The revolution is just starting - Inflacretins and their effects on humanity

Antibiotics, and contraceptive drugs are major, recent, radical influences on humanity and human evolution. Inflacretins are the next revolution.

GLP-1 receptor agonists, GIP receptor agonists, Tirzepatide, Mounjaro, Exenatide, Liraglutide, Dulaglutide, Semaglutide, Lixisenatide, Retatrutide,, Zepbound, Cagrilintide, Orforglipron, are the new wonder-drugs that will change the nature of humanity fundamentally.

GLP-1 and GIP receptor agonists (GLP-1RAs and dual agonists) demonstrate remarkable pleiotropic effects  ( in the sense of ‘: "Multi-system effects mediated through ubiquitous GLP-1 receptors and shared inflammatory pathways”’) across multiple organ systems, extending far beyond their original indication for type 2 diabetes and obesity. These medications work through tissue-specific GLP-1 receptors and shared anti-inflammatory pathways, with many benefits occurring independently of weight loss and glycaemic control.

Yes, they are mainly seen as fat-busters, slimming drugs, and secondarily, as drugs against obesity, but this only scratches the surface of how fundamentally, they are going to affect humanity, in the long term.

Essentially, though these drugs do enable radical, sustainable weight loss, and the remission of diabetes, thay are more far-reaching than that.

This is because they affect the brain directly, and also affect inflammation directly. Already these far-reaching effects are becoming apparent, though a lot more research is needed to understand exactly how they work (after all, they were developed from the venom of the Gila Monster, a venemous lizard that spends most of it time underground, and used the particular chemical, Exendin-4, to cause a spike in insulin in their victimes, and, thus, a  hypoglycaemic coma in their victims. The same effect famous in whodunit stories that arises from a massive injection of insulin.

Of course, almost everybody knows them as slimming drugs, fat-busters, that reduce users from being overweight to being a shadow of their former selves. That, though, is only the very tip of the huge iceberg.

The also are wll known for putting diabetes into remission - they don't cure it, because, if you stop taking them, the diabetes, and weight, return within a year.

What's much more amazing, and important to their future use, is the long-term consequences, mainly positive, that they offer.

This is because they are anti-inflammatory drugs. Inflammation seems a very general term, we have inflamed  wounds after an injury, we have auto-immune deseases that are inflammatory, and so forth. What they affect include - in decreasing levels of evidence, at the moment:

Type 2 Diabetes

Chronic Kidney Disease

NAFLD/MASLD

NASH

COPD

Sleep Apnoea/EDS

Liver Cirrhosis (compensated)

Cognitive Decline

Peripheral Neuropathy

Rheumatoid Arthritis

Hypertension

PCOS

IBD (Crohn's/UC)

Brain/Vascular Inflammation

Osteoarthritis

Type 1 Diabetes

Alcohol Use Disorder

Nicotine/Tobacco Use

DVT Sequelae

Gut Microbiome

Other Addictions

Vascular Eczema

Atopic Eczema

If you go through this list, it is truly amazing. Addictions, auto-immune disorders, heart problems, mental problems, and so much more!

I'm not trying to open floodgates for the treatment of all these conditions - the floodgates are already open on weight loss along. The drugs are in short supply and very expensive.

This has to change. Not that everybody with eczema should take these drugs, just for that, but, rather, if there is a primary condition, overweight, diabetes, or hypertension, these drugs make sense, as seriously effective for conditions previously thought chronic and only partly improved by various specific drugs.

Instead, I'm proposing that the current guidelines that make either diabetic, or weight control the only criteria for using these drugs ought to be widened to include treatment of all these potential comorbitities. Often people with diabetes and / or overweight, suffer from a number of these as well.

There needs to be an integrated pathway to treatment that weighs up the effect of all these comorbitities on a particular person and adapts the dose appropriately - rather than deciding that once, say, diabetes is in remission, the dose should be only a maintenance does.

To give a wider picture:

GLP-1 and GIP Receptor Agonists: Comprehensive Review of Comorbidities Ameliorated Beyond Diabetes

Core Mechanisms

GLP-1RAs achieve therapeutic effects through multiple pathways:

Anti-Inflammatory Actions:

• Inhibition of NF-κB activation
• Reduction of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β)
• AMP-activated protein kinase phosphorylation
• Decreased oxidative stress via NADPH oxidase 4 (NOX4) suppression

Direct Receptor-Mediated Effects:

• GLP-1 receptors present in brain, peripheral nerves, liver, kidneys, joints, lungs, and other tissues
• Local tissue-specific signalling independent of systemic metabolic effects

Metabolic Improvements:

• Enhanced insulin sensitivity
• Improved glucose homeostasis
• Beneficial lipid profile changes
• Weight reduction (amplifies but not always required for benefit)

I. CARDIOMETABOLIC AND ORGAN PROTECTION (Strongest Evidence)

Type 2 Diabetes

Evidence Quality: Very Strong | Mechanism Understanding: Very Well-Characterised | Status: Licensed Indication

Evidence: Foundational indication with decades of evidence demonstrating HbA1c reductions of 1-2% and cardiovascular outcome benefits.

Mechanisms:

• Enhanced glucose-dependent insulin secretion
• Suppressed glucagon release
• Delayed gastric emptying
• Improved insulin sensitivity
• Reduced hepatic glucose output

Pathway: Multiple metabolic effects → Improved glycaemic control + cardiovascular protection

Chronic Kidney Disease (CKD)

Evidence Quality: Very Strong | Mechanism Understanding: Very Well-Characterised | Status: FDA-Approved (semaglutide, December 2024)

Evidence: FLOW trial and multiple 2024 meta-analyses show dramatic renoprotection. In CKD patients with T2DM:

• 15% reduction in composite kidney outcomes
• 22% reduction in >30% eGFR decline
• 28% reduction in >50% eGFR decline
• 71% reduction in dialysis-requiring ESKD (HR 0.29)
• 72% reduction in renal death (HR 0.28)

Benefits extend to CKD patients with overweight/obesity even without T2DM. Estimated lifetime benefit when combined with RASi, SGLT2i, and finerenone: 5.5 additional event-free years.

Mechanisms:

• Direct GLP-1 receptor activation in kidney tissue
• Beneficial glomerular haemodynamic effects
• Reduced inflammatory burden and oxidative stress in kidneys
• Improved endothelial function
• BP control (mediates ~48% of benefit)
• Glycaemic control (mediates ~48% of benefit)
• Weight loss reducing "fatty kidney" and renal sinus fat deposition
• Reduced albuminuria and proteinuria

Pathway: Direct renal GLP-1R effects + improved haemodynamics + reduced inflammation + BP/glucose control + weight loss → Slowed eGFR decline + reduced albuminuria + delayed progression to ESKD

Note: Now considered the "fourth pillar" of kidney protection alongside RASi, SGLT2i, and finerenone.

Non-Alcoholic Fatty Liver Disease (NAFLD/MASLD) and NASH

Evidence Quality: Very Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label (Phase 3 trials ongoing for NASH)

Evidence:

• NASH Resolution: Semaglutide 0.4mg/day achieved NASH resolution without fibrosis progression in 59% versus 17% placebo at 72 weeks
• Tirzepatide SYNERGY-NASH (Phase II): 73.3% on highest dose achieved absence of NASH without fibrosis worsening versus 13.2% placebo at 52 weeks
• Fibrosis: Liraglutide showed fibrosis progression in only 9% versus 36% placebo (p=0.04)
• Progression Prevention: Large cohort (16,058 patients) showed significant reduction in progression to cirrhosis and complications
• Meta-analysis of 16 trials (2,178 patients) demonstrated significant histological improvement

Mechanisms:

• Autophagy-dependent lipid degradation in hepatocytes
• Improved lysosomal function
• Reduction in hepatic triglyceride accumulation
• Direct GLP-1R stimulation in liver tissue
• Weight loss as major contributor
• Improved insulin signalling
• Reduction in systemic and hepatic inflammation (CRP, IL-6, TNF-α)
• Enhanced tissue repair pathways
• Modulation of protease/anti-protease balance
• Reduced hepatic stellate cell activation

Pathway: Direct hepatocyte effects + weight loss + improved insulin sensitivity + anti-inflammatory action → Reduced steatosis + NASH resolution + slowed fibrosis progression

Liver Cirrhosis (Compensated)

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: 2024 Taiwanese study (467 matched pairs) showed GLP-1RA users had:

• Significantly lower mortality (27.46 vs 55.90 per 1000 person-years)
• Reduced decompensation risk
• Lower hepatic encephalopathy
• Decreased acute-on-chronic liver failure
• Longer cumulative duration associated with better outcomes

US studies showed lower rates of hepatic decompensation versus sulfonylureas and DPP-4 inhibitors.

