Ethics, psychology & the sciences

Capacity

The MCA 2005 governs decisions for those who may lack capacity. Its five principles: (1) ASSUME capacity unless proven otherwise; (2) support the person to make their own decision (all practicable help) before deeming them unable; (3) an UNWISE decision does not itself prove incapacity; (4) any decision for an incapacitous person must be in their BEST INTERESTS; (5) choose the LEAST RESTRICTIVE option.

Capacity

Assessing capacity has two stages. STAGE 1 (diagnostic): is there an impairment of, or disturbance in, the functioning of the mind or brain? STAGE 2 (functional): because of that, is the person UNABLE to do ANY ONE of — UNDERSTAND the information, RETAIN it (long enough to decide), WEIGH it in the balance, or COMMUNICATE the decision? Failing any one = lacks capacity for THAT decision.

Capacity

When an adult lacks capacity for a decision, it is made in their BEST INTERESTS (not just medical interests). Consider: the person's past/present wishes, feelings, beliefs and values; views of family/carers/anyone with legal authority (LPA/deputy); whether they may regain capacity (and could the decision wait?); and the least restrictive option. An IMCA is instructed for serious decisions where there is no one to consult.

Capacity

A legal framework authorising the deprivation of liberty of an adult who LACKS capacity and is under continuous supervision and control and NOT free to leave, when this is in their best interests (e.g. a confined patient with dementia in hospital/care home). Requires formal authorisation. (Being replaced by the Liberty Protection Safeguards.) Distinct from the Mental Health Act, which is for treatment of mental disorder.

Consent

An ADVANCE DECISION TO REFUSE TREATMENT lets a capacitous adult REFUSE specified future treatment for when they lose capacity; it is legally BINDING if valid and applicable (must be written, signed, witnessed and specify 'even if life is at risk' to refuse life-sustaining treatment). A LASTING POWER OF ATTORNEY (health & welfare) lets a person appoint someone to make health decisions when they lose capacity — an LPA can consent/refuse on their behalf within its scope.

Consent

For consent to be valid the person must have CAPACITY, be adequately INFORMED, and give it VOLUNTARILY (free from coercion). Consent can be express or implied and must be specific to the procedure. The amount of information required is set by Montgomery (material risks). Lack of any element invalidates consent — treating without valid consent can be battery.

Consent

Montgomery v Lanarkshire (2015) set the modern consent standard: a doctor must disclose any risk to which a REASONABLE PERSON IN THE PATIENT'S POSITION would attach significance, OR which this particular patient would. It replaced Bolam for consent — disclosure is judged by the patient's perspective, not professional custom. Drives shared decision-making and documentation of risks discussed.

Children

A child UNDER 16 can consent to their OWN medical treatment if they have sufficient maturity and intelligence to fully understand what is proposed (Gillick competent). Competence is decision-specific. A Gillick-competent child's consent is valid without parental involvement — but, unlike an adult, a competent child's REFUSAL of life-saving treatment can be overridden by a person with parental responsibility or the court.

Children

The specific criteria for giving CONTRACEPTIVE (and sexual-health) advice/treatment to an under-16 without parental consent: the young person (1) understands the advice; (2) cannot be persuaded to tell their parents/allow the doctor to; (3) is likely to have sex with or without contraception; (4) their physical/mental health will suffer without it; (5) it is in their best interests to receive it without parental consent.

Children

A person with parental responsibility can consent to treatment for a child who cannot/does not consent. For 16-17-year-olds, consent is presumed (like adults) but, as with Gillick-competent under-16s, a REFUSAL of life-saving treatment can be overridden by parental responsibility or the court — the law prioritises the child's welfare/life. Only one PR-holder's consent is needed; serious disputes go to court.

The duty

Doctors owe a duty to keep patient information confidential — it underpins trust. Information may be shared for the patient's own CARE (implied consent within the team), but disclosure beyond that generally needs the patient's CONSENT, unless required by law or justified in the public interest. The duty persists after death. Anonymised data can be used more freely.

When you CAN break it

Confidentiality can be breached WITHOUT consent when the public interest in disclosure outweighs the patient's interest in privacy — typically to prevent SERIOUS HARM to the patient or others (e.g. risk of death/serious harm, serious crime). Disclose the minimum necessary, to the right person, and tell the patient where practicable. A judgement, justified case-by-case.

When you MUST break it

The law sometimes REQUIRES disclosure regardless of consent: notifiable infectious diseases (to public health), FGM in an under-18 (mandatory reporting to police), suspected terrorism, certain court orders, and providing information to regulators/coroner. Road Traffic Act: you must give identifying details of a driver to police on request (but not clinical details). These override the default duty.

Driving

It is the PATIENT'S legal duty to inform the DVLA of a relevant medical condition (e.g. epilepsy/seizure, certain cardiac/neurological/visual conditions). The doctor should advise them to stop driving and notify the DVLA. If the patient continues to drive against advice and cannot be persuaded to stop or notify, the doctor SHOULD inform the DVLA (a public-interest disclosure), telling the patient first.

Information governance

The Caldicott principles govern the use of confidential information (justify the purpose; use the minimum necessary; access on a need-to-know basis; everyone aware of responsibilities; comply with the law; the duty to share can be as important as the duty to protect). UK GDPR/Data Protection Act 2018 give the legal framework — lawful basis, data minimisation, patient rights of access.

Framework

Beauchamp & Childress's framework: AUTONOMY (respect the patient's right to make their own informed decisions), BENEFICENCE (act in the patient's interest/do good), NON-MALEFICENCE (avoid/minimise harm — 'first do no harm'), and JUSTICE (fairness in distribution of resources and treatment). Most ethical dilemmas are analysed by weighing these, which often conflict.

Professionalism

The GMC's standards: make the care of the patient your first concern; provide a good standard of practice; keep knowledge/skills up to date; treat patients as individuals and respect their dignity; work in partnership (consent, honesty); act with honesty and integrity; never abuse trust. Breaches can lead to fitness-to-practise proceedings.

Professionalism

The professional and statutory duty to be OPEN and HONEST when something goes wrong: tell the patient (or family) promptly when harm has or may have occurred, offer an apology, explain what happened and what will be done, and report/learn. Applies even when the patient is unaware harm occurred. Distinct from, but reinforced by, honesty in GMC Good Medical Practice.

Negligence

The standard of care for DIAGNOSIS/TREATMENT: a doctor is not negligent if they acted in accordance with a responsible body of medical opinion (BOLAM) — but that opinion must also withstand logical scrutiny / be reasonable (BOLITHO). Together they set the 'breach of duty' standard in negligence. (Note: for CONSENT, Montgomery replaced Bolam with a patient-centred standard.)

Negligence

A clinical negligence claim requires FOUR elements: (1) a DUTY of care was owed; (2) the duty was BREACHED (fell below the Bolam/Bolitho standard); (3) CAUSATION — the breach caused the harm ('but for' the breach, harm would not have occurred); and (4) the harm/damage is not too remote. All four must be proven (on the balance of probabilities).

