screening for anxiety and depression. Clinical practice is still inconsistent especially for high-risk groups. We recommend systematic screening to enable tailored interventions which in turn may mitigate inequity in health outcomes.

Intensive care unit physician-delivered point of care renal tract ultrasound in acute kidney injury is feasible.

Acute kidney injury is common in critically ill patients, with ultrasound recommended to exclude renal tract obstruction. Intensive care unit clinicians are skilled in acquiring and interpreting ultrasound examinations. Intensive Care Medicine Trainees wish to learn renal tract ultrasound. We sought to demonstrate that intensive care unit clinicians can competently perform renal tract ultrasound on critically ill patients. Thirty patients with acute kidney injury were scanned by two intensive care unit physicians using a standard intensive care unit ultrasound machine. The archived images were reviewed by a Radiologist for adequacy and diagnostic quality. In 28 of 30 patients both kidneys were identified. Adequate archived images of both kidneys each in two planes were possible in 23 of 30 patients. The commonest reason for failure was dressings and drains from abdominal surgery. Only one patient had hydronephrosis. Our results suggest that intensive care unit clinicians can provide focussed renal tract ultrasound. The low incidence of hydronephrosis has implications for delivering the Core Ultrasound in Intensive Care competencies.

Does the mode of delivery in routine cardiac rehabilitation have an association with cardiovascular risk factor outcomes?

AIMS: Cardiac rehabilitation is one of the most cost-effective interventions for patients with cardiovascular disease. Worldwide supervised group-based cardiac rehabilitation is the dominant mode of delivery followed by facilitated self-managed (FSM), which is emerging as part of a cardiac rehabilitation menu. Modern research evidence, using trials and well-resourced interventions, suggests FSM is comparable to supervised rehabilitation in its outcomes for patients; however, this is yet to be established using routine clinical practice data. METHODS: Including 81,626 patients from routine clinical data in the National Audit of Cardiac Rehabilitation, this observational study investigated whether mode of delivery, supervised or FSM, was associated with similar cardiac rehabilitation outcomes. Hierarchical regression models included patient and service covariates such as age, gender, cardiac rehabilitation duration and programme staff type. RESULTS: The results showed 85% of the population received supervised cardiac rehabilitation. The FSM group were significantly older, female and predominantly in lower socioeconomic groups. The results showed that all patients on average benefit from cardiac rehabilitation, independently of mode of delivery, across all risk factors. Additional benefit of 13% and 11.4% increased likelihood of achieving the target state for physical activity and body mass index respectively when using FSM approaches. CONCLUSION: This is the first study to investigate traditional cardiovascular risk factors with cardiac rehabilitation mode of delivery using routine clinical data. Both modes of delivery were associated with comparable statistically significant positive outcomes. Despite having equivalent outcomes, FSM cardiac rehabilitation continues to be underutilised, with less than 20% of patients receiving this mode of delivery in the UK.

Proton Mobility in b2 Ion Formation and Fragmentation Reactions of Histidine-Containing Peptides.

A detailed energy-resolved study of the fragmentation reactions of protonated histidine-containing peptides and their b2 ions has been undertaken. Density functional theory calculations were utilized to predict how the fragmentation reactions occur so that we might discern why the mass spectra demonstrated particular energy dependencies. We compare our results to the current literature and to synthetic b2 ion standards. We show that the position of the His residue does affect the identity of the subsequent b2 ion (diketopiperazine versus oxazolone versus lactam) and that energy-resolved CID can distinguish these isomeric products based on their fragmentation energetics. The histidine side chain facilitates every major transformation except trans-cis isomerization of the first amide bond, a necessary prerequisite to diketopiperazine b2 ion formation. Despite this lack of catalyzation, trans-cis isomerization is predicted to be facile. Concomitantly, the subsequent amide bond cleavage reaction is rate-limiting.

Using gas-phase guest-host chemistry to probe the structures of b ions of peptides.