Important Note: Safety data limited to compensated cirrhosis. Not studied in decompensated cirrhosis.

Mechanisms:

• Prevention of disease progression through NASH/fibrosis effects
• Cardiovascular protection (cirrhotic diabetics have higher CV risk)
• Reduced systemic inflammation
• Metabolic improvements

Pathway: Multiple protective mechanisms → Reduced decompensation + lower mortality + decreased liver failure progression

Obstructive Sleep Apnoea (OSA) and Excessive Daytime Sleepiness

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: FDA-Approved for OSA (tirzepatide, December 2024)

Evidence:

• First medication approved for OSA
• Clinical trials showed 20-25.8 event/hour reductions in apnoea-hypopnoea index (AHI)
• Greater AHI improvements than mandibular advancement devices
• Exenatide reduced Epworth Sleepiness Scale scores from 12.3 to 5.7 (p=0.003) in 22 weeks

Mechanisms:

• Weight loss reducing upper airway fat deposition
• Decreased rostral-to-caudal fluid shifts during sleep
• Direct effects via GLP-1 receptors in hypothalamic nuclei regulating sleep/wakefulness
• Normalisation of neurogenesis and synaptic plasticity
• Protection against neuronal apoptosis
• Suppression of oxidative stress
• Reduction in systemic inflammation (hs-CRP)

Pathway: Weight loss + reduced airway obstruction + direct CNS effects on sleep regulation + anti-inflammatory effects → Reduced AHI + improved sleep quality + decreased daytime sleepiness

Hypertension

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Trials consistently show reductions in systolic blood pressure alongside other metabolic improvements. Tirzepatide trials demonstrated significant BP reductions.

Mechanisms:

• Reduced sympathetic nervous system activation
• Improved endothelial function
• Decreased vascular inflammation
• Weight loss effects
• Improved insulin sensitivity

Pathway: Reduced inflammation + improved endothelial function + weight loss → Lower blood pressure

II. PULMONARY CONDITIONS (Strong Evidence)

Chronic Obstructive Pulmonary Disease (COPD)

Evidence Quality: Very Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple 2023-2024 studies in patients with COPD and T2DM showed GLP-1RA use associated with:

• 48% reduction in all-cause mortality (far exceeding the 12% in general diabetic population)
• 88% lower risk of COPD exacerbations
• 77% reduced oxygen dependence
• 78% lower pulmonary hypertension risk
• 80% reduced pneumonia risk
• 77% lower pulmonary oedema risk
• 64% reduced intubation risk

Mechanisms:

• Reduction of airway inflammation
• Decreased oxidative stress through inhibition of inflammatory factors
• Improved protease/anti-protease balance
• Enhanced airway mucus homeostasis
• Reduced airway remodelling
• Direct GLP-1R activation in lung tissue
• Possible surfactant protein enhancement

Pathway: Multi-level pulmonary anti-inflammatory effects + improved airway function + weight reduction → Reduced exacerbations + improved lung function + dramatic mortality reduction

Note: The 48% mortality reduction far exceeds cardiovascular benefits alone, suggesting lung-specific protective mechanisms.

III. NEUROLOGICAL CONDITIONS (Strong to Moderate Evidence)

Cognitive Decline and Early Dementia

Evidence Quality: Strong (Phase 2b/3 Ongoing) | Mechanism Understanding: Well-Characterised | Status: Off-Label, Trials Ongoing

Evidence:

• Phase 2b ELAD trial (2024): Liraglutide reduced cognitive decline by 18% over 12 months in mild Alzheimer's disease
• Brain volume loss (frontal, temporal, parietal lobes, total grey matter) reduced by nearly 50%
• Dulaglutide study (8,828 participants) showed significant cognitive benefit

Important Note: Not effective against established Alzheimer's disease pathology (does not directly affect amyloid-β or tau), but protective against progression of early cognitive impairment.

Mechanisms:

• Enhanced brain insulin signalling (reduces insulin resistance in hippocampus)
• Neuroprotection through reduced neuroinflammation
• Normalisation of cerebral glucose metabolism
• Prevention of expected decline in blood-brain glucose transfer
• Support for synaptic plasticity and neuronal survival
• Reduction in oxidative stress

Pathway: Improved brain insulin sensitivity + reduced neuroinflammation + enhanced glucose metabolism → Slowed cognitive decline and reduced brain atrophy

Peripheral Neuropathy

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Prospective studies in 24 participants with diabetic peripheral neuropathy showed:

• Improvements in clinical neuropathy scores (baseline 3.7, post-treatment 2.3, p=0.005)
• Improved nerve conduction studies and axonal excitability
• Nerve morphology improved in 86% at one month, with 32% returning to normal
• Effects occur independently of glycaemic control

Mechanisms:

• Improved Na⁺/K⁺-ATPase pump function in peripheral nerves
• ERK1/2 signalling activation in sciatic nerve
• Reduced pro-inflammatory cytokines in peripheral serum and nerve tissue
• Enhanced expression of neuritin and nerve growth factor
• Preservation of intraepidermal nerve fibre density
• Direct GLP-1 receptor activation in dorsal root ganglia, neurons, and Schwann cells

Pathway: GLP-1R activation in peripheral nerves → ERK signalling + improved Na⁺/K⁺-ATPase → Preserved nerve structure and function + reduced neuropathic symptoms

IV. RHEUMATOLOGICAL CONDITIONS (Strong to Moderate Evidence)

Rheumatoid Arthritis

Evidence Quality: Strong, Expanding | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple 2024-2025 studies demonstrate significant improvements:

• Retrospective study of 173 RA patients on GLP-1RAs (2018-2024) showed reduced disease activity and improved cardiovascular risk markers
• ACR Convergence 2025 abstracts: RA patients on DMARDs plus GLP-1 agonists had fewer disease flares
• Semaglutide use associated with improved joint outcomes

Mechanisms:

• Direct NF-κB pathway inhibition in synovial tissue (weight-independent)
• Reduction in synovial inflammation and pro-inflammatory cytokine production
• Decreased oxidative stress via NOX4 suppression
• p38 MAPK pathway modulation

Pathway: Anti-inflammatory → Reduced synovial inflammation → Decreased joint damage and improved mobility

Osteoarthritis

Evidence Quality: Moderate | Mechanism Understanding: Emerging | Status: Off-Label

Evidence: ACR Convergence 2025 data showed GLP-1RAs delivered greater improvements in pain and physical function compared with SGLT2 inhibitors in OA patients. The effect extends beyond weight loss.

Mechanisms:

• Direct impact on articular chondrocytes and joint tissues
• Improved cartilage health through reduced inflammation
• Lower systemic inflammatory burden
• Reduced mechanical stress from weight loss

Pathway: Reduced inflammation + weight loss → Decreased cartilage damage + improved joint function

V. GASTROINTESTINAL CONDITIONS (Strong Evidence)

Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis)

Evidence Quality: Strong, Expanding Rapidly | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple 2024-2025 studies show promising results:

• Israeli nationwide cohort: GLP-1 use associated with reduced composite poor disease outcomes (steroid dependence, advanced therapy initiation, hospitalisation, surgery)
• US studies: Reduced rates of colectomy in UC (aHR: 0.37) and IBD-related surgery in CD (aHR: 0.55)
• CRP levels significantly reduced (p=0.04)
• New $3 million Helmsley Charitable Trust study (2024) investigating GLP-1RAs for promoting intestinal healing in severe Crohn's disease

Paradigm Shift: Moving from purely suppressing inflammation to actively promoting tissue repair.