Communication

A structured approach to delivering bad news: SETTING (private, uninterrupted, support present), PERCEPTION (ask what the patient already knows), INVITATION (ask how much they want to know), KNOWLEDGE (warning shot, then clear, jargon-free information in small chunks), EMOTIONS (acknowledge and respond empathically), STRATEGY/SUMMARY (plan and next steps). Pacing to the patient is central.

End of life

A DNACPR decision means cardiopulmonary resuscitation will NOT be attempted if the heart/breathing stops — it addresses ONLY CPR, not other treatment (which continues as appropriate). It is a clinical decision (CPR need not be offered if it won't work), but must be discussed with the patient (or family if they lack capacity) unless that would cause serious harm. ReSPECT is a broader personalised emergency-care plan.

End of life

Ethically and legally, WITHHOLDING a treatment and WITHDRAWING one already started are equivalent — neither is killing if the treatment is no longer in the patient's best interests (or is validly refused). Withdrawing a futile/unwanted treatment that then leads to death is allowing the disease to take its course, distinct from an act intended to cause death.

End of life

An action with a good intended effect (relieving suffering) is permissible even if it has a foreseen but UNINTENDED bad effect (hastening death), provided the intention is the good effect and the bad effect is proportionate. It distinguishes giving adequate opioids/sedation to relieve terminal distress (lawful) from administering a drug INTENDING to kill (unlawful euthanasia).

After death

The MCCD (medical certificate of cause of death) is completed by a DOCTOR who attended the deceased during their last illness — under the reformed (2024) system ANY attending doctor may complete it (the old 28-day/last-seen rule was removed), and EVERY death is now independently scrutinised by an INDEPENDENT MEDICAL EXAMINER before registration. Refer to the CORONER (and do NOT complete an MCCD) if: cause unknown; violent/unnatural/accidental/suspicious; during/after an operation or anaesthetic; industrial disease/poisoning; in custody/detention; or no attending doctor. Cremation forms are separate.

After death

England, Wales and Scotland operate DEEMED CONSENT ('opt-out') for organ/tissue donation: adults are considered willing donors unless they opted out or are in an excluded group. Families are still consulted and a known objection is respected. Donation after brainstem death or circulatory death follows strict criteria; the donation team is separate from the treating team.

After death

A patient on a ventilator whose brainstem has irreversibly ceased to function is legally DEAD (death by neurological criteria / 'brainstem death') even though the heart still beats. Diagnosis requires TWO doctors — both registered for ≥5 years, at least one a CONSULTANT, and NEITHER a member of the transplant/donation team (to avoid conflict of interest) — who EACH perform the full set of brainstem-death tests (e.g. pupillary, corneal, oculovestibular, gag/cough, apnoea), on TWO separate occasions. The legal time of death is the FIRST set. This certification (not the MCCD) is what enables organ donation from a heart-beating donor.

Recognition

Abuse categories (children and adults overlap): PHYSICAL, EMOTIONAL/psychological, SEXUAL, NEGLECT, and (for adults) FINANCIAL/material, organisational, discriminatory, domestic, modern slavery, and self-neglect. Recognition relies on inconsistent histories, implausible/changing accounts, delayed presentation, and characteristic injury patterns.

Children

Features suggesting child physical abuse: a history INCONSISTENT with the injury or developmental stage, CHANGING history, DELAYED presentation; bruising in a NON-MOBILE baby, torn frenulum, bites; fractures of differing ages, posterior rib and metaphyseal ('corner') fractures, spiral fractures in non-walkers; cigarette/immersion burns; RETINAL HAEMORRHAGES (abusive head trauma). Act: examine fully, document, consider skeletal survey/fundoscopy, refer to safeguarding.

Adults

The Care Act 2014 duty to safeguard an adult who has care/support needs, is experiencing (or at risk of) abuse/neglect, and cannot protect themselves because of those needs. Principles: empowerment, prevention, proportionality, protection, partnership, accountability. Raise a safeguarding concern to the local authority; involve the person (Making Safeguarding Personal) and consider capacity/DoLS.

Adults

Any incident or pattern of controlling, coercive, threatening, degrading or violent behaviour between people aged 16+ who are personal/intimate partners or family members — includes physical, sexual, psychological, economic and coercive control. Enquire sensitively (alone), assess risk (e.g. DASH), provide information and referral to specialist services (IDVA/MARAC for high risk). Affects safeguarding of any children in the household.

Adults

Female genital mutilation is illegal in the UK. There is a MANDATORY duty for regulated professionals to report to the POLICE any case where a girl UNDER 18 discloses FGM has been carried out, or where it is observed on examination. Adult cases are managed with safeguarding/support and risk assessment for others in the family (younger girls). Distinct from the discretionary public-interest route.

Process

If abuse/neglect is suspected: ensure immediate SAFETY (and treat injuries), DOCUMENT factually and contemporaneously (including the person's own words), do not interrogate or promise secrecy, share information on a need-to-know basis (safeguarding can justify breaching confidentiality), and refer promptly to the appropriate route — children's/adults' social care, the named/designated safeguarding lead, and police if a crime/immediate danger.

Mature

Channelling an unacceptable impulse into a socially acceptable, often constructive, outlet. The drive is still expressed — just acceptably.

Mature

Managing distress by meeting the needs of others and gaining vicarious gratification.

Mature

Consciously and deliberately postponing attention to a distressing impulse or feeling.

Mature

Openly expressing feelings without personal discomfort by focusing on the amusing or ironic aspects.

Mature

Reducing future distress by realistic planning and rehearsal of an anticipated discomfort.

Neurotic

Unconscious exclusion of distressing thoughts, memories or impulses from conscious awareness.

Neurotic

Transforming an unacceptable impulse into its conscious opposite.

Neurotic

Transferring feelings from their true, threatening target onto a safer substitute target.

Neurotic

Justifying unacceptable behaviour or feelings with plausible but false reasoning.

Neurotic

Avoiding the emotional impact of a situation by focusing on abstract reasoning, facts or technical detail.

Neurotic

Separating an idea or memory from the emotion originally attached to it, so it is recalled without feeling.

Neurotic

Attempting to symbolically reverse or negate an unacceptable thought or act with an opposing action.

Neurotic

Modelling oneself on another person, often one perceived as powerful (including an aggressor).

Immature

Attributing one’s own unacceptable feelings or impulses to another person.

Immature

Expressing unconscious wishes or conflicts through action to avoid consciously feeling them.

Immature

Expressing aggression toward others indirectly, through non-compliance, procrastination or inefficiency.

Immature

Inability to integrate positive and negative qualities; people are seen as all-good or all-bad, often alternating.

Immature

Attributing exaggeratedly positive qualities to another person (or oneself), seeing them as all-good. With its counterpart devaluation, it forms the two poles of splitting.

Narcissistic / psychotic

Refusing to accept an external reality because it is too threatening, behaving as though it is not true.

Immature

Reverting to an earlier developmental stage of functioning under stress.

Immature

Unconscious conversion of psychological distress into physical symptoms.

Immature

Taking the attributes, values or qualities of another person into oneself, adopting them as one’s own.

CBT distortion

Seeing situations in only two absolute categories, with no middle ground (also "black-and-white" or dichotomous thinking).

CBT distortion

Seeing a single negative event as a never-ending pattern of defeat, often signalled by "always" or "never".

