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D Johnson

Publications and source records attributed to D Johnson.

At least 109 records · Page 6Linked to original sources

The extent of HLA class II allele level disparity in unrelated bone marrow transplantation: analysis of 1259 National Marrow Donor Program donor-recipient pairs.

A comprehensive analysis of the HLA-D region loci, DRB1, DRB3, DRB5, DQA1, DQB1, DPA1 and DPB1, was performed to determine allelic diversity and underlying HLA disparity in 1259 bone marrow recipients and their unrelated donors transplanted through the National Marrow Donor Program. Although 43.0% of DRB1 alleles known to exist at the beginning of the study were found in this predominantly Caucasian transplant population, a few alleles predominated at each locus. In recipients, 67.1% of DRB1 alleles identified were one or two of six common DRB1 alleles. Only 118 (9.4%) donor-recipient pairs were matched for all alleles of DRB1, DQA1, DQB1, DPA1 and DPB1. While 79.4% of the pairs were matched for DRB1, only 13.2% were matched for DPB1 alleles. Almost 66% of pairs differed by more than one allele mismatch and 59.0% differed at more than one HLA-D locus. DQB1 was matched in 85.9% of DRB1-matched pairs. In contrast, only 13.9% of the pairs matched for DRB1, DQA1 and DQB1 were also matched for DPA1 and DPB1. This database, highlighting the underlying HLA disparity within the pairs, forms the foundation of an ongoing study to establish the relationship between HLA matching and successful outcome in unrelated allogeneic stem cell transplant.

Alleles↗

Regulation of both apoptosis and cell survival by the v-Src oncoprotein.

A number of oncogenes alter the regulation of the cell cycle and cell death, contributing to the altered growth of tumours. Expression of the v-Src oncoprotein in Rat-1 fibroblasts prevented cell cycle exit in response to growth factor withdrawal. Here we investigated whether survival of v-Src transformed cells in low serum is dependent on v-Src activity. We used a temperature sensitive v-Src to study the effect inactivating v-Src on transformed cells growing under low serum conditions. We found when we switched off v-Src the cells died by apoptosis characterised by activation of caspases and the stress-activated kinases, JNK (Jun N-terminal kinase) and p38 MAP (mitogen activated protein) kinase. We were able to prevent cell death by addition of serum or overexpression of Bcl-2. Thus v-Src transformed Rat-1 cells can be protected from apoptosis by serum, v-Src, or Bcl-2. We investigated how v-Src protects from apoptosis under these conditions. Amongst other effects, v-Src activates two kinases which have been shown to protect cells from apoptosis, phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1/2). We found that switching off v-Src led to a decrease in the activity of both PI3-K and ERK1/2, however, we found that adding a specific inhibitor of PI3-K (LY294002) to v-Src transformed Rat-1 cells grown in low serum induced apoptosis while a specific ERK kinase (MEK1) inhibitor (PD98059) had no effect. This suggests that v-Src protects from apoptosis under low serum conditions by activating PI3-K.

Animals↗

A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?

Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.

Alanine↗

The influence of gender and specialty on reporting of abusive and discriminatory behaviour by medical students, residents and physician teachers.

INTRODUCTION: The perception of whether a given behaviour is abusive differs between students and teachers. We speculated that attitudes towards reporting abusive and discriminatory behaviour may vary by specialty as well as by gender. METHODS: We report a cross-sectional survey of incoming medical students, medical students, residents, and teaching faculty at one Canadian medical school. The discrimination and abuse questions were in the following domains: (i) psychological abuse, (ii) sexual abuse, (iii) physical abuse, (iv) gender discrimination, (v) racial discrimination, (vi) disability discrimination, (vii) derogatory remarks regarding homosexuality. The frequency of self-reported witnessed or experienced abusive and discriminatory behaviour was compared by gender, specialty choice and stage of training. RESULTS: The response rates varied by respondent group: 44/56 (79%) of incoming medical students, 177/218 (81%) of medical students, 134/206 (65%) of residents and 215/554 (38%) of physician teachers. The frequency of these behaviours was perceived to be low by both male and female respondents. Abusive and discriminatory behaviour by physician teachers was noted more frequently by residents (P < 0.001) and physician teachers themselves (P < 0.001) compared with incoming medical students. As well, in general, women noted more abusive and discriminatory behaviour by all teachers, compared with men (P < 0. 003). Each response to the abuse/discrimination questions was also modelled as the independent variable using stepwise multiple regression. The area of specialization (surgical versus non-surgical) altered the reporting of abusive and discriminatory behaviour by women. CONCLUSION: We conclude that female surgical residents and medical students undergo a process of acclimatization to the patriarchal surgical culture. As female surgeons become physician teachers they revert to a culture more similar to that of their female non-surgical colleagues. Although a process of deidealization occurs in medical training, these attitudes are not necessarily retained throughout the practising lifetime of physicians as they regain autonomy and more personal control.