Mechanisms:

• Direct anti-inflammatory effects on intestinal epithelium
• Modulation of intestinal microbiota and group 3 innate lymphoid cells
• Induction of barrier-protective expression in Brunner's glands
• Reduction in systemic inflammation
• Enhancement of tissue repair and healing pathways
• Improved gut permeability

Pathway: Anti-inflammatory effects + microbiome modulation + tissue repair enhancement → Reduced disease activity + fewer flares + decreased need for surgery

Gut Microbiome Dysbiosis

Evidence Quality: Preliminary | Mechanism Understanding: Emerging | Status: Off-Label

Evidence: Emerging research suggests beneficial effects on gut microbiome composition.

Mechanisms:

• Direct effects on gut epithelium
• Modified gastrointestinal transit time
• Anti-inflammatory effects in gut tissue
• Potential prebiotic-like effects

Pathway: GI effects + anti-inflammatory action → Improved microbiome diversity and composition

VI. ENDOCRINE AND REPRODUCTIVE CONDITIONS (Strong Evidence)

Polycystic Ovary Syndrome (PCOS)

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple studies and meta-analyses (2024) demonstrate:

• GLP-1RAs reduce BMI more effectively than metformin (SMD −1.02)
• Improve insulin sensitivity (SMD −0.40)
• Enhance ovulation rates
• Semaglutide 2.4mg shows highest efficacy
• 62% of liraglutide-treated women achieved normal menstrual bleeding ratio

Mechanisms:

• Weight reduction as primary mechanism
• Direct effects on insulin resistance (independent of weight)
• Improvement in glucose homeostasis
• Reduction in hyperandrogenism
• Enhancement of ovulation through multiple pathways

Pathway: Weight loss + improved insulin sensitivity + reduced inflammation → Improved menstrual cyclicity + enhanced fertility + metabolic improvement

Important Note: Requires effective contraception during therapy and washout period before pregnancy attempts.

Type 1 Diabetes (Adjunct Therapy)

Evidence Quality: Moderate | Mechanism Understanding: Emerging | Status: Off-Label

Evidence: Emerging evidence for Type 1 diabetes as adjunct therapy to insulin.

Mechanisms:

• Suppressed glucagon release
• Delayed gastric emptying
• Improved insulin sensitivity
• Weight management
• Reduced glycaemic variability

Pathway: Multiple metabolic effects → Improved glycaemic control with reduced insulin requirements

VII. ADDICTION AND BEHAVIOURAL CONDITIONS (Moderate to Preliminary Evidence)

Alcohol Use Disorder (AUD)

Evidence Quality: Moderate (Promising) | Mechanism Understanding: Emerging | Status: Off-Label, Trials Ongoing

Evidence:

• Preclinical studies show consistent reductions in alcohol consumption
• Clinical trials show mixed but encouraging results
• Largest pharmacoepidemiological studies show lower alcohol-related events with GLP-1RA use
• Subgroup analysis suggests strongest effects in patients with comorbid obesity (BMI >30)

Mechanisms:

• Modulation of mesolimbic dopamine reward pathways
• Reduced alcohol-induced dopamine release
• Decreased reward salience through central GLP-1 receptors
• Modification of stress response systems
• Effects on brain areas regulating addiction (nucleus tractus solitarius, septal area)

Pathway: GLP-1R activation in reward centres → Reduced dopamine signalling + decreased reward response → Lower alcohol craving and consumption

Nicotine/Tobacco Use

Evidence Quality: Preliminary | Mechanism Understanding: Emerging | Status: Off-Label, Trials Ongoing

Evidence:

• Preclinical data show GLP-1RAs reduce nicotine self-administration and reinstatement of nicotine seeking
• Early clinical trials suggest potential to reduce cigarettes per day and prevent post-cessation weight gain

Mechanisms: Similar dopamine pathway modulation as with alcohol.

Pathway: Reduced reward from nicotine + prevention of weight gain → Improved smoking cessation outcomes

Opioids and Stimulants

Evidence Quality: Preliminary (Preclinical) | Mechanism Understanding: Emerging | Status: Research Phase

Evidence: Preliminary preclinical evidence for reduced use of opioids, cocaine, and methamphetamine. Human data very limited.

Note: This is an emerging area requiring substantial further research. Most evidence is preclinical, and clinical trials are ongoing.

VIII. VASCULAR AND CARDIOVASCULAR CONDITIONS (Moderate to Preliminary Evidence)

Vascular and Brain Inflammation

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple studies demonstrate reductions in inflammatory markers (CRP, TNF-α, IL-6, IL-1β) both systemically and in specific tissues.

Mechanisms:

• NF-κB pathway inhibition
• Direct anti-inflammatory signalling
• Reduced oxidative stress
• Improved microvascular function

Pathway: Multi-level anti-inflammatory action → Reduced vascular and brain inflammation → Improved organ function

Sequelae of Deep Vein Thrombosis

Evidence Quality: Preliminary | Mechanism Understanding: Theoretical | Status: Off-Label

Evidence: Emerging evidence for vascular protective effects through anti-inflammatory mechanisms.

Mechanisms:

• Reduced systemic inflammation
• Improved endothelial function
• Enhanced vascular health through multiple pathways

Pathway: Anti-inflammatory effects + improved endothelial function → Reduced post-thrombotic complications

IX. DERMATOLOGICAL CONDITIONS (Anecdotal Evidence)

Vascular Eczema and Atopic Eczema

Evidence Quality: Anecdotal | Mechanism Understanding: Theoretical | Status: Off-Label

Evidence: Anecdotal evidence emerging; formal studies needed. Mechanism plausible given anti-inflammatory properties.

Mechanisms (Proposed):

• Systemic anti-inflammatory effects
• Improved microvascular function
• Reduced oxidative stress
• Potential direct effects on skin immune cells

Pathway: Systemic anti-inflammatory effects + improved microvascular health → Reduced eczema severity

Note: Requires formal clinical investigation to establish efficacy.

Summary Table: Evidence Quality and Clinical Status

Condition Evidence Quality Mechanism Understanding Clinical Availability

TIER 1: STRONGEST EVIDENCE

Type 2 Diabetes Very strong Very well-characterised Licensed indication

Chronic Kidney Disease Very strong Very well-characterised FDA-approved (semaglutide)

NAFLD/MASLD Very strong Well-characterised Off-label

NASH Very strong Well-characterised Off-label, Phase 3 trials ongoing

COPD Very strong Well-characterised Off-label

TIER 2: STRONG EVIDENCE

Sleep Apnoea/EDS Strong Well-characterised FDA-approved (tirzepatide)

Liver Cirrhosis (compensated) Strong Well-characterised Off-label

Cognitive Decline Strong (Phase 2b/3 ongoing) Well-characterised Off-label, trials ongoing