CBT distortion

Dwelling on a single negative detail so that the whole picture is darkened, filtering out the positives.

CBT distortion

Rejecting positive experiences by insisting they "don’t count", maintaining a negative belief against the evidence.

CBT distortion

Arbitrarily concluding that someone is reacting negatively to you, without checking (a form of jumping to conclusions).

CBT distortion

Predicting that things will turn out badly and treating the prediction as established fact (a form of jumping to conclusions).

CBT distortion

Magnifying the importance or likely consequences of a problem to the worst possible outcome (magnification).

CBT distortion

Taking one’s emotions as evidence for the truth ("I feel it, therefore it is so").

CBT distortion

Rigid rules about how oneself or others ought to behave; violation produces guilt (about self) or anger/frustration (about others).

CBT distortion

Attaching a fixed, global negative label to oneself or others instead of describing the specific behaviour.

CBT distortion

Seeing oneself as the cause of an external event for which one was not primarily responsible.

Clinical reasoning

Locking onto an initial diagnostic impression and failing to adjust it as new, discordant information arrives.

Clinical reasoning

Accepting a diagnosis before it has been fully verified, stopping the diagnostic process too soon.

Clinical reasoning

Judging a diagnosis more likely because it comes readily to mind — typically recent, dramatic or frequently seen cases.

Clinical reasoning

Seeking and interpreting evidence that supports a favoured diagnosis while discounting evidence against it.

Clinical reasoning

Calling off the search once the first (plausible) finding is made, missing a second, coexisting problem.

Clinical reasoning

Being swayed by how information is presented rather than its content — e.g. the slant of a referral or handover.

Clinical reasoning

A diagnostic label, once attached, becomes progressively harder to remove as it is passed from person to person, accumulating certainty.

Clinical reasoning

Judging probability by how closely a case matches a typical prototype, neglecting atypical presentations and base rates.

Clinical reasoning

Ignoring the underlying prevalence of a condition when estimating its probability in a given patient.

Social cognition

Over-attributing another person’s behaviour to their character/disposition, while under-weighting their situation or context.

Clinical reasoning

Persisting with a diagnosis or management plan because of the time, effort or resources already invested in it.

Clinical reasoning

Acting on incomplete information and favouring opinion over evidence, with too much faith in one’s own judgement.

Anxiety / phobia

Marked, persistent, out-of-proportion fear of a specific object or situation (e.g. animals, heights, flying, blood-injection-injury), with avoidance or extreme distress.

Anxiety / phobia

A specific phobia subtype unique in its physiology: a biphasic vasovagal response (transient tachycardia then bradycardia/hypotension) causing fainting — unlike other phobias where arousal is sustained.

Anxiety / phobia

Marked fear of social or performance situations because of possible scrutiny and negative evaluation by others, leading to avoidance.

Anxiety / phobia

Anxiety about situations where escape might be difficult or help unavailable — crowds, public transport, open spaces, queues, or being away from home alone — leading to avoidance.

Anxiety / phobia

Recurrent, unexpected panic attacks (abrupt surges of fear with somatic symptoms peaking within minutes) plus persistent worry about further attacks or their consequences.

Behavioural model

Engel’s model: health and illness arise from interacting biological, psychological and social factors; the basis of holistic, person-centred care.

Behavioural model

Predicts health behaviour from perceived susceptibility, perceived severity, perceived benefits and perceived barriers (modified by cues to action and self-efficacy).

Behavioural model

Behaviour follows from intention, which is shaped by attitudes toward the behaviour, subjective norms (social pressure), and perceived behavioural control.

Behavioural model

The Transtheoretical (Prochaska & DiClemente) model: precontemplation → contemplation → preparation → action → maintenance, with possible relapse; matches the intervention to the stage.

Behavioural model

Parsons’ concept: being ill is a social role with two rights (exemption from normal duties; not held responsible for being ill) and two duties (must want to get well; must seek competent help and cooperate).

Behavioural model

Mechanic’s concept: the ways people perceive, evaluate and respond to symptoms — when they decide they are ill and what they do about it. "Abnormal illness behaviour" when disproportionate.

Behavioural model

Rotter’s concept: the degree to which people believe outcomes result from their own actions (internal) versus luck, fate or powerful others (external).

Behavioural model

Seligman’s concept: after repeated uncontrollable aversive events, an organism stops trying to escape even when escape becomes possible; a model of depression.

Behavioural model

Five non-sequential responses to loss/dying: denial, anger, bargaining, depression, acceptance. Not everyone experiences all, or in order.

Behavioural model

Bandura’s concept: a person’s belief in their own capacity to carry out the actions needed to achieve a goal — a strong predictor of behaviour change.

Persecutory cognition

A tendency to interpret others’ ambiguous or neutral behaviour as deliberately hostile or threatening — the cognitive style underlying suspiciousness and persecutory beliefs.

Persecutory cognition

Interpreting neutral, unrelated external events as having special personal significance or as being directed specifically at oneself. (The fixed, unshakeable form is a delusion of reference.)

Persecutory cognition

A data-gathering bias of reaching a firm conclusion on minimal evidence; strongly associated with the FORMATION of delusions ("beads task").

Persecutory cognition

"Belief inflexibility": failing to revise a strongly held belief when shown evidence that contradicts it — a reasoning bias that sustains delusions.

Persecutory cognition

The attributional style proposed in persecutory delusions: negative events are attributed to external, PERSONAL causes (the deliberate acts of other people) rather than to oneself or to circumstances.

Persecutory cognition

Automatic, selective allocation of attention toward threatening stimuli — prominent in anxiety and persecutory states, where it maintains a sense of danger.

Social cognition

Attributing one’s successes to internal factors (ability, effort) but one’s failures to external factors (bad luck, others), to protect self-esteem.

Social cognition

Attributing one’s OWN behaviour to the situation, but others’ identical behaviour to their disposition/character.

Social cognition

The belief that the world is fundamentally fair, so people get what they deserve — which leads to blaming victims when bad things happen to them.

Social cognition

Unrealistic optimism: systematically underestimating one’s OWN risk of a negative outcome relative to others — a key barrier to health-behaviour change.

Social cognition

Allowing one positive (or negative) trait to colour the whole impression of a person, generalising from a single attribute.

Clinical reasoning

Once an outcome is known, judging the earlier decision by that outcome ("I knew it all along") — closely linked to outcome bias, distorting appraisal and learning.

Clinical reasoning

Believing that a run of one outcome makes the opposite more "due", treating independent events as if they were linked.

Clinical reasoning

Judging harm caused by ACTING as worse than equal or greater harm caused by inaction — a bias toward doing nothing.

Immunoglobulins

First antibody produced in the PRIMARY immune response. Circulates as a **pentamer** (10 antigen-binding sites) → strong agglutination and a potent classical-complement activator. Too large to cross the placenta. The ABO isohaemagglutinins (anti-A/anti-B) are IgM.

Immunoglobulins

Most abundant serum immunoglobulin (~75%); four subclasses (IgG1–4). The **only** Ig that crosses the placenta → passive neonatal immunity to ~6 months. Activates classical complement, opsonises (Fc receptors on phagocytes), neutralises toxins. Anti-Rh(D) antibodies are IgG (→ haemolytic disease of the newborn).