Middle-sized b(n) (n ≥ 5) fragments of protonated peptides undergo selective complex formation with ammonia under experimental conditions typically used to probe hydrogen-deuterium exchange in Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). Other usual peptide fragments like y, a, a*, etc., and small b(n) (n ≤ 4) fragments do not form stable ammonia adducts. We propose that complex formation of b(n) ions with ammonia is characteristic to macrocyclic isomers of these fragments. Experiments on a protonated cyclic peptide and N-terminal acetylated peptides fully support this hypothesis; the protonated cyclic peptide does form ammonia adducts while linear b(n) ions of acetylated peptides do not undergo complexation. Density functional theory (DFT) calculations on the proton-bound dimers of all-Ala b(4), b(5), and b(7) ions and ammonia indicate that the ionizing proton initially located on the peptide fragment transfers to ammonia upon adduct formation. The ammonium ion is then solvated by N(+)-H…O H-bonds; this stabilization is much stronger for macrocyclic b(n) isomers due to the stable cage-like structure formed and entropy effects. The present study demonstrates that gas-phase guest-host chemistry can be used to selectively probe structural features (i.e., macrocyclic or linear) of fragments of protonated peptides. Stable ammonia adducts of b(9), b(9)-A, and b(9)-2A of A(8)YA, and b(13) of A(20)YVFL are observed indicating that even these large b-type ions form macrocyclic structures.

Fragmentation reactions of b(5) and a (5) ions containing proline--the structures of a(5) ions.

A detailed study has been made of the b(5) and a(5) ions derived from the amides H-Ala-Ala-Ala-Ala-Pro-NH(2), H-Ala-Ala-Ala-Pro-Ala-NH(2), and H-Ala-Ala-Pro-Ala-Ala-NH(2). From quasi-MS(3) experiments it is shown that the product ion mass spectra of the three b(5) ions are essentially identical, indicating macrocyclization/reopening to produce a common mixture of intermediates prior to fragmentation. This is in agreement with numerous recent studies of sequence scrambling in b ions. By contrast, the product ion mass spectra for the a(5) ions show substantial differences, indicating significant differences in the mixture of structures undergoing fragmentation for these three species. The results are interpreted in terms of a mixture of classical substituted iminium ions as well as protonated C-terminal amides formed by cyclization/rearrangement as reported recently for a(4) ions (Bythell, Maître , Paizs, J . Am. Chem. Soc. 2010, 132, 14761-14779). Novel fragment ions observed upon fragmentation of the a(5) ions are protonated H-Pro-NH(2) and H-Pro-Ala-NH(2) which arise by fragmentation of the amides. The observation of these products provides strong experimental evidence for the cyclization/rearrangement reaction to form amides and shows that it also applies to a(5) ions.

Effect of the identity of Xaa on the fragmentation modes of doubly-protonated Ala-Ala-Xaa-Ala-Ala-Ala-Arg.

The product ion mass spectra resulting from collisional activation of doubly-protonated tryptic-type peptides Ala-Ala-Xaa-Ala-Ala-Ala-Arg have been determined for Xaa = Ala(A), Ser(S), Val(V), Thr(T), Ile(I), Phe(F), Tyr(Y), Sar, Met(M), Trp(W), Pro(P), and Gln(Q). The major fragmentation reaction involves cleavage of the second amide bond (counting from the N-terminus) except for Xaa = Ser and Thr where elimination of H(2)O from the [M + 2H](+2) ion forms the base peak. In general, the extent of cleavage of the second amide bond shows little dependence on the identity of Xaa and little dependence on whether the bond cleavage involves symmetrical bond cleavage to form a y(5)/b(2) ion pair or asymmetrically to form y (5) (+2) and a neutral b(2) species. Notable exceptions to this generalization occur for Xaa equal to Pro or Sar. For Xaa = Pro only cleavage of the second amide bond is observed, consistent with a pronounced proline effect, i.e., cleavage N-terminal to Pro. When Xaa = Sar considerably enhanced cleavage of the second amide bond also is observed, suggesting that at least part of the proline effect relates to the tertiary nature of the amide nitrogen. In the competition between symmetric and asymmetric bond cleavage an attempt to establish a linear free energy correlation in relating ln(y(5)(+2)/y(5)) to PA(H-Xaa-OH) did not lead to a reasonable correlation although the trend of increasing y(5)(+2)/y(5) ratio with increasing proton affinity of H-Xaa-OH was clear. Proline showed a unique behavior in giving a much higher y(5)(+2)/y(5) ratio than any of the other residues studied.

Effect of the His residue on the cyclization of b ions.