Peripheral Neuropathy Strong Well-characterised Off-label

Rheumatoid Arthritis Strong, expanding Well-characterised Off-label

Hypertension Strong Well-characterised Off-label

PCOS Strong Well-characterised Off-label

IBD (Crohn's/UC) Strong, expanding rapidly Well-characterised Off-label

Brain/Vascular Inflammation Strong Well-characterised Off-label

TIER 3: MODERATE EVIDENCE

Osteoarthritis Moderate Emerging Off-label

Type 1 Diabetes Moderate Emerging Off-label

Alcohol Use Disorder Moderate (promising) Emerging Off-label, trials ongoing

TIER 4: PRELIMINARY/EMERGING

Nicotine/Tobacco Use Preliminary Emerging Off-label, trials ongoing

DVT Sequelae Preliminary Theoretical Off-label

Gut Microbiome Preliminary Emerging Off-label

Other Addictions Preliminary (preclinical) Emerging Research phase

TIER 5: ANECDOTAL

Vascular Eczema Anecdotal Theoretical Off-label

Atopic Eczema Anecdotal Theoretical Off-label

Key Insights

1. Pleiotropic Drug Class: GLP-1RAs demonstrate effects across virtually every organ system, transitioning from diabetes/obesity medications to broad metabolic-inflammatory disease modifiers with organ-protective properties.
2. Weight-Independent Mechanisms: Many benefits occur independently of weight loss through direct anti-inflammatory, neuroprotective, and tissue-protective mechanisms mediated by local GLP-1 receptors.
3. Shared Pathways: NF-κB inhibition, reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), improved cellular signalling, and decreased oxidative stress are common mechanisms across diverse conditions.
4. Tissue-Specific Receptors: GLP-1 receptors are present in brain, peripheral nerves, liver, kidneys, joints, lungs, gut, and other tissues, enabling direct local effects beyond systemic metabolic improvements.
5. Organ Protection Beyond Metabolic Control: Dramatic reductions in hard outcomes:
• 71% reduction in dialysis-requiring ESKD
• 48% reduction in COPD mortality
• 50% reduction in cirrhosis mortality
• 63% reduction in IBD surgery
• These effects exceed what would be expected from glycaemic control and weight loss alone
6. Combination Therapy Synergy: GLP-1RAs work synergistically with other disease-modifying drugs:
• With RASi, SGLT2i, and finerenone for CKD (5.5 additional event-free years)
• With DMARDs for rheumatoid arthritis
• Potential for multi-drug approaches to inflammatory conditions
7. Emerging Addiction Treatment: Modulation of mesolimbic dopamine reward pathways suggests potential for treating substance use disorders, with strongest evidence for alcohol use disorder in patients with comorbid obesity.
8. Paradigm Shift in IBD Treatment: Moving from purely immunosuppressive approaches to promoting active tissue repair and intestinal healing.
9. Neuroprotection: Direct effects on brain insulin signalling, neuroinflammation, and glucose metabolism offer potential for neurodegenerative disease modification, though not curative for established pathology.
10. Safety Profile Supports Broad Use: Generally well-tolerated across diverse patient populations, though specific contraindications exist (e.g., decompensated cirrhosis not studied, pregnancy contraindicated).

Research Priorities

High Priority (Strong Mechanistic Rationale, Preliminary Human Evidence):

• Long-term outcomes for rheumatological conditions
• Optimal dosing protocols for non-metabolic indications
• Comparative effectiveness of different GLP-1RAs for specific conditions
• Addiction treatment protocols and patient selection criteria
• Mechanisms of pulmonary benefits beyond weight loss
• Long-term IBD healing and remission rates

Medium Priority (Plausible Mechanisms, Need Human Data):

• Dermatological effects require formal clinical trials
• Post-thrombotic syndrome prevention and treatment
• Gut microbiome effects need mechanistic clarification

Emerging Areas (Preclinical Promise):

• Other substance use disorders (opioids, stimulants)
• Additional neurodegenerative conditions
• Cancer prevention (emerging epidemiological signals)

Patient Selection:

• Identification of patient subgroups most likely to benefit from specific indications
• Biomarkers predicting response
• Optimal timing of intervention for different conditions

Clinical Implications

GLP-1 and GIP receptor agonists represent a new class of pleiotropic medications with far-reaching effects beyond their original metabolic indications. The breadth of conditions affected, combined with generally favourable safety profiles and the availability of both weight-neutral (liraglutide, dulaglutide) and weight-reducing (semaglutide, tirzepatide) formulations, positions these medications as potential disease-modifying treatments across multiple specialities.

Healthcare providers should consider these broader benefits when prescribing for approved indications and remain alert to emerging evidence for off-label uses. Patients with multiple comorbidities may experience compounding benefits across several conditions simultaneously.

The transition from viewing these as "diabetes drugs" to recognising them as "metabolic-inflammatory disease modifiers with organ-protective properties" represents a fundamental shift in therapeutic thinking.

Camus' L'Étranger: implications of translation titles - 'The Outsider', 'The Stranger', 'The Foreigner'

Camus' "L'Étranger" has the title translated as "The Outsider" in the English version by Stuart Gilbert (1946), while  "The Stranger" is the title for the American translation by Matthew Ward (1988).

The choice is a particular interpretative decision by the translators.

Readers of Camus, even in the American translation, will not be very typical. They are, as educated people in an anti-intellectual society, almost certainly (unless themselves lacking any emotional processing) used to being alienated from the brutal, exceptionalist, zero-sum game, thuggery that passes for 'Normal', there, so 'The Stranger' might be kinder to them, since strangers can be redeemed by becoming known, unlike Meursault, as an alien, a threatening "Other" to be rejected, aligning with the national psyche of exceptionalism and xenophobia.

Whilst 'outsider' is more accurate, it'd be cruel to emphasise it. It implicitly  criticises the group that does the outsiding. It forces the reader to consider the mechanisms of exclusion and their own role within them. This is perhaps a more socially reflexive and self-critical position, chiming more readily with English literary sensibilities.

The redemptive possibility that strangers can be redeemed by becoming known offers a glimmer of hope, however faint. It implies a journey, a potential for bridging a gap. It frames Meursault's condition not as a fixed social status, "outsider", but as a problem of understanding and communication. This is a fundamentally less devastating, and perhaps more palatable, framework for a reader who already feels on the margins, alienated.

In France, "un étranger" is, first and foremost, a foreigner - someone from another country, without French citizenship. This injects a colonial and social tension, before the first page is turned.

The murder of the Arab man by Meursault, a Frenchman, is hugely significant. The Frenchman is the étranger in the title, yet he is the one with power. The title is thus deeply ironic and critical of colonial society.

The French reader understands that Meursault is an étranger to the human condition itself.

He is a stranger to common emotional language. He doesn't understand its rituals (grief, love, repentance) and is therefore alien and incomprehensible to it.

He is an outsider because this failure to perform emotions excludes him from the human community. He is judged and ejected for his otherness.

The title, in French, is not a label for Meursault alone. It is a question posed to the reader and to society. It challenges the categories of "insider" and "outsider," "native" and "foreigner," "normal" and "alien."

In essence, while the English translations force a single interpretation ("The Stranger" or "The Outsider"), the original French title is the central philosophical problem of the book itself. It is a richer, more complex, and more accusing title than either of its English counterparts.

For the French reader, "L'Étranger" is a concise and devastating critique of social, colonial, and existential hypocrisy.

A better English title might have been 'The Foreigner', and, maybe, in the US, 'The Resident Alien'.

Gerard Manley Hopkins - A nun takes the veil

Gerard Manley Hopkins

Heaven—Haven

A nun takes the veil

I wonder if this might, like Robert Frost's poem about two roads diverging, be a wildly misunderstood poem. But first, some context that proves rather illuminating.

Hopkins wrote "Heaven—Haven" whilst an Anglican undergraduate at Oxford, shortly before his conversion to Catholicism. This biographical detail transforms our reading - the poem becomes not an observation of another's vocation, but Hopkins' self-examination.

Heaven—Haven
A nun takes the veil

I HAVE desired to go
Where springs not fail,
To fields where flies no sharp and sided hail
And a few lilies blow.

And I have asked to be
Where no storms come,
Where the green swell is in the havens dumb,
And out of the swing of the sea.

The nun has, past tense, desired. 'I have desired'. It is not, necessarily, what she desires now.

When you 'take the veil' as a nun, you subjugate yourself deliberately to the rule of the order. You voluntarily surrender your own, personal, desires entirely.

So this poem cannot be about what the nun desires after taking the veil. Rather, it is what she desired, before she decided to have no desires, save those imposed on her by the rule.

But here lies the deeper reading: Hopkins is exploring his own motivations through this feminine persona. The poem reads more like a fuga mundi than an amor Dei - a flight from the world rather than love of God. Listen to the language: "Where springs not fail," "where flies no sharp and sided hail," "Where no storms come." This is the vocabulary of escape, of seeking refuge, not of joyful spiritual union.