Immunoglobulins

Dominant antibody at **mucosal surfaces** — a secretory dimer with a J chain and secretory component (saliva, tears, gut, respiratory tract, breast milk → neonatal mucosal protection). Selective IgA deficiency is the commonest primary immunodeficiency (often asymptomatic; risk of anaphylaxis to IgA-containing blood products).

Immunoglobulins

Lowest serum concentration. Binds high-affinity FcεRI on **mast cells & basophils**; antigen cross-linking triggers degranulation (histamine, tryptase, leukotrienes) → **type I hypersensitivity**. Raised in atopy (asthma, eczema, allergic rhinitis) and parasitic (helminth) infection.

Hypersensitivity

**Immediate, IgE-mediated.** Allergen cross-links IgE on mast cells → degranulation within minutes → histamine/leukotrienes → vasodilation, bronchospasm, oedema. Spectrum: anaphylaxis, allergic rhinitis/asthma, urticaria/angio-oedema, atopic eczema.

Hypersensitivity

**Antibody (IgG/IgM) against a fixed cell-surface or matrix antigen** → complement activation + opsonisation/ADCC, or receptor stimulation/blockade. Examples: autoimmune haemolytic anaemia, ITP, Goodpasture (anti-GBM), pemphigus vulgaris (anti-desmoglein), Graves (anti-TSHR, stimulatory), myasthenia gravis (anti-AChR, blocking), haemolytic disease of the newborn, ABO transfusion reactions.

Hypersensitivity

**Soluble antigen–antibody (immune) complexes** deposit in tissues (skin, joints, kidney, vessels) → complement activation → neutrophil-driven inflammation. Examples: SLE, post-streptococcal glomerulonephritis, serum sickness, extrinsic allergic alveolitis (farmer's lung), polyarteritis nodosa.

Hypersensitivity

**Delayed, T-cell mediated (48–72 h)** — sensitised CD4 T-cells release cytokines → macrophage activation; no antibody. Examples: tuberculin (Mantoux) reaction, contact dermatitis (nickel), granuloma formation (TB, sarcoid), chronic transplant rejection, T1DM β-cell destruction.

Complement

Triggered by **antibody (IgG/IgM)–antigen complexes** binding C1 → C4+C2 → C3 convertase (C4b2a) → C3b (opsonin) + C3a → C5 convertase → C5b initiates MAC; C3a/C5a are anaphylatoxins, C5a chemotactic. C4 and C3 are consumed in active autoimmune disease.

Complement

**Antibody-independent** — spontaneous C3 hydrolysis ("tick-over") amplified on pathogen surfaces (Factor B, Factor D, properdin) → C3 convertase (C3bBb) → amplification loop. Key innate defence before specific antibody exists. Dysregulation (Factor H/I deficiency) → atypical HUS and age-related macular degeneration.

Complement

The membrane attack complex: C5b recruits C6–C8 then multiple C9 polymerise → transmembrane pore → osmotic lysis. Critical against **Neisseria** (thin cell wall).

Vaccines

Weakened whole organism → strong, durable immunity, often from one/two doses. UK examples: **MMR, varicella-zoster, BCG, rotavirus, intranasal flu (children), yellow fever, oral typhoid**.

Vaccines

Non-replicating → safe in immunosuppression/pregnancy; usually need boosters. **Inactivated**: polio (IPV), hepatitis A, rabies. **Subunit/conjugate/toxoid**: HPV, Hib, pneumococcal, meningococcal, hepatitis B, tetanus/diphtheria. **mRNA**: COVID-19.

Immunodeficiency

Severe combined immunodeficiency — profound **T-cell defect** (± B/NK). X-linked (γc chain) or autosomal recessive (ADA deficiency). Failure to thrive, persistent/severe infections, chronic candidiasis and diarrhoea from the first months. Treat: protective isolation, IVIG, prophylaxis, haematopoietic stem-cell transplant (curative). UK newborn screening (TREC) being rolled out.

Immunodeficiency

X-linked (BTK mutation) → arrest of B-cell maturation → **no mature B cells, all immunoglobulin classes very low**. Boys present after ~6 months (maternal IgG wanes) with recurrent encapsulated-bacteria infection (pneumococcus, Hib). Treat with immunoglobulin replacement.

Transplant & HLA

**MHC class I (HLA-A,B,C)** on all nucleated cells → present to CD8 T-cells. **MHC class II (HLA-DR,DQ,DP)** on antigen-presenting cells → present to CD4. Solid-organ matching prioritises DR>B>A. Disease links: **HLA-B27** ankylosing spondylitis/reactive arthritis; **DR3/DR4** T1DM; **DQ2/DQ8** coeliac; **B*57:01** abacavir hypersensitivity; **B*15:02** carbamazepine SJS.

Transplant & HLA

**Hyperacute** (minutes–hours): pre-formed recipient antibody (ABO/HLA) → thrombosis; prevented by cross-matching. **Acute** (days–months): T-cell mediated → treat with steroids/anti-thymocyte globulin. **Chronic** (months–years): vascular intimal fibrosis, irreversible. **GvHD**: donor T-cells attack host (rash, diarrhoea, deranged LFTs) — after marrow transplant or non-irradiated cellular products.

Inheritance

One mutant allele suffices; ~50% of offspring affected; **vertical** transmission through generations, both sexes. Variable penetrance/expressivity common. Examples: Huntington, NF1/2, Marfan, ADPKD, familial hypercholesterolaemia, HHT, hereditary spherocytosis, BRCA, FAP, MEN, tuberous sclerosis, achondroplasia.

Inheritance

Two mutant alleles needed; carriers asymptomatic; 25% of offspring of two carriers affected; often **skips generations**; consanguinity raises risk. Examples: cystic fibrosis, sickle cell, β-thalassaemia, haemochromatosis, Wilson, α1-antitrypsin deficiency, PKU, Friedreich ataxia, congenital adrenal hyperplasia.

Inheritance

Mutant gene on the X; **affected males, carrier females**; no male-to-male transmission; daughters of an affected man are obligate carriers. Examples: Duchenne/Becker muscular dystrophy, haemophilia A/B, G6PD deficiency, red–green colour blindness, Lesch-Nyhan, Bruton's, Fabry.

Inheritance

Genes on mitochondrial DNA — **maternal transmission only** (sperm mitochondria don't contribute); all children of an affected mother may be affected; heteroplasmy → variable severity (threshold effect). Examples: LHON, MELAS, MERRF, mitochondrial diabetes & deafness, Leigh syndrome.

Inheritance

Unstable repeats expand each generation → **earlier onset and greater severity** in successive generations (anticipation). **Huntington** (CAG, chr 4; worse with paternal transmission), **fragile X** (CGG, FMR1), **myotonic dystrophy** (CTG, DMPK), **Friedreich ataxia** (GAA, AR).

Chromosomal

Three copies of chromosome 21 (95% meiotic non-disjunction, risk ↑ with maternal age; ~4% Robertsonian translocation; ~1% mosaic). Features: hypotonia, upslanting palpebral fissures, epicanthic folds, single palmar crease, flat occiput; **AVSD/VSD**, duodenal atresia, hypothyroidism, leukaemia (ALL/AML), early Alzheimer's.

