Prevention and early treatment of the long-term physical effects of COVID-19 in adults: design of a randomised controlled trial of resistance exercise-CISCO-21.

BACKGROUND: Coronavirus disease-19 (COVID-19) infection causes persistent health problems such as breathlessness, chest pain and fatigue, and therapies for the prevention and early treatment of post-COVID-19 syndromes are needed. Accordingly, we are investigating the effect of a resistance exercise intervention on exercise capacity and health status following COVID-19 infection. METHODS: A two-arm randomised, controlled clinical trial including 220 adults with a diagnosis of COVID-19 in the preceding 6 months. Participants will be classified according to clinical presentation: Group A, not hospitalised due to COVID but persisting symptoms for at least 4 weeks leading to medical review; Group B, discharged after an admission for COVID and with persistent symptoms for at least 4 weeks; or Group C, convalescing in hospital after an admission for COVID. Participants will be randomised to usual care or usual care plus a personalised and pragmatic resistance exercise intervention for 12 weeks. The primary outcome is the incremental shuttle walks test (ISWT) 3 months after randomisation with secondary outcomes including spirometry, grip strength, short performance physical battery (SPPB), frailty status, contacts with healthcare professionals, hospitalisation and questionnaires assessing health-related quality of life, physical activity, fatigue and dyspnoea. DISCUSSION: Ethical approval has been granted by the National Health Service (NHS) West of Scotland Research Ethics Committee (REC) (reference: GN20CA537) and recruitment is ongoing. Trial findings will be disseminated through patient and public forums, scientific conferences and journals. TRIAL REGISTRATION: ClinicialTrials.gov NCT04900961 . Prospectively registered on 25 May 2021.

Screening for anxiety and depression in cancer patients: the effects of disease and treatment.

The General Health Questionnaire 28 (GHQ 28), Hospital Anxiety and Depression Scale (HADS), and Rotterdam Symptom Checklist (RSCL) seemed promising in their ability to detect anxiety and depression in cancer patients. To compare their screening performance, 513 patients were recruited from four cancer centres, and visited at home by a trained interviewer. Paired combinations of questionnaires (GHQ 28 + HADS, GHQ 28 + RSCL or RSCL+HADS) were used, and then the Psychiatric Assessment Schedule was administered to enable a psychiatric diagnosis to be made using DSM III diagnostic criteria. A receiver operating characteristics curve was drawn by plotting the true positive rate (sensitivity) against the false positive rate (1-specificity) for each possible score on each questionnaire. In the overall sample, the HADS and RSCL performed well comparably. The HADS did best in those free of disease and when the disease was judged to be stable. Only the RSCL performed well in those with progressive disease. Both the HADS and RSCL were effective in those on treatment. The GHQ was superior to the RSCL in those off treatment. The choice of questionnaire and threshold score should take disease and treatment status into account, but all three questionnaires have a definite role in screening out anxiety and depression.

Effect of chronic ethanol treatment in vivo on excitability in mouse cortical neurones in vitro.

1. The effects of cessation of chronic ethanol ingestion on seizure activity in vivo and on the characteristics of the evoked synaptic potentials in cortical neurones in vitro have been investigated in mice. Withdrawal from chronic ethanol treatment increased handling seizure ratings in mice between 4 and 16 h post-withdrawal. This ethanol-induced increase in seizure rating was unaffected by carbamazepine (30 mg kg(-1)) but significantly reduced at a higher concentration (130 mg kg(-1)). 2. Intracellular recordings were made from cortical layer II neurones in vitro from control mice and from mice following chronic ethanol ingestion. Evoked synaptic potentials were generated in these neurones through intralaminar stimulation. 3. Neurones from control mice displayed an evoked potential consisting of a fast excitatory postsynaptic potential (e.p.s.p.) mediated by AMPA-type glutamate receptors and an inhibitory postsynaptic potential (i.p.s.p.) mediated via GABA(A) receptors. Application of pentylenetetrazole (PTZ) or bicuculline onto these neurones inhibited the i.p.s.p., caused a large increase in both the amplitude and duration of the e.p.s.p. and initiated spontaneous excitatory activity. The resulting large evoked e.p.s.p. was mediated via both NMDA- and AMPA-type glutamate receptors. 4. Most neurones (77%) from ethanol treated mice displayed an evoked potential which comprised a large e.p.s.p. and no i.p.s.p. The e.p.s.p. consisted of several distinct components and in addition these neurones displayed spontaneous paroxysmal depolarizing shifts. This multi-component e.p.s.p. was mediated through both NMDA- and AMPA-type glutamate receptors. A population (23%) of neurones from ethanol treated mice exhibited evoked potentials which possessed both inhibitory and excitatory components and these neurones were effectively identical to those obtained from control mice. 5. Carbamazepine reduced the duration of the e.p.s.p. in neurones from ethanol treated mice and in PTZ-treated control neurones. 6. Prolonged ethanol ingestion is known to create a neurochemical imbalance in cortical neurones resulting in abnormal neurotransmission. The present study highlights the functional consequences that arise as a result of these neurochemical changes leading to over-excitation of neurones and pronounced epileptiform activity.