The alliteration itself reinforces this sense of retreat - the harsh consonants of "sharp and sided" give way to the softer sounds of "green swell" and "havens dumb." Hopkins is crafting a tone that moves from turbulence to stillness, from engagement to withdrawal.

What's entirely absent is the gaudium of the matrimonium spirituale - that joy found throughout the Marian tradition and encapsulated in the Magnificat. This reads more like a dirge than a celebration. The imagery is one of cessation rather than transformation: springs that don't fail (rather than springs that eternally flow), storms that don't come (rather than peace that surpasses understanding).

Hopkins, writing as an Anglican contemplating Catholicism, seems to have fundamentally misunderstood the nature of religious vocation. He presents it as an ending rather than a beginning, as the cessation of desire rather than its ultimate fulfilment in divine love.

This misapprehension may well explain why his early years as a Jesuit proved so wretched. He entered religious life expecting the quietude described in this poem - a haven from life's storms - only to discover that authentic spiritual life demands not the elimination of passion but its redirection toward divine love.

The tragedy Hopkins describes - someone with "transcendent desires for calm, peace, beauty" surrendering them for institutional obedience - reflects his own impoverished understanding of what religious commitment actually entails. The poem becomes, inadvertently, a critique of his own motivation: was his calling genuine spiritual yearning or merely sophisticated escapism?

Reading "Heaven—Haven" this way, we see JMH wrestling with whether his attraction to religious life springs from authentic vocation or from a desire to retreat from the world's complexity. The fact that he chose to explore this through the persona of a nun suggests he recognised, perhaps unconsciously, the problematic nature of his own spiritual motivations.

The poem's enduring power lies not in any celebration of religious life, but in its honest examination of the difference between true calling and mere refuge-seeking - a distinction that would prove painfully relevant to Hopkins' own subsequent struggles with his vocation.

Though, having said that, for me, the appeal is the poem itself, rather than the theology.

---

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Cicadas don't always use prime numbers

They're expecting huge amount of cicadas in America this year - because the 17 year cycle cicadas are due out; they last hatched in 2008. This brood has a particularly large geographic distribution.

Last year, 2024, was also particularly active for cicadas, in North America, because two broods emerged at the same time, 13-year and 17-year broods emerged at the same time.

I think it's interesting that only American cicadas use prime numbers in this way. South African, and other cicadas, emerge most years. We called them 'Christmas Beetles' from the time of year they emerged.

We had beautifully harmonious cicadas most years in our garden in Pietermaritzburg.

Often in mid-January, in the heat, there'd be a number of cicadas in different trees singing at the same time, which created an hypnotic beat-frequency, like a stereo record, seeming to sweep backwards and forwards around the garden.

It was the perfect accompaniment to a soft, hot morning, sometimes punctuated by lawn mowers in the distance, or the sound of water sprayed from a hose.

https://www.citizen.co.za/southlands-sun/news-headlines/local-news/2023/03/06/everything-you-need-to-know-about-the-life-cycle-of-cicadas/

Collaborative Negotiation

 The best training course that I ever attended, when working at Hewlett-Packard, in the 1980s, was a course called 'Collaborative Negotiation'.

It has helped me enormously, over the decades since!

The essence of Collaborative Negotiation is to understand that negotiation is not a 'zero-sum game', where the 'win' of one party comes only at a 'loss' to the other. This is not true, a good negotiation ought to be a win-win collaboration towards the best solution for both parties.

The first step to using Collaborative Negotiation is to understand that everything is a negotiation and everything is negotiable.

The main route to success is for both parties to do their best to understand the motivation, needs, both tangible, and emotional, and use that understanding to find novel, unexpected solutions that meet these needs for all parties.

This requires work, imagination, and emotional intelligence - practicing negotiation every day, whenever the opportunity arises, helps build these skills.

Whenever you are presented with a situation that doesn't seem ideal, realise it is a negotiation and try to understand the position of the person you are working with.

Then you, and the other party, can frame the situation in a way that makes more sense, and, from that, work towards a solution.

The practice of collaboration, and the importance of negotiation is the core of my book Collaborative Consulting: Service Management Scenarios.

If you are interested in having things work out better, but don't feel comfortable bullying others, or tricking them, or using confrontation to get your own way, I strongly recommend the book to you.

https://www.amazon.co.uk/Collaborative-consulting-service-management-scenarios/dp/0113313918

TikTok ban - and the Tor Browser

There is a move for the US, and, now, US governnents to ban TikTok.

The claim is based on Sinophobia - claiming that it presents some sort of danger that Facebook, X(twitter), Instagram, and other platforms do not have.

This is bogus. All social media platforms 'spy' on users. If that is an issue, the argement could only be to ban all social media.

The actual reason, as is pretty well known, is that TikTok supports free speech. This access to free speech has led to lots of users, quite properly, discussing their horror at the genocide against Palestineans, being carried out by the Apartheid State of Isreal. They hope to suppress this discussion in order to continue their complicty with the war crime of collective punishment, by supplying arms and money to Isreal.

There is a solution, if this ban comes about.

Users of TikTok need to download the Tor browser:

https://www.torproject.org/download/

Then use this browser to create, and use, accounts on TikTok.

This will circumvent the ban, and allow free speech to continue - aiding the humanitarian effort to stop the genocide in Gaza.

Exploring the 'randomness' of /dev/urandom, and xored derivatives

 For quite a lot of cryptography, you need a good source of random numbers, particularly for one-time pads. It's difficult to get fast sources of natural event based numbers, so some sort of compromise is common.

Using /dev/urandom as found on linux and other Unix systems, like macOS, is generally considered quite a good source.

*** Update  - 19th March 2024 ***

The article stands, but more investigation has showed me that the major problem with /dev/urandom is that it is highly biased against repeated numbers. This is not representative of a good pseudo-random generator.

Compared to 𝛑, /dev/urandom gives very few repeated numbers ( 00, 66, 99 etc.), and hardly any occurences of multiple repeats (00000, 66666, 99999). This is a weakness to cryptanalysis.

So, if using /dev/urandom, it would be wise to process all sequences to add ('at random') repeats of numbers, allowing even long strings of repeats, maybe up to 8 repeated numbers, inserted at pseudo-random intervals.

*** End of Update ***

The initial statistics

To get a good characterisation of a sequence of 'random' numbers, you need quite a lot of them, so I generated 152,256,840,500 four digit hex numbers, like this:

od -x -An  </dev/urandom >fill_with_urandom

The 1.52 * 10^11, or just over a tenth of a billion, numbers take up 709Gb, and took 10 hours, 3 minutes and 59 seconds to generate on a Mac mini M2. 

To get an idea of the shape, I counted the number of times each hex number, from 0000 to ffff occurred. That's 65536 numbers. 

So the expected frequency would be 2323255 for each number, if they turned up equally often. The statistics give:

Min:              2316807  

Max:     2329592 

Mean:     2323255 

Standard Deviation:    1529.303 

Median:     2323255 

Fivenum:             2316807 2322219 2323255 2324284 2329592 

Skewness:     0.0004868033  

Kurtosis:             3.004057

As you can see, the mean is exactly that, and the standard deviation only 1529, which is only .0658%. The mean and median are the same, which also shows a very even spread of frequencies.

If the figures were distributed exactly in a normal distribution, the Skewness would be 0 and the Kurtosis 3. So it is extremely close.

Using XOR to produce a new sequence of numbers

In theory, if you xor one random sequence with another, you ought to get another, quite different random sequence. I thought it would be interesting to do just this.

First I produced a new sequence by xoring each number with its neighbour, doing it in groups of eight - making up the eighth number by xoring the first with the eighth. Using the same Mac mini M2, this took 34 hours, or  1 day, 10 hours, 13 minutes and 44 seconds.