Chromosomal

**Edwards (trisomy 18)**: rocker-bottom feet, micrognathia, overlapping clenched fingers, cardiac/renal defects. **Patau (trisomy 13)**: holoprosencephaly, cleft lip/palate, polydactyly, microphthalmia. Both: severe malformation, very poor prognosis (most die within the first year).

Chromosomal

**Turner (45,X)**: short stature, webbed neck, widely spaced nipples, primary amenorrhoea/ovarian dysgenesis, **bicuspid aortic valve & coarctation**, normal intelligence. **Klinefelter (47,XXY)**: tall, small firm testes, infertility, gynaecomastia, reduced secondary sexual hair, mild learning difficulty; low testosterone, high LH/FSH.

Imprinting

Same locus (15q11–13), opposite parent-of-origin. **Prader-Willi** (loss of paternal contribution): neonatal hypotonia/poor feeding → later hyperphagia, obesity, hypogonadism, short stature, mild learning difficulty. **Angelman** (loss of maternal contribution): severe learning difficulty, ataxic 'puppet' gait, seizures, inappropriate laughter, minimal speech.

Pharmacogenomics

Inherited variation altering drug response. **TPMT** deficiency → azathioprine/6-MP myelosuppression (test before starting). **DPYD** deficiency → 5-FU/capecitabine toxicity. **CYP2C19** poor metaboliser → clopidogrel under-activation. **HLA-B*57:01** → abacavir hypersensitivity. **HLA-B*15:02** → carbamazepine SJS. **G6PD** deficiency → haemolysis with oxidant drugs.

Screening & counselling

**Combined test (11–14 wk)**: nuchal translucency + PAPP-A + free β-hCG + maternal age. **Quadruple test (14–20 wk)** if combined missed: AFP, unconjugated oestriol, β-hCG, inhibin A. Higher-chance result → offer **NIPT** (cell-free fetal DNA, very high sensitivity) or diagnostic **CVS (11–14 wk)/amniocentesis (≥15 wk)**.

Test characteristics

**TP / (TP + FN)** — probability a test is positive in those WITH the disease. A property of the test (not prevalence-dependent). A highly sensitive test, when **negative**, rules disease OUT (**SnNOUT**). Good for screening (don't miss cases).

Test characteristics

**TN / (TN + FP)** — probability a test is negative in those WITHOUT the disease. A highly specific test, when **positive**, rules disease IN (**SpPIN**). Used to confirm after a sensitive screen.

Test characteristics

**PPV = TP/(TP+FP)** (of those testing positive, fraction truly diseased); **NPV = TN/(TN+FN)**. Unlike sensitivity/specificity, **both depend on prevalence** (pre-test probability): even a very specific test has poor PPV in a low-prevalence population (Bayes).

Effect measures

**RR = risk(exposed)/risk(unexposed)** — from cohort/RCT. **OR = odds(exposure|case)/odds(exposure|control)** — from case-control (risk can't be computed directly). OR ≈ RR when the outcome is rare. Both: 1 = no effect; CI crossing 1 = not significant. **ARR = risk difference; NNT = 1/ARR; RRR = 1−RR.**

Effect measures

**NNT = 1/ARR** — patients treated to prevent one additional bad outcome (lower = more effective). **NNH = 1/ARI** — patients exposed to cause one additional harm. Always quote the time-frame and comparator.

Study design

Participants **randomly allocated** to intervention vs control; blinding (single/double) reduces bias; **intention-to-treat** preserves randomisation. Highest-level individual study for causation. CONSORT reporting.

Study design

Groups defined by **exposure** and followed forward to measure outcome incidence → yields incidence and **relative risk**. Good for common outcomes and several outcomes of one exposure; prospective ones are long/expensive; loss to follow-up = attrition bias.

Study design

Starts from **outcome**: cases (with disease) vs controls (without) compared for past exposure → **odds ratio**. Efficient for rare diseases and multiple exposures; cheap/fast; prone to **recall and selection bias**.

Bias & error

A third variable associated with BOTH exposure and outcome and NOT on the causal pathway, distorting the apparent association. Address by **design** (randomisation, restriction, matching) or **analysis** (stratification, multivariable regression).

Bias & error

**Lead-time bias**: screening advances the diagnosis date so survival-from-diagnosis looks longer though death is unchanged. **Length-time bias**: screening preferentially catches slow-growing (better-prognosis) disease, overstating benefit. **Overdiagnosis**: detecting disease that would never have caused harm.

Screening & public health

Conditions for a worthwhile screening programme: important condition; understood natural history with a recognisable latent/early stage; a suitable, acceptable test; an accepted, effective treatment with facilities; agreed policy on who to treat; cost-effective; and a continuous (not one-off) process.

Inference

**p** = probability of a result at least this extreme if the null hypothesis were true (p<0.05 is the usual threshold; it is NOT the probability the hypothesis is true). **95% CI** = range that would contain the true value in 95% of repeated studies; a CI crossing the null (1 for RR/OR, 0 for differences) = non-significant. Wider CI = less precision (narrows with larger n).

Screening & public health

Registered medical practitioners must notify the local **UKHSA Health Protection Team** on clinical suspicion (don't wait for lab confirmation). Includes measles, mumps, rubella, meningococcal disease, TB, whooping cough, food poisoning, acute infectious hepatitis, scarlet fever, COVID-19, and others. **HIV and gonorrhoea/chlamydia are NOT notifiable** (separate confidential STI surveillance).

Acid–base

**↓pH with ↑PaCO₂** from alveolar hypoventilation — CO₂ retention. Causes: COPD/asthma exacerbation, opioid or sedative overdose, neuromuscular weakness (GBS, myasthenia), chest-wall/OSA. Acute: little renal compensation (HCO₃ near normal); chronic: kidneys retain HCO₃ over days.

Acid–base

**↑pH with ↓PaCO₂** from hyperventilation — blowing off CO₂. Causes: anxiety/pain, early PE, early sepsis, salicylate poisoning (early), high altitude, pregnancy (progesterone drive).

Acid–base

**↓pH, ↓HCO₃, raised anion gap** [Na − (Cl + HCO₃); normal 8–12] — unmeasured acid anions. **MUDPILES**: Methanol, Uraemia, DKA, Propylene glycol, Iron/Isoniazid, Lactic acidosis (sepsis/shock), Ethylene glycol, Salicylates.

Acid–base

**↓pH, ↓HCO₃, normal anion gap** (hyperchloraemic) — bicarbonate is lost and replaced by chloride. Causes (**HARDUPS**): Hyperalimentation, Acetazolamide/Addison's, Renal tubular acidosis, Diarrhoea, Ureteroenterostomy, Pancreatic fistula, Saline excess. Diarrhoea and RTA are the big ones.

Acid–base

**↑pH with ↑HCO₃**. Causes: vomiting/NG loss (H⁺ and Cl⁻), loop/thiazide diuretics, mineralocorticoid excess (Conn's, Cushing's), milk-alkali. **Urinary chloride** separates saline-responsive (low, vomiting/diuretics) from saline-resistant (high, mineralocorticoid).