The MS(n) spectra of the [M + H](+) and b(5) peaks derived from the peptides HAAAAA, AHAAAA, AAHAAA, AAAHAA, and AAAAHA have been measured, as have the spectra of the b(4) ions derived from the first four peptides. The MS(2) spectra of the [M + H](+) ions show a substantial series of b(n) ions with enhanced cleavage at the amide bond C-terminal to His and substantial cleavage at the amide bond N-terminal to His (when there are at least two residues N-terminal to the His residue). There is compelling experimental and theoretical evidence for formation of nondirect sequence ions via cyclization/reopening chemistry in the CID spectra of the b ions when the His residue is near the C-terminus. The experimental evidence is less clear for ions when the His residue is near the N-terminus, although this may be due to the use of multiple alanine residues in the peptide making identifying scrambled peaks more difficult. The product ion mass spectra of the b(4) and b(5) ions from these isomeric peptides with cyclically permuted amino acid sequences are similar, but also show clear differences. This indicates less active cyclization/reopening followed by fragmentation of common structures for b(n) ions containing His than for sequences of solely aliphatic residues. Despite more energetically favorable cyclization barriers for the b(5) structures, the b(4) ions experimental data show more clear evidence of cyclization and sequence scrambling before fragmentation. For both b(4) and b(5) the energetically most favored structure is a macrocyclic isomer protonated at the His side chain.

Cyclization of peptide b9 ions.

The product ion mass spectra obtained by CID of the b(9) ions derived by loss of neutral alanine from the MH+ ion of the peptides Tyr(Ala)9, (Ala)4Tyr(Ala)5, and (Ala)8TyrAla are essentially identical, indicative of full cyclization reaction to a common intermediate before fragmentation. This leads to abundant nondirect sequence ions in the product ion mass spectra of the b9 ions. The product ion mass spectra of the b8 ions from the first two peptides also are essentially identical. The fragmentation of the MH+ ions also leads to low intensity nondirect sequence ions in the product ion mass spectra. N-terminal acetylation blocks the cyclization and eliminates nondirect sequence fragment ions in the product ion mass spectra.

To b or not to b: the ongoing saga of peptide b ions.

Modern soft ionization techniques readily produce protonated or multiply protonated peptides. Collision-induced dissociation (CID) of these protonated species is often used as a method to obtain sequence information. In many cases fragmentation occurs at amide bonds. When the charge resides on the C-terminal fragment so-called y ions are produced which are known to be protonated amino acids or truncated peptides. When the charge resides on the N-terminal fragment so-called b ions are produced. Often the sequence of y and b ions are essential for peptide sequencing. The b ions have many possible structures, a knowledge of which is useful in this sequencing. The structures of b ions are reviewed in the following with particular emphasis on the variation of structure with the number of amino acid residues in the b ion and the effect of peptide side chain on b ion structure. The recent discovery of full cyclization of larger b ions results in challenges in peptide sequencing. This aspect is discussed in detail.

Fragmentation reactions of some peptide b3 ions: an energy-resolved study.

The fragmentation reactions of b3 ions of nominal structure AAAoxa, YAAoxa, AYAoxa and AAYoxa have been studied as a function of collision energy, allowing the construction of breakdown graphs expressing in a qualitative way the energy dependence of the fragmentation reactions. The primary fragmentation reactions of the AAAoxa b3 ion involve formation of the a3* (a3-NH3) ion and the b2 ion, with the latter becoming the dominant product at higher internal energies. For both YAAoxa and AYAoxa b3 ions the pathway to a3* is relatively minor with formation of b2 the dominant primary fragmentation reaction. For the AAYoxa b3 ion, in addition to a3*, abundant formation of the tyrosine (Y) iminium ion is observed with only minor formation of the b2 ion. The results support and expand upon the detailed mechanism of fragmentation of b3 ions proposed by Cooper et al. (J. Am. Soc. Mass Spectrom. 2006; 17: 1654).

Scrambling of sequence information in collision-induced dissociation of peptides.

Collision-induced dissociation (CID) of protonated YAGFL-NH2 leads to nondirect sequence fragment ions that cannot directly be derived from the primary peptide structure. Experimental and theoretical evidence indicate that primary fragmentation of the intact peptide leads to the linear YAGFLoxa b5 ion with a C-terminal oxazolone ring that is attacked by the N-terminal amino group to induce formation of a cyclic peptide b5 isomer. The latter can undergo various proton transfer reactions and opens up to form something other than the YAGFLoxa linear b5 isomer, leading to scrambling of sequence information in the CID of protonated YAGFL-NH2.

Fragmentation reactions of deprotonated peptides containing proline. The proline effect.