The same statistics as above, gives:

Min: 2317159 

Max: 2330445 

Mean: 2323255 

Standard Deviation: 1530.588 

Median: 2323262 

Fivenum: 2317159 2322224 2323262 2324284 2330445 

Skewness: 0.001143814 

Kurtosis: 3.001915 

This is impressively different. The mean and median are different. However, the spread is almost exactly the same, 1530, instead of 1529 for the standard deviation.

What I found interesting were the last two.

The Skewness is   0.001143814  compared to 0.0004868033 the first being 2.35 times bigger! Though they are tiny numbers, that is a big difference.

The Kurtosis is 3.001915 compared to 3.004057, again, small, but the difference is about double.

Using XOR a second time

I now performed exactly the same operation as above, but using the new sequence as a starting point. This gave:

Min: 2316959 

Max: 2330963 

Mean: 2323255 

Standard Deviation: 1523.088 

Median: 2323254 

Fivenum: 2316959 2322234 2323254 2324272 2330963 

Skewness: 0.005033493 

Kurtosis: 3.03291 

The standard deviation at 1523 is similar to the previous two  1530, 1529 but different enough to show a different shape.

This is confirmed, with:

                       1st                         2nd                    3rd

Skewness:  0.001143814   0.0004868033.     0.005033493 

Kurtosis:    3.001915          3.004057            3.03291 

This time both are very different to the previous two - the skewness five times the first set, and the kurtosis difference ten times greater. All three showing very different shapes.

The final test - xoring the previous sequence

 Instead of over each set of eight numbers, taking five lines at a time, and xoring sets of 40 numbers at a time (with the 40th result being the 1st xored with the 40th). This gives:

Min: 2317132 

Max: 2330652 

Mean: 2323255 

Standard Deviation: 1523.587 

Median: 2323256 

Fivenum: 2317132 2322226 2323256 2324275 2330652 

Skewness: 0.00861003 

Kurtosis: 3.021 

The standard deviation is very similar to the previous run,  1523.587 vs  1523.088. The mean and median again differ by only one, but in the opposite direction.

Then: 

                       1st                         2nd                    3rd                4th

Skewness:  0.001143814   0.0004868033.     0.005033493.  0.00861003 

Kurtosis:    3.001915          3.004057            3.03291           3.021

Conclusions 

These results, using 152 milliard four digit hexadecimal numbers give /dev/urandom a fairly thorough test, showing it is, indeed, highly stochastic.

The experiments using xor, show that xoring a sequence of numbers, with itself, produces another random sequence that is significantly different, including having a different shape, but is still a good pseudo-random sequence.

The latter two sequences do show an increased skewness, and a greater distance from a standard deviation.  In a sense, suggesting they have become more stochastic.

It looks as if it would be interesting to try a final experiment, with, the 4th sequence, but, maybe, taking it in batches of 80 numbers.

 

Eulogy to my halogen air-fryer / oven

Our halogen oven / air-fryer is a delight, and amazing technological improvement from the, already wonderful, invention of the air-fryer itself.

Having just cleaned my halogen air-fryer for the third time, since getting it last November, I thought eulogise it here, rather than boring people on Facebook with all the detail, I'll just point here, so most people can ignore it.

Yes, it is so easy, and satisfying to clean that I've cleaned it to sparkling clarity three times - it took ten minutes this time, because I'd made the mistake of cooking pastry (salmon en croute) on the grill, rather than on a piece of foil, usually, after its 'self-clean', it takes a minute to wipe it down.

Meanwhile our conventional oven has probably been cleaned annually over the past few years, maybe a little more often, but always an unpleasant, tedious job, including lots of powerful, pongy chemicals and the need to wear gloves.

Oh, and in case you're wondering, an 'eulogy' (eu = good, logy = words) is not only for the dead, our air-fryer is still in robust good health being in use most days, often for the perfect toasted cheese snack.

Over Christmas, I remarked, when we'd just had loin of wild venison, with roast potatoes - all cooked in 25 minutes. The venison is, accounting for the recency effect, the best I've had. Pink in the middle, succulent, moist, and tasty beyond my imagining. 

In a conventional oven, it'd have taken much longer, and would certainly have been dryer (despite the bacon wrapping and sauce), with a less full flavour. I'm very deply impressed!

The versatility is hugely impressive. The only single thing I've had to cook in our conventional oven is the Christmas goose, simply because it was too huge to fit - it only just fitted in the oven. Everything else, including the goose pie, made from that goose, has been halogened - I think a verb form of 'halogen' is now required.

Being able, with no effort, to see the food as it cooks, is a huge benefit, and the lovely warm glow of the oven makes the kitchen, in Winter, seem even more welcoming than usual.

The have to be some things that are less than perfect. The main one is that, the top, being very hot after cooking, can't be put down, so you have to get things out one-handed. The solution will be to put a large, sturdy hook above the oven, where the lid can be hung when getting things out - I'm going to make sure it's high enough and properly positioned so it's difficult to burn your forearms whilst doing this.

Apart from that, it is is quite magnificent. 

TheT lhat halogen oven is quite something! We've just had loin of wild venison, with roast potatoes - all cooked in 25 minutes. The venison is, accounting for the recency effect, the best I've had. Pink in the middle, succulent, moist, and tasty beyond my imagining.

In a conventional oven, it'd have taken much longer, and would certainly have been dryer (despite the bacon wrapping and sauce), with a less full flavour. I'm very deeply impressed!

Seeing - myopia, presbyopia, astigmatism - why can't children get new lenses?

 Seeing is an essential part of being

Being able to see matters. If we can't see, we are unable to take a full part in normal human activities. Replacing our natural lenses with plastic lenses is an amazingly effective way of restoring sight to people with myopia, presbyopia and astigmatism, but it is usually only used when people have cataracts.

I have been short-sighted (myopic) all my life - before my lens replacement, I was measured as being -12 diopters in terms of my myopia, my astigmatism was extreme, and, beyond that, I was able to see things less clearly, and differentiate colours badly, because of my presbyopia (old-age related vision decline) and my cataracts (that were clouding my vision).

This is not a sob-story about me. Many people are in just this position, and, often, when much younger than I was when my lenses were replaced.

When I was very young, my myopia was diagnosed, and I was prescribed the usual thick bottle-bottom lenses. I thought these were a huge improvement.

Later in life, I heard about Lasik, laser surgery to improve vision. So, I went for it. It was one of the most painful experiences of my life. As the laser cut away my eye, I could smell the burning. I was unable to be exposed to any bright lights, without pain, for three days afterwards. It took me several weeks to recover. I still felt pleased, after that, that I had done it, because I thought that my vision was so much better. I still needed glasses to read, and I still couldn't see things as other people saw them, but I didn't know that, so I thought it was a brilliant improvement.

Several years later, my optician examined my eyes, and said that I was developing cataracts. He referred me to a surgeon. This was a major turning point in my life.

The surgeon arranged for an operation to replace my lenses with plastic lenses - not the lenses in my glasses, the lenses in my eyes. I was quite apprehensive about this, because the lasik surgery had been so horribly painful for so long.

I need not have worried. My lens replacement surgery was completely painless - I really mean that, I had no discomfort whatsoever, none at all.

I could not believe the difference! Suddenly, colours were bright and I could see a huge range of colours. I could also see features far away, on the mountain, so clearly that I thought they might be artificial. When I went to the supermarket, for the first time, I could read all the signs, above the aisles, saying what was being sold there - before, I'd thought it was some sort of joke to expect people to read them, unless they were immediately below them, and I wondered why they bothered... Now I could see that the far aisle was for pickles and pasta - it was a revelation!

Yes, I still need reading glasses to see something close up. Yes, years, now, after the operation, the unbelievable brilliance of colour that I saw after my operation has settled down - our brain accommodates to things and they seem less exceptional. Still, my experience of the world is so rich and varied, and clear, compared to what it was during the first fifty years of my life that it continues to amaze me. Just this afternoon, I was looking at a tree at the bottom of the garden, and marvelling at how I could see all the leaves, not a a blur, but as leaves, and I could see the bright blue of the sky and the many different greens of the tree - for most of my life, this has been impossible.