Electrolyte interpretation

Assess **volume status first**. **Hypovolaemic**: D&V, diuretics, Addison's (urine Na >20 = renal loss). **Euvolaemic**: SIADH (urine osm >100, urine Na >30, low serum osm), hypothyroidism, primary polydipsia. **Hypervolaemic**: heart failure, cirrhosis, nephrotic syndrome.

Electrolyte interpretation

ECG progression: **tall tented T waves → flattened/absent P → broad QRS → sinusoidal → VF/asystole**. Emergency Mx (UK Renal Association): **IV calcium gluconate** (cardiac-membrane stabilisation, doesn't lower K), then **insulin (10 units) + 25 g glucose** ± **nebulised salbutamol** to shift K intracellularly; treat the cause and remove K (e.g. potassium binders, dialysis).

LFT interpretation

**Hepatocellular**: ALT/AST ≫ ALP — viral/autoimmune/ischaemic/drug (paracetamol) hepatitis; **AST:ALT >2 + ↑GGT** suggests alcohol; ALT>AST in most others. **Cholestatic**: ALP & GGT ≫ ALT — biliary obstruction (stones, malignancy), drugs (co-amoxiclav, flucloxacillin), PBC (AMA), PSC (UC, MRCP beading). Isolated ALP rise → check GGT to confirm hepatic (vs bone) origin.

Serology interpretation

**HBsAg** = current infection (acute or chronic). **Anti-HBs** = immunity (vaccine or cleared infection). **Anti-HBc IgM** = recent/acute (window). **Anti-HBc IgG (total)** = past exposure (not vaccine). **HBeAg** = high infectivity/replication. Vaccinated only → anti-HBs positive, everything else negative.

Haematinic interpretation

**Iron deficiency**: ↓ferritin, ↑TIBC/transferrin, ↓transferrin saturation. **Anaemia of chronic disease**: ↓/normal iron, ↓TIBC, normal/↑ferritin (acute-phase). **Haemochromatosis/overload**: ↑↑ferritin, ↑↑transferrin saturation (>45%). Ferritin is an acute-phase reactant — **<30 µg/L confirms iron deficiency in any adult**, but a normal ferritin doesn't exclude it in inflammation.

Haematinic interpretation

Both → **macrocytic (MCV >100) megaloblastic** anaemia with hypersegmented neutrophils. **B12 deficiency** additionally causes neurology — subacute combined degeneration (dorsal columns + corticospinal). Causes: pernicious anaemia (anti-IF/parietal), terminal-ileal disease, vegan diet, metformin. **Replace B12 BEFORE folate** in combined deficiency (folate alone can precipitate SACD).

Bone & calcium interpretation

**Primary hyperparathyroidism**: ↑Ca, ↑PTH, ↓PO₄ (adenoma). **Vitamin D deficiency/osteomalacia**: ↓Ca, ↓PO₄, ↑PTH (secondary), ↑ALP. **CKD-MBD (secondary HPT)**: ↓Ca, ↑PO₄, ↑PTH, ↑ALP. **Paget's**: isolated ↑ALP with normal Ca/PO₄. Always interpret calcium corrected for albumin. **Hypercalcaemia with a SUPPRESSED PTH = PTH-INDEPENDENT** — malignancy (PTHrP, bone mets, myeloma), granulomatous disease (sarcoid/TB → ↑1,25-vitamin D), vitamin D excess. Key rule: hypercalcaemia should suppress PTH, so a PTH that is high or even mid-normal is INAPPROPRIATE and still means primary hyperparathyroidism.

Glucose emergencies

**DKA** (T1DM): glucose >11 (or known DM) + ketones >3 + pH 30, osmolality >320, no significant ketones/acidosis; slower onset, profound dehydration; rehydrate first, cautious insulin only if glucose not falling.

Vascular interpretation

Ratio of ankle to brachial systolic BP. **0.9–1.3 = normal**; **0.5–0.9 = peripheral arterial disease** (intermittent claudication); **<0.5 = critical limb ischaemia** (rest pain, tissue loss); **>1.3 = incompressible/calcified vessels** (diabetes, CKD — falsely high, unreliable). Venous-ulcer compression bandaging needs an ABPI ≥0.8 first.

Fluid interpretation

**Pleural: protein >30 g/L = exudate** (if borderline 25–35 use **Light's criteria**: fluid:serum protein >0.5, fluid:serum LDH >0.6, or fluid LDH >⅔ upper serum limit). **Exudate** = leaky capillaries (infection/parapneumonic, malignancy, TB, PE, pancreatitis, RA/SLE). **Transudate (<30 g/L)** = pressure imbalance (heart failure, cirrhosis, hypoalbuminaemia/nephrotic, hypothyroidism). Low pleural glucose/pH → empyema/RA/TB/malignancy; high amylase → pancreatitis/oesophageal rupture. **Ascites uses SAAG** (serum − ascites albumin): **≥11 g/L = portal hypertension** (cirrhosis, HF, Budd–Chiari); **<11 = exudative** (malignancy, TB, pancreatitis).

Muscle & AKI interpretation

Creatine kinase (normal ~25–200 U/L) rises with muscle injury. **Rhabdomyolysis = CK >1000** (usually >5000, can reach tens of thousands) — crush/long-lie, seizures, statins, extreme exertion, ischaemia. Myoglobin release → **pigment (myoglobinuric) AKI** plus **hyperkalaemia, hyperphosphataemia, hypocalcaemia**; treat with aggressive IV fluids. A CK in the hundreds is NOT rhabdomyolysis.

Lipid interpretation

**Heterozygous familial hypercholesterolaemia (FH)** — autosomal-dominant LDL-receptor defect (~1 in 250): **isolated very high total/LDL cholesterol** (often >7.5), near-normal triglycerides, tendon xanthomata, premature CAD / family history of early MI. **Familial combined hyperlipidaemia**: ↑cholesterol AND ↑triglycerides. **Severe hypertriglyceridaemia / chylomicronaemia**: TG >10 → pancreatitis + eruptive xanthomata. Primary prevention: QRISK ≥10% → atorvastatin 20 mg; FH is treated regardless of QRISK.

Endocrine interpretation

Interpret TSH against T4. **Primary hypothyroidism**: ↑TSH, ↓T4 (Hashimoto, post-RAI/thyroidectomy). **Subclinical hypothyroidism**: ↑TSH, normal T4. **Primary hyperthyroidism**: ↓TSH, ↑T4/T3 (Graves = TSH-receptor Ab; toxic nodule; thyroiditis). **Secondary (pituitary)**: TSH inappropriate for the T4 — e.g. ↓T4 with a low/normal TSH = central hypothyroidism. **Sick euthyroid**: ↓T3 (± ↓T4/TSH) in any acute illness — don't check TFTs when acutely unwell.

Renal interpretation

**Pre-renal** (commonest): hypovolaemia/hypotension/sepsis — the intact kidney avidly reabsorbs → **urea rises out of proportion to creatinine, urine Na <20, FeNa <1%**, corrects with fluids. **Intrinsic/renal**: ATN (prolonged pre-renal, contrast, rhabdomyolysis), glomerulonephritis (RBC casts, proteinuria), interstitial nephritis (drugs, eosinophils) — **urine Na >40, FeNa >2%, muddy-brown casts**. **Post-renal**: obstruction (stones, prostate, pelvic malignancy) — **hydronephrosis on USS**, palpable bladder; relieve the obstruction.