Adult↗

Tension-free vaginal tape for primary genuine stress incontinence: a two-centre follow-up study.

OBJECTIVE: To assess the safety and efficacy of the tension-free vaginal tape procedure in the treatment of primary genuine stress incontinence. PATIENTS AND METHODS: A two-centre follow-up study was conducted on 40 women with urodynamically confirmed primary genuine stress incontinence who had a tension-free vaginal tape inserted under local anaesthesia with sedation. Operative details were recorded and all patients followed up both subjectively, and objectively with repeat urodynamic studies and pad testing. RESULTS: The mean (range) age of the women was 51.1 (33-86) years, the median parity 2 (0-4) and mean body mass index 25.1 (19-35). The mean anaesthesia and operative duration was 42 (25-65) min; 93% of the women resumed immediate spontaneous voiding with no need for catheterization. The mean inpatient stay was 2.2 (2-4) days (where 2 days is equivalent to one night in hospital). The follow-up was conducted at a mean interval of 12.3 (6-24) months. Subjectively, 80% of women were cured and 17.5% significantly improved; objectively, genuine stress incontinence was cured in 95%. Symptomatic postoperative detrusor instability was found in 15% of women and symptoms of voiding dysfunction identified in 5% of women. There were no defects in healing or tape rejection. CONCLUSION: The tension-free vaginal tape procedure is a promising new technique that, in this short-term analysis, appears to be safe and effective. Intra-operative complications are uncommon and both hospital stay and recovery are short. Voiding complications are rare but symptomatic postoperative detrusor instability had an incidence of 15%.

Adult↗

Is all ventricular fibrillation the same? Influence of mode of induction on characteristics of ventricular fibrillation.

INTRODUCTION: Little information is available on the relationship between the mode of induction of ventricular fibrillation (VF) to VF characteristics. METHODS AND RESULTS: VF was induced from the anterior left ventricle by programmed electrical stimulation, burst pacing, alternating current (AC), high current S2 at a site remote from S1, T wave shock, and intersecting wavefronts in seven normal dogs and seven dogs with chronic myocardial infarction. Using two electrode arrays, 112 electrograms were recorded from the anterior and lateral wall. Cycle lengths were analyzed and activation vectors were created by summing orthogonally recorded bipolar electrograms. The magnitude of the vector loops was integrated over time to produce an "ensemble vector" index (EVI) whose magnitude is high when beat-to-beat activation direction is consistent and low when activation direction is variable. T wave shock-induced VF had a significantly longer cycle length 1 to 5 seconds after VF onset than other modes of induction (P < 0.05). The frequency-corrected EVI was significantly larger for AC current and T wave shock-induced VF as opposed to all other modes of VF induction in early VF (P < 0.0001). After 10 seconds of VF, these differences persisted only on the anterior wall. CONCLUSION: VF induced in animals by T wave shock and AC current had different characteristics than VF induced by other methods. These findings may have implications for our understanding of VF pathophysiology.

Animals↗

Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome.

Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used. ARMS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles. A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families. Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome). Eleven different mutations in the 22 families were detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P=2. 4x10-7; 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34. 50+/-7.65 years vs. 30.45+/-1.28 years, P<.01). Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations.

Acrocephalosyndactylia↗

Enhanced detection of blood flow in the normal canine prostate using an ultrasound contrast agent.