So, with all this wonder, and improvement, what is my point?

Why can't we offer young children, with bad myopia and bad astigmatism, lens replacement? Why should they wait until they are old enough to have cataracts?

If only, as a child, my lenses had been replaced, my life would have been quite different. I'd have found microscopes and telescopes useful instruments - as it was, I wondered why anybody bothered, because, to me, they just offered blurs. I could have seen the beauty of mountains, I might have been able to play sport - I hated rugby and cricket because I could not see the ball. It seem silly to say this, but, when they sneered at me for dropping the ball it was because I only actually saw the ball when it was a metre of so from me, far too late to catch it.

Can't we spare children this diminished perceptions?

Can't we give people with bad eyesight good lenses?

I really think that we should. Contact lenses, glasses, laser-eye-surgery, all seem to offer improvement, b ut, from personal experience, I know they are actually quite useless. The only thing that really works to fix your eyesight is new artificial lenses.

Depression - it's not just feeling bleak

 I've been depressed twice.  By that, I mean diagnosed as clinically depressed, no simply 'feeling bleak'

There's something wrong with the diagnosis of 'depression', because it is so very easy to think that it is the same as 'being depressed' - It is not

The first time I was clinically depressed was back in the 1990's. I was not coping with life, and used the company mental health option to uget an interview with as 'counsellor'. He listened to me for about half an hour, then showed me a picture of the signs of depression, and explained that I fell into all of these, from what I'd said.

So, I went to my GP, and got a prescription for Prozac. The odd thing was that it worked at once, within a week, I was feeling better. SSRIs are not supposed to work that quickly, but the did. It might have been the   placebo effect, but, within three days, I felt better, and started to engage with life.

 I was lucky. I got better, and started to understand the reasons for my depression. Mainly, it was because I'd broken up a relationship

So, I'm an analytical sort  of person. I score quite high on the autism scale, meaning that I analyse things, before feeling them.

Twenty years later, I suffered a few set-backs. My wife was diagnosed with breast cancer, and I spent time with her during her treatment. Her brother dies. My father died. I was stabbed seven times by a burglar. I was suffering severe financial difficulties, and I couldn't see a way out.

What's really peculiar is that, from all of the above, I didn't realise that depression was a likely outcome.

I found that I couldn't do anything. I spent my time in bed.

I started to think about suicide. I looked at sites that sold inert gassed, such a nitrogen, that I knew would establish an easy death. I worked our ways to kill myself - but, at the same time, tried to make a distance, so that the means to kill myself were not immediately to hand. I had to be that, if I killed myself, I was not just on the spur of the moment.

I told GP about these suicidal thoughts, and he referred me to a psychiatrist, who, after a chat, said, a if it was obvious that I was depressed.

I understood, then, what the problem was. I'd managed, over several years, to keep mysense of self under control by going to Amsterdam and having huge doses of psilocybin, in the form of truffles, from magic mushrooms. These helped me centre myself, and resolved the depression completely.

It has still been a struggle. I'm coping today, but I look out for the signs - I mainly sleep around 11 hours a day, which is more than it should be, but, I'm coping, despite that.

What's amazing to me now, that I'm better, is that I still sleep far more than most people. The great thing is that I've not had any thoughts of killing myself for over a year.

It's odd, really, that it should be such a defining thing, but, if you are reading this, please accept that it is. The practical working out of how you are going to take your own life isn't what you think it is - it's not a conclusion, it's a symptom.

Understand that, and you're on the way back to happiness.

The power, and weakness of metaphor

We use metaphors all the time, hardly noticing that we do. They're an essential part of our thinking apparatus, enabling us to transfer notions from one, usually concrete, domain into other abstract domains.

They're so powerful, ubiquitous and unnoticed, that it's useful to see what happens when one doesn't work.

In the late 1970s,  was lucky enough to meet the HP programmable calculator, the 9100A. It was the size of a microwave oven and you could store instructions on little magnetic strips to execute as programs later.

It didn't have an alphanumeric keyboard, the commands available were on the keys - as with later HP handheld calculators, one key could have more than one meaning. The screen showed the x,y and z registers. You could connect a plotter to it, and the physics department had given me the exercise to plot the orbit of the earth around the sun.

Mostly everything made sense, but there was one part of the set-up that puzzled me considerably.

There were a few keys connected to 'flags'. You could 'set' or 'clear' a flag, and then test to see if a flag was 'set' or 'cleared'. I could understand why these were useful, because they allowed simple binary decisions to be made, based on earlier results.

What didn't make sense to me was the term 'flag', and it being used in this way. I knew about flags as things made of cloth that were run up flagpoles by people who were keen on that sort of thing - the same sort of people, usually, who were keen on uniforms, marching about, and killing people.

It wasn't clear to me how these flags were connected to the ones on the 9100. What was, to me, particularly puzzling was how anybody would think of a flag as 'set' or 'clear' and how you'd know which state a flag was in. If the flag metaphor was used, I'd have expected 'raised' or 'lowered' or 'half-mast' to be the terms used.

I wasn't able to resolve this from the manual, because it seemed to assume familiarity with flags used in this way, and nowhere described where the metaphor came from.

It was about four years later, when I visited California for the first time, that I discovered what it was all about. I'd seen photographs of letterboxes in America, and noticed them in films. They were cylindrical, with a flattened bottom and a hinged door. I was surprised by their uniformity, being used to seeing many different designs, not just one.

The other feature they had was a key-shaped bit of metal mounted about half way down. This, I discovered, was the source of the metaphor. This wasn't just a bit of decoration, but a signalling device. People who lived in the US knew this, and called the bit of metal a 'flag'. The protocol was that, when he deliver the post, the postman would raise the 'flag', thus 'setting' it. This signalled to somebody looking across the front garden that there was new post. When you collected the post, you'd put the 'flag' down (clearing the flag), to indicate that the postbox was empty. [I've now been corrected, you can see in the comments below. Apparently you, the owner of the letterbox 'set' the flag to indicate a letter was waiting to be collected, and the postman 'clears' it, by putting it back down, indicating that the letter has been collected, and that you have new post - the opposite of how I'd understood it... making it even clearer how difficult it can be to understand a metaphor from an alien source].

The alternative etymology, that might be behind the letterbox usage, is the 'flag' used on a taximeter to indicate if it is free, or 'for hire', or occupied, 'hired'. The OED doesn't give etymology for the computing use, so this isn't certain.

Clearly, the makers of the HP9100A, who lived in California, and worked for Hewlett-Packard, who'd paid for me to travel to California, as their employee, knew all about this, and thought the principle universal. Which was why there was no explanation of what 'setting' or 'clearing' these 'flags' was about.

In the years since, when meeting difficult metaphors, or thinking of a metaphor to describe something myself, I've often remembered this problem. If you are going to use a metaphor, you have to make sure that your audience will be familiar with whatever it is that you are going to use as a metaphor. Otherwise it will fail to communicate your idea - or, if it does, it'll involve a special effort of interpretation by the reader to work out what you were getting at.

Management Dream

Notes:

- First day as  a new manager

- Big HP office glass box in the middle. Decided not to bags a desk, but hover between the exposed space, with light, near the corridor, and the cave-like space in the middle. Hoping to have us moved some where better.

- Asked team to come up with agreement on what to use for rotas & scheduling by lunchtime - if they came to blows, I'd be excused as it was a first day

- Decided to order printers - discussed options like fan-fold, holes, considered noise - thought it a good plan to find out about my budget, learn how purchasing worked, and find out how noise-averse our neighbours were, and, by this means, who they were, and whether they'd help us move somewhere else.