Oxygenation interpretation

A **pulse oximeter reads oxyhaemoglobin** and is fooled by abnormal haemoglobins. **Carbon monoxide poisoning**: CO binds Hb 240× tighter than O₂ (carboxyhaemoglobin) → real tissue hypoxia but **SpO₂ and PaO₂ read falsely NORMAL** (dissolved O₂ is unaffected); diagnose on a **co-oximeter (carboxyhaemoglobin level)**, treat with high-flow 100% O₂ (hyperbaric if severe). **Methaemoglobinaemia** (dapsone, local anaesthetics, nitrates): Fe³⁺ can't carry O₂ → SpO₂ stuck around **85%** regardless of O₂; chocolate-brown blood; treat with **methylene blue**.

Renal interpretation

**Nephrotic**: **proteinuria >3.5 g/24h (ACR high, PCR >300), hypoalbuminaemia, oedema, hyperlipidaemia** — a leaky filtration barrier with BLAND urine (no casts). Causes: minimal change (children), membranous, FSGS, diabetic nephropathy, amyloid. Risk: VTE (antithrombin loss). **Nephritic**: **haematuria with RED-CELL CASTS, hypertension, oliguria, mild-moderate proteinuria, AKI** — inflammatory glomerulonephritis. Causes: post-streptococcal, IgA nephropathy, anti-GBM (Goodpasture), ANCA vasculitis, lupus.

Endocrine interpretation

Cortisol interpretation hinges on **suppressibility and ACTH**. **Cushing's screen**: overnight/low-dose dexamethasone should suppress cortisol to <50 nmol/L — **failure to suppress = Cushing's syndrome**. Then localise: **ACTH suppressed** = adrenal (tumour) or exogenous steroid; **ACTH high** = pituitary (Cushing's disease — suppresses on high-dose dex) or ectopic (no suppression). **Short Synacthen test**: cortisol fails to rise after ACTH = **adrenal insufficiency (Addison's)**. Random cortisol is unreliable (diurnal); interpret against the stimulus/suppression.

Pharmacokinetics

**Bioavailability (F)** = fraction of an administered dose reaching the systemic circulation unchanged. IV F = 1.0 by definition. Reduced by incomplete gut absorption, intestinal efflux and **first-pass metabolism** (gut wall + liver). High first-pass drugs (GTN, propranolol, morphine, lidocaine) need a much larger oral than parenteral dose, or a non-oral route.

Pharmacokinetics

**Vd = total drug in body / plasma concentration** — an apparent volume. **Low Vd** (warfarin, heparin) = drug stays in plasma → often dialysable. **High Vd** (digoxin, amiodarone, TCAs) = extensive tissue binding → long half-life, NOT effectively dialysable. Lipophilic drugs have high Vd and cross the blood–brain barrier/placenta.

Pharmacokinetics

**Steady state in ~5 half-lives**; same to wash out after stopping. **Loading dose = Vd × target concentration** (gets there immediately); **maintenance = clearance × target**. Long-t½ drugs (amiodarone ~58 days, fluoxetine/norfluoxetine) take weeks to reach steady state and to clear — explaining persistent interactions after stopping.

Pharmacokinetics

**First-order**: elimination rate proportional to concentration → constant half-life (most drugs). **Zero-order**: a fixed amount eliminated per unit time (enzymes saturated) → no constant half-life; small dose increases cause disproportionate level rises. Zero-order drugs: **phenytoin, ethanol, high-dose aspirin/salicylates**.

Drug metabolism

Increase CYP enzyme synthesis over days–weeks → **faster metabolism → LOWER levels** of substrates (warfarin, COC, DOACs, ciclosporin, antiretrovirals). Mnemonic **PC BRAS**: Phenytoin, Carbamazepine, Barbiturates, Rifampicin, Alcohol (chronic), Sulfonylureas/Smoking, St John's wort.

Drug metabolism

Block CYP enzymes within hours → **slower metabolism → HIGHER levels** of substrates (toxic INR on warfarin, statin myopathy). Mnemonic **SICKFACES.COM**: Sodium valproate, Isoniazid, Cimetidine, Ketoconazole/fluconazole, Fluoxetine, Acute alcohol, Chloramphenicol, Erythromycin/clarithromycin, Sulfonamides, Ciprofloxacin, Omeprazole, Metronidazole + grapefruit juice.

Pharmacodynamics

Four targets by speed: **1. Ligand-gated ion channels** (ms) — nicotinic ACh, GABA-A, NMDA. **2. G-protein-coupled receptors** (seconds) — β-adrenergic, muscarinic, opioid, dopamine, most drug targets. **3. Kinase-linked / enzyme-linked** (minutes) — insulin, growth factors. **4. Nuclear receptors** (hours) — glucocorticoids, thyroid hormone, sex steroids, vitamin D (gene transcription).

Adverse drug reactions

**A — Augmented**: dose-related, predictable extension of pharmacology (most common; e.g. insulin→hypoglycaemia, ACEi→AKI). **B — Bizarre**: idiosyncratic/immunological, not dose-related (anaphylaxis, malignant hyperthermia). **C — Chronic** (steroid osteoporosis). **D — Delayed** (teratogenesis, malignancy). **E — End-of-use** (withdrawal: β-blocker rebound, opioid/benzodiazepine, steroid). **F — Failure** of therapy.

Prescribing safety

Drugs with a **narrow therapeutic index** need plasma-level monitoring: **vancomycin, gentamicin/aminoglycosides, digoxin, lithium, phenytoin, theophylline, ciclosporin/tacrolimus, methotrexate**. Timing matters (e.g. lithium 12 h post-dose; gentamicin trough).

Prescribing safety

Avoid in pregnancy: **warfarin, ACEi/ARB, sodium valproate, isotretinoin/retinoids, methotrexate, lithium (Ebstein anomaly), tetracyclines, fluoroquinolones, aminoglycosides, trimethoprim (1st trimester, folate antagonist)**. Safer alternatives: LMWH (anticoagulation), labetalol/nifedipine/methyldopa (BP), levothyroxine, paracetamol, penicillins/cephalosporins.

Prescribing safety

**'Triple whammy' AKI**: ACEi/ARB + diuretic + NSAID — avoid, especially in the elderly/volume-depleted. **STOPP/START** criteria flag inappropriate/omitted drugs in older people. Watch QT-prolonging combinations, serotonergic combinations (serotonin syndrome), and anticholinergic burden in cognitive impairment.

Inflammation

Rapid, **neutrophil-driven** response. Five cardinal signs: rubor, calor, tumor, dolor, functio laesa. Vascular changes (vasodilation, ↑permeability → exudate) + cellular events (neutrophil margination, diapedesis, chemotaxis to C5a, IL-8, LTB4, fMLP). Mediators: histamine, bradykinin, prostaglandins, complement.

Inflammation

Persistent inflammation (weeks–years) with **lymphocytes, plasma cells and macrophages**; tissue destruction and repair occur together → **fibrosis**. Causes: persistent infection (TB), autoimmunity (RA), prolonged irritant/foreign material. May follow unresolved acute inflammation or arise de novo.