RATIONALE AND OBJECTIVES: To evaluate the sonographic appearance of normal prostate vascularity in dogs before and after injection of a new ultrasound contrast agent, NC100100. METHODS: Thirty-five intravenous injections of NC100100, in doses ranging from 0.00625 to 0.05 microL microbubbles/kg, were administered to seven anesthetized mongrel male dogs. Transrectal color Doppler imaging and power Doppler imaging were used to perform the assessment. The visibility of the vascular pattern of the prostate was assessed, including dynamics of contrast inflow, blood flow symmetry, and duration times. RESULTS: Before contrast administration, the vascular pattern was poorly visualized in all cases. After contrast injection, the visibility of the vascular architecture improved significantly for both modalities. Independent of the imaging method used, higher doses tended to be more effective than lower doses. Contrast kinetics in the prostate vessels was demonstrated with a mean time from injection of the ultrasound contrast agent to enhancement of the Doppler signals in the subcapsular arteries (+/-1 SD) of 13+/-3 seconds, and the ultrasound contrast agent reached the central periurethral veins 3 to 6 seconds later. A spokelike radial pattern of internal prostatic vessels observed with enhanced ultrasound could also be seen on silicone microfil x-ray images. The Doppler enhancement persisted for a mean time ( +/-1 SD) of 904 seconds (approximately 15 minutes) +/- 225 seconds and tended to increase with increasing dose. CONCLUSIONS: NC100100 significantly improves the detection of blood flow in the normal canine prostate and allows more accurate depiction of the vascular architecture of the prostate.

Animals↗

Chronic fatigue syndrome: occupation, medical utilization, and subtypes in a community-based sample.

Most studies of chronic fatigue syndrome (CFS) have been based on patients recruited from primary or tertiary care settings. Patients from such settings might not be typical of patients in the general population. The present investigation involved examining individuals with CFS from a community-based study. A random sample of 18,675 respondents in Chicago was first interviewed by telephone. A group of individuals with chronic fatigue accompanied by at least four minor symptoms associated with CFS were given medical and psychiatric examinations. From this sample, a physician review group diagnosed individuals with CFS. Those diagnosed with CFS were subclassified based on a variety of categories, including duration of illness, mode of illness onset, and presence or absence of a stressful life event directly preceding onset. In addition, we examined medical utilization among those diagnosed with CFS, as well as whether individuals with CFS were disproportionately represented in health care professions. Important differences emerged on measures of sociodemographics, symptoms, and functional disability. The implications of these findings and others are discussed.

Adult↗

Social network methods for endemic foci of syphilis: a pilot project.

BACKGROUND: Social network methods have improved our understanding of sexually transmitted disease transmission dynamics, and may be of use in routine field operations for partner notification. GOAL: To augment traditional syphilis-control activities with social network methods in an Atlanta area with high syphilis morbidity. STUDY DESIGN: Disease investigators conducted interviews, used network diagrams to prioritize their work, and relied on network connections for finding hard-to-reach persons. RESULTS: A total of 396 contacts were elicited from 48 infected and 50 uninfected persons. The cumulative prevalence of syphilis was 12.6%, and 24 persons infected with HIV were identified. Network methods disclosed a large, interconnected group (276 persons) characterized by high network centrality and the substantial presence of small, interactive subgroups (microstructures). CONCLUSION: The network approach is a feasible field technique, and can identify core groups involved in the intense transmission of syphilis. The targeted, network-based approach may be useful in attempts to eliminate syphilis.

Adult↗

The benefit/risk profile of rabeprazole, a new proton-pump inhibitor.