- Went to find out about site meetings -- delighted to find a manager who said there were several a day, but kept a jar filled with minutes from all those worth knowing about, about six rolls of minutes - said he kept it fairly up to date

- My manager away, broken leg, skiing accident

- Leave out the bit about kangaroos and needing a seprate kanga-bog for the little ones

- Wondered whether to take my team out to lunch, it being the first day, thought about whether it'd be the canteen or local pub, realising either would set all sorts of precedents,. Decided to suggest the canteen, but allow myself to be persuaded the pub would be a better idea, as long as it was informal and not me taking everybody out. The excuse of leaving that to my manager, when he came back with his leg in plaster, seemed sound

- Had wondered if I should start clearing up the area and bags a desk, or if I should find where facilities was and see if they could help (unlikely on the first day, but I'd learn who'd given them the best bribes last year). 

- I wasn't quite sure who my team was, there were various people floating about the area. I hoped that lunch and the group task would sort it out, more or less.

On the merit two-dimensionalality

If you left your tennis racquet out in the rain, without its press, you learnt that being three-dimensional is not always a blessing.

My last tennis racquet was made of ultra-light metal, and strung with plastic, nylon, I think, so you could keep it in the bath, and it'd still work. It didn't even have a cover.

Two books that I prized greatly as a child were volumes I & II of 'How things work'. I think they were a present. I'd have thought they might have been from my mechanically minded uncle, but I think they were more probably from my parents, or brother. Probably my brother.

My uncle once gave me a set of chest-expanders for Christmas. I had no idea that anybody would use such things voluntarily, and still don't understand people who do. I was so disgusted that I didn't, fortunately, probably, even think about how the springs could have been adapted into a trebuchet.

'How things work' were wonderful books. Volume I rather better than Volume II, which seemed something of an afterthought, but they didn't explore the medical, surgical or veterinary worlds much, so there wasn't anything about the making of tennis racquets and what went on at the cat-gut factory. I looked, specially, so I know this, and still don't know if they use(d?) machines or people who were very good with scissors.

Wikipedia tells me they use sheep or goats, rather than cats, something that'd have been hard to find out then. This aside in wikipedia has me wondering 'Lean animals yield the toughest gut', so, if you're going to use somebody's guts for garters, make sure he's not too skinny.

Technological improvement is a wondrous thing, but, somehow, it seems sad that boys of today don't have a chance to think of the relative merits of the four-screw press over the fast-release lever press for racquets, or to wonder what happens at the cat-gut factory.

Plagiarism dream

Told by a fellow student (or senior student, or lecturer) that the professor and head of department have a heard an accusation of plagiarism against me.

It turns out that it isn't. I'm accused of having a book on (by?? - it's a dream, maybe my unconscious doesn't know Socrates didn't write any books) Socrates prominently displayed in my room, but not to have read it - hardly plagiarism, hardly a crime. I protest that there's nothing wrong with that, then the accusation is spelt out in more detail. I've told people about things in the book, as if I've read the book, whilst I've still been reading through it - keeping one chapter ahead of the class, as it's known. This, too isn't a crime.

However, I'm delighted to realise that both the prof. and the head of department (It's not sure why there's an heirarchy here, you'd expect it to be one and the same person, unless it's an aspro) have believed the accusation, believed it is wrong, and also known how it's done. So, I think, in the dream, must have been guilty of it themselves.

On waking I wonder how such a strangely convoluted dream could come about, and how I'd not thought that the lecturer, prof., and head of department may not have done it themselves, but encountered other students that had done it.

Anyway, I clearly felt better to be vindicated, at least in my own mind, and, in the dream, flew (well, an extended floating jump) from the back, at the top of the tiered lecture theatre down to the front in a series of triumphant, sweeping dance-like descending stages - slowing my descent by touching the side-wall, or panelling on the side-wall.

The bunny gardener

The Bunny gardener.

We’d only been waiting a few minutes, when I saw the large, white rabbit walking purposely up the hill, along the pavement, towards us, unaccompanied.

I was with my brother in the small, trim garden. The others had gone ahead to chapel, and, if there was time, we were to join them. I think we were in Wales, at the house of a relative - though not an aunt, as she didn’t look like any of our three aunts. It was a very quiet Sunday morning with nobody about.

The bunny came into the garden, gave us a nod, and started to take care of the most obvious chores, nibbling off a dying branch from one of the rose bushes and dragging it to the heap in the corner that was clearly going to be the bonfire later.

Then he came to look at the provisions we’d laid out for him, clearly satisfied with the milk, carrots and, I think, oatmeal. Then he gave a start, almost gave us a disapproving look, and started looking through one of the bags we’d brought the provisions in with the air of somebody not expecting to find anything.

It suddenly came to me, I remembered out instructions. I said:

‘I’m so sorry! I realise that we didn’t get the mutton kebabs. We’ll get some as soon as we can, and have them ready for you when you come back on….’

‘..Wednesday’, my brother said. I’d not remembered the day.

The bunny stopped looking, and went back to gardening. I don’t think he could speak, but, if he had, it’d have surprised me less than him arriving on his own.

It was, we’d learned, a standard arrangement, you got hold of the bunny, through a ‘phone call, and he turned up at the stipulated time, getting on with the job happily, and extremely efficiently, wanting only to have the right provisions. 

Unusually, he was a carnivorous rabbit, at least to the extent of mutton kebabs.

We went inside, leaving him to work, deciding, without much regret, well, without any, actually, that we were too late to make chapel. We settled down to wait, after having made a note to get the kebabs, and, a few minutes later, everybody came back from chapel.

It was a most vivid dream. The rows of houses, with small front gardens, on each side of the road curving downwards are sharp in my memory, as was the garden of the house itself, with somewhat fussy brick flowerbeds in front of the chocolate-boxy house. It was the chapel, and the general atmosphere, that made me think it must be Wales, though it was very certainly much to smart and affluent to be sad Rhymney.

I’m no fan of dream interpretation, since, more often as not, cigars are just cigars and bunnies, rabbits.

I also know that other people’s dreams are of very little interest, only our own dreams fascinate us.

Still, since this was one of the more outré dreams I’ve ever had, I thought I’d write it down, whilst I remembered. 

I know why, particularly, I wasn’t keen on going to chapel. When I went, with my mother, in Rhymney, when eleven, I wanted to sing the familiar hymns, but found the hymnbooks impenetrable, being written in Welsh. 

We’ve never had rabbits as pets. I know no bunnies. So I’ve no idea why I dreamt of the bunny gardener, but I’m pleased that I did. Peculiar as it was, it was a most peaceful and pleasant dream.

The oddest thing about it was that I thought it odd that the bunny came to us unaccompanied, usually, in dreams, you don’t question that sort of thing.

A magical Easter morning

I was treated to an amazing experience this morning. I drove into town, on my 'bike, as usual, for my swim, at the Long Street Baths. It's a magnificent, clear, bright sunny morning, with Table Mountain sharp and clear, after the recent, blessèd rain.

As I walked into the changing-rooms, empty, as you'd expect on a holiday, I was transfixed by the beautiful sound of a hymn being sung in the pool-hall. As you'd expect, the acoustics of a large municipal swimming pool are impressive.

There were about twenty people, around the shallow-end, singing mindfully, eyes closed, with close harmonies, and extemporized descants, over a confident, joyful, rhythmic and unhurried rendition - every word clearly annunciated. My mother once said that the only thing that ever made her a little homesick, for the valleys of Wales, was the sound of a Zulu congregation. 

There's no need for a choir, in Wales, as in Africa, the congregation expect, and are expected, to carry the sound entire.

It was, of course, quite unaccompanied by any instrument.

I swam, as they sang, together with two other fortunate swimmers.

It was a mass, full-immersion baptism - if it can be a 'mass baptism' with only half a dozen baptizees. 

One, by one, as we swam, they six were lowered into the water, then, emerging, clapped by all, and photographed by flashing cell-phones. 

Smiles of delight welcoming them back to the dry poolside.

Vanity can't have been discussed much, during their catechism, because one baptizee wrapped a large, green plastic bag about her head, so as not to spoil her hairdo.

As I changed back, and got ready to return home, the closing hymn was echoing through the changing-rooms, that, for  that moment, were the cloisters of heaven.