The collision-induced dissociation (CID) fragmentation reactions of a variety of deprotonated peptides containing proline have been studied in detail using MS(2) and MS(3) experiments, deuterium labelling and accurate mass measurements when necessary. The [M--H--CO(2)](-) (a(2)) ion derived from H-Pro-Xxx-OH dipeptides shows an unusual fragmentation involving loss of C(2)H(4); this fragmentation reaction is not observed for larger peptides. The primary fragmentation reactions of deprotonated tripeptides with an N-terminal proline are formation of a(3) and y(1) ions. When proline is in the central position of tripeptides, a(3), y(2) and y(1) ions are the primary fragmentation products of [M--H](-), while when the proline is in the C-terminal position, a(3)and y(1) ions are the major primary products. In the latter case, the a(3) ion fragments primarily to the ''b(2) ion; further evidence is presented that the ''b(2) ions have a deprotonated oxazolone structure. Larger deprotonated peptides having at least two amino acid residues N-terminal to proline show a distinct preference for cleavage of the amide bond N-terminal to proline to form, mainly, the appropriate y ion. This proline effect is compared and contrasted with the similar proline effect observed in the fragmentation of protonated peptides containing proline.

Site of alkylation of N-methyl- and N-ethylaniline in the gas phase: a tandem mass spectrometric study.

N-Methylaniline (NMA) was ethylated and N-ethylaniline (NEA) was methylated under chemical ionization conditions using C(2)H(5)I and CH(3)I, respectively, as reagent gases. The structures of the resulting m/z 136 adduct ions have been probed using metastable ion and collision-induced dissociation (CID) methods. From the similarity of the spectra obtained and from the presence of structure-diagnostic ions at m/z 59 (CH(3)NHC(2)H(5) (+*)) and m/z 44 (CH(3)NHCH(2) (+)), it is concluded that predominantly N-alkylation occurs in both systems. This interpretation was aided by the use of C(2)D(5)I and CD(3)I as reagents. Adduct ions of m/z 136 were also formed by ethylation of the isomeric toluidines and by methylation of the ring-ethylanilines. The resulting CID mass spectra were distinctly different from those obtained for the m/z 136 ions obtained by alkylation of NMA and NEA. Protonation of N-ethyl-N-methylaniline using CH(3)C(==O)CH(3) as Brønsted acid reagent produced an m/z 136 species whose CID mass spectrum also featured intense ion signals at m/z 59 and 44. This observation led to the conclusion that protonation with acetone as reagent results, in this case, in dominant N-protonation. However, the CID mass spectrum of the m/z 136 ion formed when CH(3)OH was the protonating agent featured a weak signal at m/z 44 and no signal at m/z 59. Hence it was concluded that the latter m/z 136 ion contains a larger contribution from the ring-protonated adduct.

Fragmentation of deprotonated N-benzoylpeptides: formation of deprotonated oxazolones.

The fragmentation reactions of deprotonated N-benzoyl peptides, specifically hippurylglycine, hippurylglyclyclycine, and hippurylphenylalanine (hippuryl = N-benzoylGly) have been studied using MS2 and MS3 experiments as well as deuterium labeling. A major fragment ion is observed at m/z 160 ([C9H6NO2]-) which, upon collisional activation, mainly eliminates CO2 indicating that the two oxygen atoms have become bonded to the same carbon. This observation is rationalized in terms of formation of deprotonated 2-phenyl-5-oxazolone. Various pathways to the deprotonated oxazolone have been elucidated through MS3 experiments. Fragmentation of deprotonated N-acetylalanylalanine gives a relatively weak signal at m/z 112 which, upon collisional activation, fragments, in part, by loss of CO2 leading to the conclusion that the m/z 112 ion is deprotonated 2,4-dimethyl-5-oxazolone.

Amide bond cleavage in deprotonated tripeptides: a newly discovered pathway to "b2 ions.

The fragmentation reactions of the [M-H](-) ions of the tripeptides H-Gly-Leu-Sar-OH, H-Leu-Gly-Pro-OH and H-Gly-Leu-Gly-OH have been investigated in detail using energy-resolved mass spectrometry, isotopic labelling and MS(3) experiments. It is shown that the major route to the "b(2) ions involves loss of a neutral amine from the a(3) ([M-H-CO(2)](-)) ion rather than being formed directly by fragmentation of the [M-H](-) ion. When there is no C-terminal amidic hydrogen (Sar, Pro), loss of a neutral amine is the dominant primary fragmentation reaction of the a(3) ion. However, when there is a C-terminal amidic hydrogen (Gly), elimination of the N-terminal amino acid residue is the major fragmentation reaction of the a(3) ion and formation of the "b(2) ion is greatly reduced in importance. It is proposed that the "b(2) ions are deprotonated oxazolones.