Acid-related diseases such as gastro-oesophageal reflux disease (GORD) and peptic ulcer are a common cause of morbidity and if inadequately treated can lead to serious complications. The proton-pump inhibitor rabeprazole has been extensively evaluated in well-controlled trials in North America and Europe for the acute treatment of erosive or ulcerative GORD and gastric and duodenal ulcers and for the long-term maintenance of GORD healing. The results show that rabeprazole has a favourable benefit/risk profile for each indication. Rabeprazole 10 and 20 mg given once daily in the morning was highly effective in producing and maintaining healing, providing symptom relief, and improving overall well-being. Healing rates for rabeprazole were equivalent to omeprazole in all indications, and superior (GORD healing and duodenal ulcer healing) or equivalent (gastric ulcer healing) to the histamine 2-receptor antagonist ranitidine. Symptom relief provided by rabeprazole was equivalent or superior to comparator drugs. Rabeprazole was well tolerated in both short- and long-term studies. The incidence of treatment-emergent signs and symptoms related to rabeprazole was low, and these were generally mild or moderate in severity. The overall rate of discontinuations due to adverse events was approximately 3%. There were no deaths related to rabeprazole therapy. These findings indicate a favourable benefit/risk profile for each intended use.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Effect of underlying heart disease on the frequency content of ventricular fibrillation in the dog heart.

Although prior studies have examined the frequency content of local electrogram characteristics during fibrillation, little is know about the effects of underlying heart disease on these parameters. This study was designed to compare the frequency content of local electrograms during VF in canine models of acute ischemia, subacute infarction, and chronic myocardial infarction (MI) to those in control animals to test the hypothesis that underlying heart disease can alter the basic characteristics of VF. VF was induced using burst pacing in three groups of mongrel dogs. Five dogs were evaluated 8 weeks after LAD occlusion MI, five were evaluated 5 days after experimental MI, and 5 had VF induced before (control) and immediately after LAD occlusion (ischemia). During VF, unipolar electrograms were recorded from 112 sites on the anterior LV and electrograms were evaluated 15 and 30 seconds after VF initiation in each group. Electrograms were analyzed by fast Fourier transform. No significant time dependent changes in VF characteristics were noted. The peak frequency was highest in control animals and 8-week MI, intermediate in 5-day MI, and lowest in acute ischemia (P < 0.01 for pairwise comparisons). In contrast, the fractional of energy within a bandwidth of 25% peak amplitude was highest in acute ischemia, (P < 0.001) and similar in the other three groups. Infarction decreased total energy by approximately 50%. In conclusion, the pressure of ischemia or infarction alters the frequency content of VF in a complex fashion. In addition to decreasing the peak frequency, the shape of the power spectral curve is altered in models of structural heart disease. These results suggest that the electrophysiological changes produced by infarction or ischemia alter the structural organization of ventricular fibrillation.

Animals↗

Electrophysiological and anatomic heterogeneity in evolving canine myocardial infarction.

Although the heterogeneity of electrophysiological properties is increased after myocardial infarction, the degree of this heterogeneity has not been well quantitated and its relationship to the histological changes that occur after infarction has not been carefully examined. The purpose of the present study was to test the hypothesis that alterations in electrophysiological properties in healing canine infarction are related to particular histological changes. Experimental infarction was produced by left anterior descending coronary ligation. Six dogs were used as controls, six were studied 5 days following, and six were studied 8 weeks following infarction. Pacing thresholds, effective refractory periods, and activation-recovery times were determined at 112 sites on the anterior left ventricle using a multiple electrode plaque. Conduction velocity, conduction-heterogeneity index--a measure of conduction disturbance--and histology of the epimyocardium underlying the plaque were assessed. The effective refractory periods and activation-recovery times were greater in both infarction groups, most prominently in the subacute group. In subacute infarction, significant postrepolarization refractoriness was present. In healed infarction, conduction velocity was decreased and the conduction-heterogeneity index was increased compared to controls and subacute infarction. Dispersion of excitability and repolarization was associated with more extensive local scarring. Dispersion of myocardial fiber angles was associated with the conduction-heterogeneity index. Some but not all of the electrophysiological changes noted in the animals with infarction were also seen in sham operated animals. Thus, heterogeneity in repolarization and refractoriness is greatest in the subacute phase of myocardial infarction and is associated with the extent of local cell death. In contrast, disturbances in conduction are greatest in healed infarction and associated with disarray of myocardial fibers.

Animals↗

Assessment of health knowledge after "a healthy adventure".