Antagonism of levcromakalim by imidazoline- and guanidine-derivatives in rat portal vein: involvement of the delayed rectifier.

1. In rat whole portal veins, guanabenz (100 nM to 10 microM) and antazoline (100 nM to 100 microM) each increased the amplitude, frequency and duration of spontaneous contractions. In addition, guanabenz (30 microM) and antazoline (30 microM) each antagonized the ability of levcromakalim (3 nM to 10 microM) to inhibit the spontaneous contractions of this tissue. 2. Whole-cell voltage-clamp recordings were made from freshly-isolated rat portal vein cells dispersed by a collagenase/pronase enzyme treatment. The ability of several agents (antazoline, cirazoline, clonidine, guanabenz and phentolamine, each containing an imidazoline or guanidine moiety), to modulate potassium (K) currents and to inhibit the actions of levcromakalim was investigated. 3. Antazoline, cirazoline, clonidine, guanabenz and phentolamine (each at a concentration of 30 microM) had little effect on control non-inactivating currents but inhibited the delayed-rectifier current, IK(V). 4. Levcromakalim (1 microM) induced a non-inactivating current, IK(ATP), and also inhibited the delayed rectifier current, IK(V). 5. Glibenclamide (1 microM) had no effect on control delayed rectifier or non-inactivating currents, but it inhibited the simultaneous induction of IK(ATP) and reduction of IK(V) produced by levcromakalim (1 microM). 6. Antazoline, cirazoline, clonidine and guanabenz (each at a concentration of 30 microM) prevented the induction of IK(ATP) by levcromakalim (1 microM). Phentolamine (30 microM) and clonidine (30 microM) each inhibited the IK(ATP) generated by levcromakalim (1 microM). 7. It is concluded that a variety of agents which possess either an imidazoline (antazoline, cirazoline, clonidine and phentolamine) or a guanidine (guanabenz) moiety within their structure inhibit the delayed rectifier current, IK(V). This action may thus be mediated via a so-called non-adrenoceptor imidazoline binding site. Furthermore, the ability of these ligands to inhibit IK(V) and to antagonize both the induction of IK(ATP) and the vasorelaxation produced by levcromakalim is consistent with the view that the channel (KATP) which underlies IK(ATP) is a voltage-insensitive state of the delayed rectifier K-channel (Kv).

Levcromakalim may induce a voltage-independent K-current in rat portal veins by modifying the gating properties of the delayed rectifier.

1. Smooth muscle cells of the rat portal vein were dispersed by enzymatic treatment and recordings of whole-cell currents under calcium-free conditions were made by the voltage-clamp technique. The effects of the potassium (K)-channel opener, levcromakalim, on K-currents were compared with those of agents which modify protein phosphorylation. 2. Levcromakalim (1-10 microM) added to the extracellular (bath) fluid caused the development of a non-inactivating current (IK(ATP)) and simultaneously inhibited the delayed rectifier current (IK(V)) in a concentration-dependent manner. On prolonged exposure to levcromakalim (10 microM), IK(ATP) declined and IK(V) was further diminished. 3. Addition to the pipette (intracellular) solution of the selective inhibitor of protein kinase C, calphostin C, itself had no effect on K-currents and did not modify the induction of IK(ATP) or the simultaneous inhibition of IK(V) produced by 1 microM levcromakalim. 4. Addition of the protein kinase inhibitor (PKI(6-22)amide, 1 microM) to the pipette solution caused the production of a glibenclamide-sensitive, non-inactivating current and inhibited IK(V). 5. In an assay system, levcromakalim (10 microM) did not inhibit the activity of purified protein kinase A (Type 1 or Type 2). 6. Addition to the pipette solution of the phosphatase inhibitor, okadaic acid (1 microM), did not itself modify K-currents and had little effect on the simultaneous induction of IK(ATP) and inhibition of IK(V) by levcromakalim (1 microM). 7. When the pipette solution contained 1 mM MgATP (but was depleted of substrates for ATP production), a non-inactivating, glibenclamide-sensitive K-current developed spontaneously in 5 out of 11 cells with the simultaneous reduction of IK(V). In 3 of the 6 remaining cells, addition of the dephosphorylating agent, butanedione monoxime (5 mM) to the bath inhibited IK(V) and stimulated a glibenclamide-sensitive non-inactivating current. 8. Depletion of intracellular Mg2+ slightly enhanced IK(V). Under these conditions, levcromakalim (1 microM and 10 microM) did not significantly induce IK(ATP) or inhibit IK(V). 9. It is concluded that the effects of levcromakalim on K-currents can be mimicked by procedures designed to reduce channel phosphorylation. The results are consistent with the view that levcromkalim dephosphorylates the delayed rectifier channel, KV, which becomes converted into a voltage-independent, non-inactivating form known as KATP. The possible mechanisms which underlie this interconversion are discussed.