Inflammation

Aggregates of activated **epithelioid macrophages** ± multinucleate giant cells. **Caseating (necrotic centre)**: TB (ZN-positive AFB), some fungi. **Non-caseating**: sarcoidosis, Crohn's, foreign-body reaction. **Necrotising with vasculitis**: GPA (c-ANCA).

Definitions

**SIRS** (≥2 of): T >38 or 90, RR >20, WCC >12 or 2 despite fluids. **qSOFA** ≥2 of: RR ≥22, altered mentation, SBP ≤100.

Cell death

Pathological cell death with membrane failure and inflammation. **Coagulative** (most ischaemia — heart, kidney): architecture preserved. **Liquefactive** (brain infarct, abscess): tissue digested to pus. **Caseous** (TB): cheese-like. **Fat** (pancreatitis, breast trauma): saponification + calcium. **Fibrinoid** (vasculitis, malignant hypertension): vessel-wall protein deposition. **Gangrenous**: dry (mummified) vs wet (infected).

Cell death

**Programmed cell death — no inflammation**. **Intrinsic (mitochondrial)**: stress/DNA damage → cytochrome c → caspase-9 → caspase-3; regulated by Bcl-2 (anti) / Bax (pro). **Extrinsic (death-receptor)**: Fas/TNF → caspase-8 → caspase-3. Apoptotic bodies cleared silently by phagocytes.

Neoplasia

**Benign**: well-circumscribed/encapsulated, slow, low mitotic rate, well-differentiated, no invasion or metastasis. **Malignant**: infiltrative, ill-defined, rapid, high (often atypical) mitoses, poorly differentiated/anaplastic, local invasion, metastasis, necrosis and neo-angiogenesis.

Neoplasia

**Metaplasia**: reversible change of one differentiated cell type to another (Barrett's: squamous→columnar; smoker's bronchial columnar→squamous). **Dysplasia**: disordered growth with cytological/architectural atypia — pre-malignant, reversible if the stimulus is removed. **Anaplasia**: complete loss of differentiation — a hallmark of malignancy.

Carcinogenesis

**Chemical/physical**: aromatic amines→bladder; aflatoxin→HCC; asbestos→mesothelioma/lung; smoking→lung/bladder/head & neck; alcohol→oral/oesophageal/breast/HCC; UV→skin; ionising radiation→thyroid/leukaemia. **Viral/microbial**: HPV, EBV, HBV/HCV, HHV-8, HTLV-1, H. pylori (gastric adenocarcinoma + MALT).

Diagnostics

Used mainly to MONITOR (not screen): **PSA** prostate; **AFP** HCC & yolk-sac germ-cell (+ antenatal NTDs); **CA 125** ovarian; **CA 19-9** pancreatic; **CEA** colorectal; **β-hCG** trophoblastic/germ-cell; **calcitonin** medullary thyroid. Most are non-specific (rise in benign disease) so they are not screening tests.

Diagnostics

Beyond H&E: **Ziehl–Neelsen** acid-fast bacilli (TB); **Congo red** amyloid (apple-green birefringence under polarised light); **PAS** glycogen/fungi/basement membranes; **Perls' Prussian blue** iron; **Warthin–Starry silver** spirochaetes/H. pylori; **Grocott/GMS** fungi.

Innate killing

When a phagocyte engulfs a microbe, membrane **NADPH oxidase** reduces O₂ to **superoxide (O₂•⁻)** — a sharp rise in oxygen consumption (the 'burst'). Superoxide is dismutated to H₂O₂; **myeloperoxidase** then converts it to hypochlorous acid (HOCl, 'bleach') → potent oxygen-DEPENDENT microbicidal killing inside the phagolysosome.

Upper-limb nerves

Lateral cord of the brachial plexus (**C5–C7**). Pierces coracobrachialis; supplies the **anterior (flexor) compartment of the arm** — biceps brachii, brachialis, coracobrachialis → **elbow flexion** + forearm supination. Terminates as the **lateral cutaneous nerve of the forearm** → sensation over the LATERAL forearm.

Upper-limb nerves

Posterior cord (**C5–T1**). Supplies all **extensors** of arm/forearm (triceps, wrist & finger extensors, supinator) → loss gives **WRIST DROP**; sensation over the dorsal first web space. Vulnerable in the **radial groove of the humerus** (mid-shaft fracture) and to compression — **'Saturday-night palsy'** (arm draped over a chair while intoxicated).

Upper-limb nerves

Medial + lateral cords (**C6–T1**). Supplies most forearm flexors + the thenar **LOAF** muscles (Lateral two lumbricals, Opponens pollicis, Abductor pollicis brevis, Flexor pollicis brevis); sensation over the **lateral 3½ digits** (palmar). Compressed at the wrist = **carpal tunnel syndrome**; a high lesion gives the 'hand of benediction' on attempted fist.

Upper-limb nerves

Medial cord (**C8–T1**). Supplies **most intrinsic hand muscles** (interossei, medial two lumbricals, hypothenar, adductor pollicis) + FCU and the medial half of FDP; sensation over the **medial 1½ digits**. Vulnerable at the **medial epicondyle/cubital tunnel** and Guyon's canal → claw hand, weak finger abduction, positive **Froment's sign**.

Brachial plexus

**Upper** brachial-plexus injury (**C5–C6**) — excessive increase in the head–shoulder angle (shoulder dystocia at birth; a fall onto the shoulder). Paralyses abductors/external rotators + elbow flexors → arm **adducted, internally rotated, elbow extended, forearm pronated** = the **'waiter's tip'** posture.

Brachial plexus

**Lower** brachial-plexus injury (**C8–T1**) — excessive ABDUCTION traction (grabbing a branch in a fall; arm pulled overhead at delivery). Paralyses the intrinsic hand muscles → **claw hand**; T1 sympathetic-fibre loss can give an ipsilateral **Horner's syndrome** (ptosis, miosis, anhidrosis).

Abdominal wall

The **deep (internal) inguinal ring lies LATERAL to the inferior epigastric vessels**. An **INDIRECT** hernia enters through it, so the inferior epigastric vessels lie immediately **MEDIAL to the neck of an indirect sac**. A **DIRECT** hernia pushes through **Hesselbach's triangle** — MEDIAL to the vessels (boundaries: inferior epigastric vessels laterally, lateral border of rectus medially, inguinal ligament inferiorly). Canal contents: spermatic cord (M) / round ligament (F) + ilioinguinal nerve.

Patient safety

Harm caused by healthcare itself rather than by the underlying disease — adverse drug effects, healthcare-associated infection, procedural complications, pressure damage from immobility, delirium precipitated by admission, and the cumulative harm of over-investigation. It is among the commonest causes of avoidable inpatient harm, and it is the category doctors are least practised at looking for, because it requires suspecting our own actions.

Uncertainty & investigation

An unexpected abnormality found on an investigation performed for an unrelated reason — the "incidentaloma". As imaging volume and resolution rise, these are increasingly common, and the harm they cause is real: anxiety, further investigation, invasive biopsy and occasionally treatment of something that would never have caused symptoms (overdiagnosis).