This study evaluated the general health education program for third graders at Hult Health Education Center (Hult HEC). A quasi-experimental, nonequivalent pretest-posttest control group design with four groups was employed to collect pretest and posttest data from 168 third graders. The four groups included a control group, a traditional classroom health education group, a group that visited Hult HEC, and a group that visited Hult HEC and incorporated center curricular materials in the classroom. Analysis of covariance (ANCOVA) was calculated to test for posttest differences among the four groups, while reducing the effects of initial group pretest score differences. A statistically significant difference occurred in posttest scores among the four groups (F = 120.62, df = 4, 163, p = .0001). Post hoc testing revealed the best results were obtained when combining curricular materials with a visit to the Hult HEC.

Analysis of Variance↗

Pattern of premature degenerative changes of the cervical spine in patients with spasmodic torticollis and the impact on the outcome of selective peripheral denervation.

OBJECTIVES: To characterise the pattern of and risk factors for degenerative changes of the cervical spine in patients with spasmodic torticollis and to assess whether these changes affect outcome after selective peripheral denervation. METHODS: Preoperative CT of the upper cervical spine of 34 patients with spasmodic torticollis referred for surgery were reviewed by two radiologists blinded to the clinical findings. Degenerative changes were assessed for each joint separately and rated as absent, minimal, moderate, or severe. Patients were clinically assessed before surgery and 3 months postoperatively by an independent examiner using standardised clinical rating scales. For comparison of means a t test was carried out. To determine whether an association exists between the side of degenerative changes and type of spasmodic torticollis a chi(2) test was used. Changes in severity, disability, and pain before and after surgery were calculated using a Wilcoxon matched pairs signed ranks test. RESULTS: Fourteen out of 34 patients had moderate or severe degenerative changes. They were predominantly found at the C2/C3 and C3/C4 level and were significantly more likely to occur on the side of the main direction of the spasmodic torticollis (p = 0.015). There was no significant difference in age, sex, duration of torticollis, overall severity, degree of disability, or pain between the group with either no or minimal changes and the group with moderate or severe changes. However, in the second group the duration of inadequate treatment was longer (10.1 v 4.8 years; p=0.009), head mobility was more restricted (p = 0.015), and head tremor was more severe (p = 0.01). At 3 months postoperatively, patients with n or minimal degenerative changes showed a significant improvement in pain and severity whereas no difference was found in those with moderate or severe changes. CONCLUSIONS: Patients with spasmodic torticollis have an increased risk of developing premature degenerative changes of the upper cervical spine that tend to be on the side towards which the head is turned or tilted and compromise outcome after surgery. Effective early treatment of spasmodic torticollis with botulinum toxin seems to have a protective effect. Patients with spasmodic torticollis and restricted head mobility who do not adequately respond to treatment should undergo imaging of the upper cervical spine. Patients with imaging evidence of moderate or severe degenerative changes seem to respond poorly to selective peripheral denervation.

Adult↗

Decreased expression of apM1 in omental and subcutaneous adipose tissue of humans with type 2 diabetes.

We have screened a subtracted cDNA library in order to identify differentially expressed genes in omental adipose tissue of human patients with Type 2 diabetes. One clone (#1738) showed a marked reduction in omental adipose tissue from patients with Type 2 diabetes. Sequencing and BLAST analysis revealed clone #1738 was the adipocyte-specific secreted protein gene apM1 (synonyms ACRP30, AdipoQ, GBP28). Consistent with the murine orthologue, apM1 mRNA was expressed in cultured human adipocytes and not in preadipocytes. Using RT-PCR we confirmed that apM1 mRNA levels were significantly reduced in omental adipose tissue of obese patients with Type 2 diabetes compared with lean and obese normoglycemic subjects. Although less pronounced, apM1 mRNA levels were reduced in subcutaneous adipose tissue of Type 2 diabetic patients. Whereas the biological function of apM1 is presently unknown, the tissue specific expression, structural similarities to TNFalpha, and the dysregulated expression observed in obese Type 2 diabetic patients suggest that this factor may play a role in the pathogenesis of insulin resistance and Type 2 diabetes.

Adiponectin↗

Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial.

PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide. PATIENTS AND METHODS: The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)). RESULTS: The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens. CONCLUSION: As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.

Antineoplastic Combined Chemotherapy Protocols↗