Effects of P1060 and aprikalim on whole-cell currents in rat portal vein; inhibition by glibenclamide and phentolamine.

1 Smooth muscle cells of the rat portal vein were dispersed by enzymatic treatment and recordings of whole-cell currents were made by the voltage-clamp technique. The effects of the potassium (K) channel openers, P1060 (0.3-10 microM) and aprikalim (3-30 microM) on these currents were investigated. Antagonism of these agents by glibenclamide and phentolamine was also studied. 2 When cells were clamped at -10 mV, P1060 (1 microM) and aprikalim (3 microM) each induced a slowly-developing K-current (IKCO), the noise of which gradually increased. The rate of onset of IKCO was greater for P1060 than for aprikalim. Current-voltage plots showed that P1060 and aprikalim each caused an approximately 25 mV negative shift of the reversal potential at zero current. 3 P1060 (1 microM) and aprikalim (3 microM) each inhibited the slowly activating, slowly inactivating delayed rectifier current, ITO. 4 Addition of MgATP (5 mM) to the recording pipette inhibited the generation of IKCO by P1060 (1 microM) and reduced the accompanying inhibition of ITO. 5 Stationary fluctuation analysis of the current noise associated with IKCO induced by P1060 (1 microM) or aprikalim (3 microM) at a holding potential of -10 mV indicated that the unitary conductance of the underlying K-channels was 10.5 pS at 0 mV under the quasi-physiological conditions of the experiment. 6 In the absence of K-channel openers, neither phentolamine (30-100 microM) nor glibenclamide (1 microM) affected the magnitude of control non-inactivating currents. However, phentolamine (30-100 microM), but not glibenclamide (1 microM) inhibited the control delayed rectifier current ITO. 7. After induction of IKCO by P1060 (1 microM) or aprikalim (3 microM), subsequent exposure to glibenclamide(1 microM) or phentolamine (30 microM) inhibited this current. After aprikalim-induced reduction of ITO had developed, subsequent exposure to glibenclamide was able partially to reverse the inhibition of ITO whereas phentolamine was without effect. Pre-exposure to glibenclamide (1 microM) prevented both the generation of IKCO by aprikalim (3 microM) and the inhibitory effect of this agent on ITO.8. It is concluded that P1060 and aprikalim each induce the current IKCO by opening the same small conductance, ATP-sensitive K-channel (KATP), an effect which can be inhibited by glibenclamide orphentolamine. The opening of KATP by both P1060 and aprikalim probably involves competition between these agents and ATP for the ATP-control site associated with the channel. Inhibition of the delayed rectifier current, ITO, by P1060 and aprikalim was glibenclamide-sensitive and may be caused by the induction of a state of run-down in the channel which underlies this current.

Darbepoetin alfa.

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anaemia associated with chronic kidney disease. In single-dose studies in patients undergoing dialysis, the mean terminal half-life for intravenous darbepoetin alfa was approximately 3-fold longer than for intravenous recombinant human erythropoitin (r-HuEPO, epoetin alfa; 25.3 vs 8.5 hours). The mean terminal half-life after subcutaneous administration of darbepoetin alfa was 48.8 hours. In randomised nonblind trials in patients undergoing dialysis, darbepoetin alfa (0.45 pg/kg) given once weekly for the correction of anaemia increased haemoglobin (Hb) levels to a similar extent as darbepoetin alfa three times weekly or r-HuEPO two or three times weekly. A double-blind, randomised clinical trial reported that switching patients from a three-times weekly regimen of r-HuEPO to once weekly darbepoetin alfa with additional placebo twice weekly (all intravenously) maintained Hb levels between 9.0 and 13.0 g/dl to a similar extent as continued treatment with r-HuEPO three times weekly. In a randomised nonblind study, r-HuEPO-naive patients with chronic renal insufficiency received either subcutaneous darbepoetin alfa once weekly or r-HuEPO twice weekly. 93% of patients receiving darbepoetin alfa and 92% of patients receiving r-HuEPO achieved a Hb increase of > or = 1.0 g/dl from baseline and the mean increase in Hb level over the initial 4 weeks was similar for both treatments. The number and frequency of adverse events, withdrawals and deaths reported in clinical trials did not differ between patients receiving darbepoetin alfa and patients receiving r-HuEPO. There have been no reports of immune responses to darbepoetin alfa in 1534 patients receiving treatment for up to 2 years.

Inhibition of KATP channel activity by troglitazone in CRI-G1 insulin-secreting cells.

Patch-clamp recording techniques were used to examine the effect of troglitazone on KATP channel activity in Cambridge rat insulinoma-G1 (CRI-G1) insulin-secreting cells. In both inside-out and outside-out patch recordings, bath application of troglitazone reduced KATP channel activity. This inhibition was independent of the membrane voltage and was poorly reversible. In whole-cell studies, troglitazone inhibited KATP channel currents with an IC50 of 697 +/- 92 nM and an associated Hill coefficient of 1.2 +/- 0.2. In current clamp recordings 10 microM troglitazone depolarised the CRI-G1 cell membrane by 36.8 +/- 3.9 mV with a concomitant decrease in membrane conductance. However, in contrast to the rapid depolarisation produced by tolbutamide, the effects of troglitazone developed more slowly, usually taking 15-20 min to develop.

Uptake of cervical screening in general practice: effect of practice organisation, structure, and deprivation.

OBJECTIVES - To investigate associations between uptake for cervical screening in general practice and the organisation of screening, features of practice structure, and deprivation. SETTING - Greater Glasgow Health Board area in the west of Scotland, which covers a socioeconomically varied population. METHODS - General practice questionnaire survey and interview based study. The main outcome measure was the uptake rate for each participating practice over the five and a half years ending 31 December 1993. This was used to determine whether practices achieved 80% uptake to trigger maximum payment for cervical screening services. RESULTS - Forty seven percent (n = 92) of all practices in the Greater Glasgow Health Board area agreed to take part in the research, with complete data collected for 87 practices. Participation varied according to number of partners in the practice and the average deprivation score of the practice. Uptake rates ranged from 48-2% to 92-9% (median 77.5%, interquartile range 69.8% to 83.4%). Thirty seven practices (43%) achieved the 80% target. None of the recommended features of good organisation of cervical screening showed any statistically significant association with uptake rates. In stepwise multiple regression four variables were shown to have independent associations with uptake. These were the number of partners in the practice, the average deprivation of the practice, the presence of a female general practitioner, and using a practice's own lists for sending out letters of invitation. In stepwise logistic regression just two of these variables contributed to the prediction of achieving 80% uptake namely, average deprivation and number of partners. There were no significant interactions between deprivation and the organisation of screening in relation to uptake. CONCLUSIONS - Organising cervical screening in general practice according to accepted standards is less important in predicting uptake than more intractable features of the practice such as the size of the partnership, its average deprivation level, the presence of a female general practitioner, and using their own (presumed more accurate) register of addresses to call women. A flexible incentive scheme may more fairly reward the efforts of those general practitioners who achieve high uptake rates but who do not trigger remuneration at the 80% level.

Costs and remuneration for cervical screening in general practice in the west of Scotland.

OBJECTIVES: To investigate associations between costs and remuneration for cervical screening in general practice in relation to skill mix, features of practice structure and deprivation levels in the local area; and, to identify efficient policies for organising cervical screening in general practice. METHOD: Questionnaire survey and interview study in 87 general practices in Greater Glasgow Health Board an area in the west of Scotland which covers a socio-economically varied population. The main outcome measures were remuneration to cost ratios (RCRs) for cervical screening and their natural logarithms (logRCRs). RESULTS: Both the costs of cervical screening and RCRs varied widely between the 87 practices taking part. RCRs ranged from 0.29 to 14.67 (mean 2.64, median 2.18, interquartile range 1.15-2.98). Twenty-one per cent (18) of practices earned less than they spent on the organisation of screening, whilst 9% (8) of practices had PCRs of more than 5:1. RCRs were significantly lower if medical staff were involved in either taking smears or dealing with results. RCRs did not vary by social deprivation score, despite uptake being lower in practices in more deprived areas. This was explained by nurses working in practices in deprived areas being more likely to take smears than nurses working in more affluent areas. Sensitivity analyses were undertaken, altering key time and cost assumptions. As a result, the absolute values of the RCRs changed, although the overall pattern of association did not, with the exception of doctor involvement in processing results which was no longer significant when average general practitioners' income was substituted for locum rates. CONCLUSIONS: Practices in deprived areas may be responding to greater pressure of work by making optimal use of skill mix within the primary health care team. A more graduated incentive payment scheme may more fairly reward practices in deprived areas which are less likely to achieve 80% uptake due to relatively intractable features of practice structure. Assuming that practice nurses provide an equivalent quality of service to that provided by general practitioners, results suggest that doctor-nurse substitution would be cost-effective for general practice based cervical screening. Resource savings (principally doctor's time) could be redeployed to other areas of primary health care.

The extent and nature of emergency nurse practitioner services in Scotland.

Emergency Nurse Practitioners (ENPs) are being used in an increasing proportion of A&E departments across England and Wales. This paper reports the findings of a postal survey sent to all (94) A&E departments in Scotland including the smaller GP run units. The aim of the study was to document the extent and nature of ENP services in Scotland. Nurses were found to be practising as ENPs in 47% of Scottish A&E departments. The majority (70%) of nurses practising as ENPs had been educated for the role on courses for ENPs. Nurses working as ENPs were being paid at all grades ranging from the lowest grade for a staff nurse (D-grade) through to H-grade. ENPs are practising in all types of A&E department. Most ENPs have been formally trained for the role, however huge variation exists in educational preparation and in remuneration for this expanded nursing role.

Laser-driven acceleration of electrons in a partially ionized plasma channel.

The generation of quasimonoenergetic electron beams, with energies up to 200 MeV, by a laser-plasma accelerator driven in a hydrogen-filled capillary discharge waveguide is investigated. Injection and acceleration of electrons is found to depend sensitively on the delay between the onset of the discharge current and the arrival of the laser pulse. A comparison of spectroscopic and interferometric measurements suggests that injection is assisted by laser ionization of atoms or ions within the channel.

A review of cervical cancer and cervical screening: implications for nursing practice.

In this paper we review epidemiological and other research evidence on cervical cancer and cervical screening. We outline recent research evidence implicating sexually transmitted human papillomavirus as one of the causes of cervical cancer, but stress the uncertainty surrounding the causes and natural history of the disease. We go on to discuss evidence on risk factors associated with increased incidence of and mortality from cervical cancer, including age, sexual behaviour, smoking, socioeconomic status and prolonged use of oral contraceptives. Cervical screening has reduced mortality in some countries, and we outline the necessary features of a successful, effective screening programme before going on to describe why screening failed in Britain, at least until the late 1980s. Current screening policy is designed to remedy this, and we discuss its implications, and those of previous research, for nursing practice.

Evaluation of a programme of workshops for promoting the teaching of critical appraisal skills.

The aim of this study was to assess the effectiveness of four training workshops at the inception of a programme to cascade critical appraisal skills training throughout Scotland. Data were collected from all participants and organizers at four commissioned critical appraisal skills training workshops in Scotland. The collection of data involved three components: a survey of workshop participants before and after each workshop to determine knowledge of the principles of clinical effectiveness; semi-structured interviews with organizers before, during and after the programme of commissioned workshops to assess views on the workshops; and a postal survey to determine involvement in critical appraisal activities following the initial workshops. The main outcome measures were 'change in knowledge' and subsequent involvement in teaching. An average of 41 people attended each workshop. Participants improved their scores on understanding of clinical effectiveness. Not all of the improvement can be ascribed to the workshops, however, because control item scores also improved, albeit to a lesser extent. The workshops were perceived as an acceptable way of acquiring critical appraisal skills, but doubts were expressed about whether participants would be able to roll out the programme on their own. Of the 32 (42%) attendees who were involved in CASP-style workshops after the initial workshops, 26 (34%) providing aspects of teaching, and a further six (8%) were participants. The evaluation of the CASP workshop technique suggests that it does improve knowledge of clinical effectiveness, but concerns remain about the viability and reliability of this approach as it rolls out training within Scotland.